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House 44 Bridges the Physical World with Virtual Realms with The Ark
The pioneering members club brings together a community of like-minded individuals and entrepreneurs through a new, shared reality HONG KONG SAR - Media OutReach - 13 July 2022 -With geek-cool tech terms such as 'the metaverse', 'web 3.0' and 'blockchain' dominating the discourse in today's tech-driven digital age, there is no question that the way in which we work, play and interact is going to look vastly different in the not-too-distant future. For some, this unfamiliar new-age territory can be rather daunting. Breaking down these barriers for those who wish to immerse themselves in this ground-breaking 'new reality' is Hong Kong-based community organisation, House 44. First established in 2020 as a referral-only membership club — connecting like-minded individuals while leveraging individual members' assets and expertise — House 44 is now expanding to a parallel virtual space by establishing its own digital frontier at the cutting edge of technology with its newest initiative, The Ark.
"The way our society is built and the way it functions today tends to favour those who come from a privileged background, and it can be difficult for others to find adequate resources and guidance. House 44 was created to eradicate these inequalities by giving people the resources they need, and in turn a fair chance to achieve success," said Roland Li, Co-founder of House 44.
'The Ark': The House 44 Metaverse
With the onset of the pandemic and its lasting effects on society, there is no denying that nearly every aspect of our daily life is changing dramatically. Now, more than ever, people need a second space outside of the real world. Leveraging the power of the digital space, House 44 is determined to bring this alternate reality to its members, as the first members community with its own functional metaverse in Hong Kong. Named 'The Ark', a fitting title to denote a genesis or new beginnings, the House 44 metaverse allows members and friends to meet in the virtual world, connect, socialise and play games, and even attend masterclasses covering a wide range of subjects from crypto trading and NFT investments, to more leisurely pursuits such as wine appreciation and cooking classes.
In this virtual world, members can also learn more about House 44's history and roots, its various services and how they can be leveraged to grow real-world businesses. What's more, this embrace of the digital realm is the first step in House 44's ambitions to expand globally. With active members already in the UK and Singapore, House 44 and 'The Ark' aim to bring everyone together under one umbrella, bridging continents, connecting mind-sets and facilitating innovation and creation.
"Innovation is the catalyst for rapid expansion," said Roland. "Our metaverse is something that we envision as a space to facilitate growth, and as a company that is constantly on the lookout for the next frontier, we are beyond excited to dive into this realm and its infinite possibilities."
Where Digital Assets Flourish
In a world where the term 'metaverse' is still often met with raised eyebrows and question marks, it is common to hear: "Why is the metaverse important, and what does it actually mean?" As one of the companies in Asia leading the exploration of the metaverse, House 44 envisions a world where this still-niche concept has flourished into a common one, where people are able to effortlessly move between physical and virtual realms, while leveraging the advantages of both. From digital ownership to non-fungible tokens (NFTs), virtual experiences are the future, and the applications are endless. Whether it's setting up a virtual productivity platform for your company or exploiting virtual avenues to drive marketing and recognition for your product, successful business owners need to have fluency with this new landscape.
With non-fungible tokens garnering increasingly more interest in recent years, House 44 is not only equipping its community with a deeper understanding of the value of digital assets and how to invest in these projects, but also has plans to introduce its very own NFT collection. Involving several members in the process of production, these stakeholders, including many new members of 'The Ark', will be able to collect, trade and buy into the art. Not only that, holders of House 44's NFTs will have access to exclusive content and unique experiences, making this a highly anticipated project for the web 3.0 space.
From Work to Play: The Next Frontier
Inviting its members to dip their toes in this wild and limitless universe, 'The Ark' epitomises a trailblazing space where work meets pleasure. Modelled after retro role-playing games (RPGs) from the 90s with nods to cult classic games such as Final Fantasy, members are welcomed into a fully interactive experience within the metaverse. Key highlights include co-working spaces to share ideas and converse about business, as well as breakout areas for entertainment and socialising. As the metaverse expands, 'The Ark' will be the central assembly point for House 44 meetings and events, where everything from investment tips to cooking recipes will be shared.
"One key resource that many lack is a network or community that allows them to leverage and tap into other peoples' expertise and experience. This is especially important in today's world where, time and time again, the most successful businesses and brands always have the strongest community to support them," said Felix Li, Co-founder of House 44.
With the overarching vision to provide people from all walks of life with more resources and the tools they need to succeed and flourish, House 44 is fully invested in materialising its vision for 'The Ark', creating a ground-breaking space for the next generation of entrepreneurs. Society is inarguably on a fast-moving trajectory toward the expansion of virtual worlds, and it is imperative that House 44 sets the stage for this digital transformation. Through this initiative, Roland and Felix hope to empower House 44's members to reach new heights in this arena.
With an exciting line-up in store and the imminent launch of 'The Ark' at hand, House 44 is now opening its doors for membership applications. For more information on requirements and fees, please visit https://house44.io or send an email to info@house44.io.
Download high resolution images here
Hashtag: #House44 #TheArk
About House 44
House 44 is a hybrid offline and online SoFi (social finance) platform, driven by a passionate and fun-loving community. Considered as an angel number, '44' denotes the achievements and success which come with dedication and hard work, both individually and as a team. House 44 was established based on these values, connecting people and offering a community where these virtues are practiced. The company's main mission is to provide access to the industry's top utilities and assets for members and partners, creating an environment where entrepreneurship, innovation, and the creation of wealth can prosper.
Since founding the company in 2020, brothers Roland and Felix Li have extended the brand to include health, beauty and fitness; entertainment and lifestyle; education; and wealth creation as its core pillars. In 2022, the company launched 'The Ark', one of Asia's first digital metaverses where the House 44 community can connect and be inspired.
Roland and Felix Li are long-time entrepreneurs, having invested in, and started a number of business ventures over the past decade. Throughout their years of experimentation within different industries and working with a wide range of people, the one common occurrence they found was how a lack of resources and mentorship could often make entrepreneurship an impossible task, particularly for those coming from lower-income or under-privileged backgrounds. Wishing to give everyone a more equitable chance and create a more level playing field, Roland and Felix conceived the idea of a fraternity of sorts — a community where people could feel a sense of identity and belonging, while benefitting from active resources to foster success in business.
From the start, House 44 has built its brand on the idea of bringing together a community. From services expanding across a wide range of interests and industries — including wine clubs, music festivals and state-of-the-art beauty and fitness centres — to its retail arm which promotes everything from extraordinary Bordeaux vintages to health and wellness products, the brand has reached a wide and engaged audience, and expanded across continents. With one of its core missions to remain at the forefront of technology, House 44 is excited to announce its leap into the future with a host of virtual offerings to complement its firmly established physical products and services. House 44 will be one of the first members' clubs in Hong Kong to explore the virtual space, and it is inviting everyone from novices to aficionados along for the ride.


Futures rose as much as 0.9% in NY after slipping 5% the previous two sessions.
Worries over a supply glut have pushed oil prices to settle below US$40 a barrel for the first time in more than three months.
The supply glut is upsetting industry expectations, with BP, Royal Dutch Shell and Exxon Mobil Corp. reporting second-quarter earnings last week that were worse than estimated.
The US government will issue official inventory data on Wednesday. "Now, are we out of the woods yet?"
Due to below average draws, this summer; the inventories are 30 % above the five-year averages. It hasn't closed below $40 since April 18 when it ended the day at $39.78. Total volume traded was about 46 percent below the 100-day average.
Brent crude was up 11 cents a barrel at $41.91 at 1121 GMT. Gas prices dropped to an average of $2.13 a gallon on Monday, compared with $2.66 this time previous year, according to AAA. The global benchmark traded at a premium of $1.50 to WTI for October. Bank of America Merrill Lynch head of commodities research told Bloomberg Television that oil will likely be back above $50 a barrel towards the end of this year. Oil rallied from a 12-year low near $27 in January to a 2016 high of nearly $53 in June, supported by an initiative from OPEC and outside producers including Russian Federation to freeze output and by hopes that the supply glut would ease.
Supplies at Cushing, Oklahoma, the key delivery point for Nymex crude, fell by 1.12 million barrels last week, the EIA said.
International Brent crude futures were trading at.85 per barrel, up a mere 5 cents from their last close, and failing to retake and maintain.
However, other analysts said recent price falls were overblown, with Citi saying bears, who speculate on falling prices, having "gone wild in oil at United States dollars 40".
Hip-hop star Trina wrote: "I'm praying for @ ToyaWright her mom and her family during this disgusting tragedy". The brothers were discovered inside a vehicle , shortly after midnight on Saturday in the city's 7th Ward.
West Texas Intermediate crude futures are approximately 20 percent, down from their 2016 peaks above $50 a barrel scaled in early June, technically positioning it in bear market territory, as an indication of an ongoing recovery in USA drilling activity shared with elevated stocks of fuel products weighed.
Supplies could swell further as member nations in the Organization of Petroleum Exporting Countries work to restore halted output. Already high stockpiles of these refined products rose further when the demand for the product became significantly less than it should be to consume all the gasoline that had been refined to compensate for low prices.
Right now, DeAndre Hopkins is making a million a year, which is an obscenely low price for a player of his caliber. Strong has looked noticeably quicker at camp while seeing increased reps with DeAndre Hopkins holding out.
Andy Barth, a representative of Howard County Executive Allan Kittleman, confirmed one death and two missing at 9:20 a.m. Police said several people were trapped in partially submerged vehicles in the Woodberry area.
Last week, it was Ivanka Trump introducing her dad, tonight it's Chelsea Clinton introducing her mom. Clinton said Trump is offering America "empty promises" and what she called "bigotry and bombast".
The NPA said that they would only declare a truce, if Duterte investigates his troops, who alleged violated the ceasefire order. According to CNN Philippines , PNP Chief Ronal Dela Rosa said police would follow Duterte's instructions.


cheap canada goose uk There is many repositories of patches with some common changes. You edit the Xlib code directly with no indirection of abstractions. I used it for a couple years before jumping to Awesome.Awesome is has canada goose clearance a very extensive and well documented sets of API including:Titlebars, bars, popup, tooltip, menus, etc, etc, etcPlus many modules and external body canada goose outlet toronto factory of code such as u/PapyElGringo config or the Elena config, which had so many upvote it has been post of the month for 2 consecutive month cheap canada goose uk.


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redpajama_set_name: RedPajamaGithub


You can go that route however it will not deliver the best reduction due to the fact the floor is not floating. I this situation I would float the ceiling below which would deliver a far better reduction.
I don't want to go with a floating ceiling because I am a tall guy and don't want to lose the ceiling height in the basement. From other posts I've read they say it is better to sound proof at the point of contact which would be the floor above. So what is my best option if I don't do anything from the ceiling below?
Do you have the tolerence for 1/2 hardie backer with Green glue sandwiched in between...then put down the vinyl flooring?


It was an October afternoon when I walked into Loud&Clear's digital agency's office in the hopes of landing myself an internship. I was sweating. Not the kind 'Oh I just walked up the stairs on a hot day' sweat, I mean the kind of sweat that you wipe off your upper lip with a trembling hand and smudge your make up.
12 months later I'm happy to say that I am now their Digital Marketing Assistant (and a little less happy to say that I've learnt more in my 12 months at Loud&Clear than I have in my Bachelor's Degree so far…). We are a full service digital agency and as much as I admire the Designer's artistic flair and the Account Manager's abilities to always seem busy but still have time to find hilarious gifs to send on Slack, I love the marketing side of things the most. I like seeing the analytics and I like following the trends of consumers. We have a range of clients and we use different Content Management Systems (CMSs) depending on their marketing agenda's, budget and website traffic.
Recently we partnered with both Sitecore and Kentico. We actually used the Sitecore DMS to build our own new website. They are some of the most amazing and intelligent systems I've encountered and I know about South Korea's schooling system. Before I started in my role I had no idea what Sitecore or Kentico were but after years of experience we know them like the back of our hands.
"the power to own every customer experience".
For example, Sitecore allows marketers to see how many people in Melbourne have visited their website and clicked on a certain tab or page. Marketers can then use this information to tailor their experience and display different content or ads to different people to encourage them to behave as they wish while on their website.
If someone from Melbourne views a page on a website run by Sitecore they may see something different to a person viewing in Canberra for example. This 'something' is marketed for Melbournians which would encourage them to stay on their website, buy a product, donate, click on another link, leave a comment etc. Sitecore runs with the big boys in the CMS race and sets itself apart from other platforms like WordPress or Kentico.
These flexible and expandable features of Sitecore are accessible because they use a .NET framework, and have been since they were established in 2002. Currently Sitecore uses .NET 2.0/4.0; the same framework used by Toshiba and Canon. The use of the CMS is similar in look and feel to a basic Windows desktop with 'Home', 'Content' and 'Media Library' folders. It is a diverse system; anything can be expanded or overwritten in the name of customization.
In regards to ecommerce, Sitecore is best suited to those looking to sell small multiples of products rather than large volumes, but ecommerce is only a very marginal part of Sitecore's complete capabilities. Both our own Sitecore expert and the Sitecore VP Enablement Services Officer for Greater Asia, Robert Holliday, agree that the best feature of Sitecore is the "very advanced personalization capabilities".
I questioned Robert about Sitecore's clients and their success stories. The non-for-profit organization The Smith Family uses Sitecore as their CMS. Robert informed me that they wanted to increase donations. Since using Sitecore "they have seen that overall donations have increased by 33% … that was in six months". As well as this, of the total donations made to The Smith Family, 25% are now made online after moving to Sitecore. Robert did admit that Sitecore was quite a complex system to operate and that "if the organization doesn't have a digital team then they should outsource".
If Sitecore is the Ferrari of CMS then Kentico is something like the Toyota Corolla. It will get you from A to B (and at an affordable price) but with none of the sophistication and style that Sitecore offers. Kentico has been argued to have more of an ecommerce approach to its Content Management than Sitecore. Kentico's ecommerce platform is well established and well integrated into Kentico since 2008 and as such allows its users to easily blend an ordering system into a website.
It is used by more than 18,000 Web sites in 90 countries, and operates on ASP.NET and Microsoft SQL Server. It has been used by brands such as Sony and Starbucks. ZebraCaps were even voted the best example of an ecommerce project that utilized the Kentico CMS. Although they don't quite match up to Sitecore's standards, Kentico does offer some good personalization tools and customization options, however its interface can be slightly hard to use at times and has been known to be 'fiddly' in places. Kentico suits smaller budget projects with less ambitious goals.
In summary, if you have a smaller budget and are looking for a CMS to focus on a small ecommerce project then Kentico is the way to go. It is easy enough to use that a member of existing staff with some coding and development experience should be able to use it. However, if you are ambitious and need a powerful CMS to work on a project with many goals that include ecommerce I would suggest you consider outsourcing a team of professionals and go with Sitecore. Both may be very advanced Content Management Systems and have proven results but both offer a different product, and it is important that this is considered before either is chosen.
Suyati offers services in both Kentico and Sitecore. Would you like to know more? Then drop a mail to services@suyati.com.
April Lipson is the Digital Marketing Assistant at Loud&Clear, a digital agency based in Melbourne. When she's not working on ecommerce projects, you can find her traveling around Australia in search of new sights and experiences.


Bolzano was chosen as logistic seat for its strategic connection with international markets.
Our business offers outsourcing services for wine cellars and distribution chains. We organize and carry out the shipping for supermarkets, wine shops and other specialist dealers. Moreover, we offer our customers a range of additional logistic services, related to the goods' supply and distribution. We are able to provide tracking information of the shipped goods even after the delivery has taken place, as we operate with Serial Shipping Container Code (SSCC), NVE and EAN128.
Thanks to ca. 40 partners, a surface of 20.000 mq, equipped with excellent tools and a high computerized system, we can offer a very efficient logistic service.
From our logistic centers annually leave ca. 13.000 shipments and 250.000 pallets.


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Minnesota Department of Administration remove filter
2012 (11) remove filter
Arts Access (1)
Five Wings Arts Council
Legislative-Citizen Commission on Minnesota Resources
Minnesota State Colleges and Universities
2012 Como Park Zoo and Conservatory
As a core to Como's mission on education, updating the aging interpretive signage and adding interactive and technology based interpretive and hands-on experiences is important. The cost to develop, design and produce these items is needed for African Hoofstock, Large Cats and the Japanese Gardens. The displays will demonstrate Como Zoo's commitment to world-wide conservation measures.
2012 Minnesota Film and TV Board
Minnesota Film and TV Board
Under Minn. Laws 2011, 1st Special Session, Chapter 6, Article 4, Section 2, Subd. 6, the Minnesota Film and TV Board was appropriated $500,000 the first year and $500,000 the second year for grants to Minnesota residents to create film or television productions that promote Minnesota's cultural heritage and for the film production jobs program under Minnesota Statutes, section 116U.26. This appropriation is available until June 30, 2015.
2012 Minnesota Public Television Association (MPTA)
Per Minnesota Laws, 2011, 1st Special Session, Chapter 6, Article 4, Section 2, Subdivision 6, this funding is for grants to the Minnesota Public Television Association for production and acquisition grants accordance to Minnesota Statutes, section 129D.18.
KSMQ Public Television, Austin
KAWE Lakeland Public Television, Brainered/Bemidji
2012 Science Museum of Minnesota
The Science Museum of Minnesota's work with schools is a continuation of efforts undertaken in the FY12-13 biennium, generously funded by an appropriation from the Arts and Cultural Heritage Fund. With previous Legacy funds, we undertook a museum-wide evaluation of our offerings to schools and how we could better serve our student and educator audiences.
2012-2013 Minnesota Children's Museum Rochester
Upon learning of State support for the Rochester project, the Museum implemented changes to our governance, staffing and operations structure to effectively expand our capacity. Initial exhibit, program, IT, marketing and communication plans have been launched for the opening. The Museum recently signed a lease agreement on a 5,000 square foot space that will provide engaging learning experiences for up to 30,000 anticipated visitors in the first year of operation. The address of the new Museum is 1643 ½ North Broadway, River Center plaza, MN 55906 and the new phone number is 507-218-3100.
2012-2013 Minnesota Children's Museum
Per Minnesota Laws, 2011, 1st Special Session, Chapter 6, Article 4, Section 2, Subdivision 6, is for grants to the Minnesota Children's Museum. These amounts are for arts, arts education, and arts access and to preserve Minnesota's history and cultural heritage
Disabled Veterans Rest Camp
The Disabled Veterans Rest Camp (DVRC), located on Big Marine Lake in Washington County, is open to all military veterans and military families. Founded in 1926 to help disabled veterans recover from World War I, the non-profit, campground relies on donations and volunteers to host most activities that provide relief and recreation. With so many more Guard and Reserve deployments, more veterans and their families are turning to the camp for family fund and recreation while their loved one is deployed and during the transition back to civilian life.
Grants Administration for State Fiscal Years 2012 and 2013
Department of Administration
Per Minnesota Laws, 2011, 1st Special Session, Chapter 6, Article 4, Section 2, Subd. 6, "These amounts are appropriated to the commissioner of administration for grants to the named organizations for the purposes specified in this subdivision.
Public Radio Competitive Grants Fiscal Year 2012
Ampers member stations, Minnesota Public Radio (MPR)
Per Minnesota Laws, 2011, 1st Special Session, Chapter 6, Article 4, Section 2, Subdivision 6, the Minnesota Department of Administration requested proposals to create, produce, acquire, or distribute radio programs that educate, enhance, or promote local, regional, or statewide items of artistic, cultural, or historic significance.
State Capitol Preservation Commission
Veterans on the Lake Resort
Veterans on the Lake Resort, a not-for-profit resort, will provide a barrier-free setting for a memorable outdoor recreation experience for disabled persons, with priority to disabled veterans, veterans, their families, friends and supporters; designed with veterans in mind, recognizing what they have contributed to and sacrificed for our nation; ensuring that they can fully participate in Minnesota's outdoor cultural heritage.
Well drilling to provide larger reservoir of water to meet peak demand

redpajama_set_name: RedPajamaCommonCrawl


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USA Today Previews Night Manager; New Photos at Variety
This week, Variety spotlights photos from The Night Manager, while USA Today previews the show. Plus, Hugh Laurie describes Roper to The Sydney Morning Herald. Read on for more:
• Variety releases images of The Night Manager, a six-part miniseries that "follows British soldier-turned-luxury hotel manager Jonathan Pine (Tom Hiddleston), who's recruited to infiltrate the network of arms dealer Richard Onslow Roper (Hugh Laurie)."
• USA Today previews The Night Manager, which debuts Apr. 19, saying, "When it comes to pedigrees, it's hard to top this six-part British import."
• Hugh Laurie tells The Sydney Morning Herald that Roper is "a pirate who has put himself beyond the normal realm of laws and customs and revels in that. But there is a kind of weariness underneath that, where he can't believe he's getting away with it and knows that someday, someone is going to come knocking."
• Financial Times marvels at The Night Manager's locations, "as the action skips from one glamorous location to the next."
• IGN posts a new trailer for The Night Manager, where "Tom Hiddleston and Hugh Laurie face off."
• While watching The Night Manager, The Pool declares it's "the character of Angela Burr, played with forceful brilliance by Olivia Colman, that has proved to be the lynchpin of the series."
To stay up-to-date on all the latest news about The Night Manager, sign up for The Night Manager Newsletter.
follow The Night Manager:
AMC Announces Limited Series Based on John le Carré's The Spy Who Came in From the Cold
The Night Manager Nominated for Four Golden Globes
The Night Manager Earns a Television Critics Award Nomination
The Night Manager Q&A — Simon Cornwell (Executive Producer)


Consumers are moving off of the desktop and on to their mobile devices, but advertisers are not following them at the same pace. Just 5% of online advertising revenue in 2011 came from mobile, according to the Interactive Advertising Bureau.
In an effort to change this equation–and increase its own mobile ad revenue–YouTube introduced a new type of ad for its mobile website today. Called TrueView, it gives users a choice of whether to watch a video ad and only charges the advertiser when they do so.
While the ad format has been available on YouTube's standard website since 2010, YouTube's mobile advertising has until now been focused on banner ads and promoted videos. YouTube executives told the New York Times that TrueView is particularly suited for mobile because it doesn't interrupt users with unwanted content when they are on the go.
Facebook has also been experimenting in the mobile ad realm lately–bringing sponsored stories to mobile and creating a new ad product for developers who want to market their own apps.


Aluminum coil is produced from cast slabs put through tandem reducing mills. Aluminum coils offer reduced weight and allow special surface applications with unique characteristics.
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6000 series Aluminum-Magnesium-Silicon alloys are easy to machine and can be precipitation hardened to increase yield strength.


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Dr. Strangelove (Blu-ray Details)
Added on: 1/3/2021 15:10
Other Reviews, etc
Dr. Strangelove, or: How I Learned to Stop Worrying and Love the Bomb
Dr. Strangelove: Special Edition (US)
Men in Black I and II
The Ladykillers - 60th Anniversary Collector's Edition
Ladyhawke
The Ladykillers: The StudioCanal Collection
Marley & Me
Cult horror classic The Evil Dead arrives on Blu-ray in October
The Back-up Plan with Jennifer Lopez hits Blu-ray and DVD in September
Woody Harrelson stars in comedy Defendor out on DVD this September
Not the Messiah one time live Python event hits DVD and Blu-ray in June
Zombieland hits Blu-ray and DVD in March
Sexy comedy The Ugly Truth out on DVD and Blu-ray in February
Classic big screen Jack Rosenthal comedy The Lovers comes to DVD in May
British black hit-man comedy The Liability hits DVD and Blu-ray this May
British black comedy Sightseers holidays its way to Blu-ray and DVD in March
BBC Worldwide releases in February part one
Will Ferrell stars in Casa De Mi Padre out on Blu-ray and DVD this October
2010, Black Comedy, Blu-ray, Classic, Cold War, Comedy, Czech, English, George C. Scott, Hungarian, Keenan Wynn, Nuclear Bomb, Peter Sellers, PG, Polish, Region B, Shepperton studios, Slim Pickens, Sony Pictures Home Entertainment, Spanish, Stanley Kubrick, Sterling Hayden, Terry Southern
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To include this image in articles, reviews, blog entries, etc, paste the following code into the appropriate "Image Code"or "Cover Image"box:
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Poke Ball and Fancy patterns, to be exact. Are they Shiny Locked?
Every event Pokemon that is not supposed to be shiny is shiny locked.
Source-experience with events and this.
commented Jul 8, 2014 by !'•-Indigo-•'!
The Fancy Vivillon is unfortunately shiny locked.
The Pokeball Vivillon is not released yet.
answered Jul 8, 2014 by !'•-Indigo-•'!
Actually the Poké Ball Pattern Vivillon was distributed via local wireless at the temporary Pokémon Center store in Paris, France from June 4th to June 21st 2014.
Could I get vivillon patterns in 1 location?
Can I have 2 vivillon patterns at once?


Hi There. Nothing like a challenge to get something to post on the blog. This month's challenge at Challenge YOUrself is a colour challenge. Fun, fresh summer hues, and you'll be surprised to see how many different direction the design team took them in.
I had fun trying out some techniques on this one. I used a combination of thin layers of gesso and Golden absorbant ground as a base, before adding stencilled Gelatos, splashes of watercolour and spray ink as well as a few stamps.
I couldn't resist topping it off with some iRESISTables sprays and some funky melted thingies.


This multi-bag filter housing is equipped with proven and easy to-use rugged eye-bolt cover closure. The housing volume is optimized to minimize product loss. Units are available in 2, 3, 4, 6, 7 and 8 filter bag configurations and come standard with filter bag size 02 stainless steel restrainer baskets. Positive O-ring sealing provides bypass-free, safe filtration while the unique 3-point hold down ensures a high-quality seal between each filter bag and the housing body. It is available in Carbon steel, 304 or 316L stainless steel for high corrosion resistance with customize fittings, surface finish, coating & design code as per application.


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Q: Does iOS11 handle viewport different? On my iPad Mini I can only install up to iOS 9.3, the website looks fine there and on any other device. But colleagues with a new iPad and iOS 11.0.3 have the website only filling about 60% of the screen (both portrait and landscape mode).
see iPod photo a colleague sent me
I made the website for 100% screen width on all devices and never had a problem, worked fine the last 2 years. I would say the website code is sober, the problem comes from iOS. But since I can only check iOS 9.3 or iOS 11, I do not exactly know at which version of iOS the error exactly started.
I can not find any information whatsoever about where this may come from or other people mentioning such a problem. Does iOS11 handle viewport different?

redpajama_set_name: RedPajamaStackExchange


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Report| Volume 85, ISSUE 5, P679-691, November 13, 2009
A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma
Maria Teresa Landi
Division of Cancer Epidemiology, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
Nilanjan Chatterjee
Kai Yu
Lynn R. Goldin
Alisa M. Goldstein
Melissa Rotunno
Lisa Mirabello
Kevin Jacobs
William Wheeler
Information Management Services, Inc., Rockville, MD 20852, USA
Meredith Yeager
Andrew W. Bergen
Center for Health Sciences, Molecular Genetic Program, SRI International, Menlo Park, CA 94025, USA
Qizhai Li
Key Laboratory of Systems and Control, Academy of Mathematics and System Science, Chinese Academy of Science, Beijing 100190, P.R. China
Dario Consonni
Unit of Epidemiology, Fondazione Istituto di Ricevero e Cura a Carattere Scientifico, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena and Department of Occupational and Environmental Health, University of Milan, Milan, 20122, Italy
Angela C. Pesatori
Sholom Wacholder
Michael Thun
American Cancer Society, Epidemiology and Surveillance Research, Atlanta, GA 30301, USA
Ryan Diver
Martin Oken
Hubert H. Humphrey Cancer Center, Robbinsdale, University of Minnesota, Minneapolis, MN 55455, USA
Jarmo Virtamo
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, 00280, Finland
Demetrius Albanes
Zhaoming Wang
Laurie Burdette
Kimberly F. Doheny
Center for Inherited Disease Research, Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA
Elizabeth W. Pugh
Cathy Laurie
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
Paul Brennan
International Agency for Research on Cancer, Lyon, 69372, France
Rayjean Hung
Samuel Lunenfeld Research Institute, Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3L9, Canada
Valerie Gaborieau
James D. McKay
Mark Lathrop
Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH), Paris, 75010, France
Ying Wang
Ming-Sound Tsao
Department of Pathology, University Health Network, Princess Margaret Hospital and University of Toronto, Toronto, ON M5T 3L9, Canada
Margaret R. Spitz
Department of Epidemiology, M.D. Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
Yufei Wang
Section of Cancer Genetics, Institute of Cancer Research, Surrey, SM2 5NG, UK
Hans Krokan
Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, N-7489, Norway
Lars Vatten
Frank Skorpen
Egil Arnesen
Department of Community Medicine, University of Tromso, Tromso, N-9037, Norway
Simone Benhamou
INSERM and Fondation Jean Dausset-CEPH, Paris, 75010, France
Christine Bouchard
Geneva Cancer Registry, Geneva, 1205, Switzerland
Andres Metsapalu
Institute of Molecular and Cell Biology and Estonian Genome Project of the University of Tartu, Estonian Biocentre, Tartu, 51010, Estonia
Tonu Vooder
Mari Nelis
Kristian Välk
John K. Field
Roy Castle Lung Cancer Research Program, The University of Liverpool Cancer Research Center, Liverpool, L3 97A, UK
Chu Chen
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Gary Goodman
Patrick Sulem
deCODE Genetics, Reykjavik, 101, Iceland
Gudmar Thorleifsson
Thorunn Rafnar
Timothy Eisen
Department of Oncology, University of Cambridge, Cambridge, CB2 2RE, UK
Wiebke Sauter
Institute of Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, D-85764, Germany
Albert Rosenberger
Department of Genetic Epidemiology, University of Göttingen Medical School, Göttingen, D-37073, Germany
Heike Bickeböller
Angela Risch
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, D-69120, Germany
Jenny Chang-Claude
H. Erich Wichmann
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig Maximilians University, 81377 Munich, Germany
Klinikum Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
Kari Stefansson
Richard Houlston
Christopher I. Amos
Joseph F. Fraumeni Jr.
Sharon A. Savage
Pier Alberto Bertazzi
Margaret A. Tucker
Stephen Chanock
Neil E. Caporaso
Open ArchivePublished:October 15, 2009DOI:https://doi.org/10.1016/j.ajhg.2009.09.012
Previous ArticleATRIUM: Testing Untyped SNPs in Case-Control Association Studies with Related Individuals
Next ArticleThe Relationship between Imputation Error and Statistical Power in Genetic Association Studies in Diverse Populations
Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.13–1.33, p = 3.02 × 10−7), but not with other histologic types (OR = 1.01, p = 0.84 and OR = 1.00, p = 0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR = 1.24, 95% CI = 1.17–1.31, p = 3.74 × 10−14 for AD; OR = 0.99, p = 0.69 and OR = 0.97, p = 0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.
Recently, three genome-wide association studies (GWAS) of lung cancer and subsequent pooled GWAS analyses identified inherited susceptibility variants on chromosome 15q25,
Hung R.J.
McKay J.D.
Gaborieau V.
Boffetta P.
Hashibe M.
Zaridze D.
Mukeria A.
Szeszenia-Dabrowska N.
Lissowska J.
Rudnai P.
A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.
Amos C.I.
Wu X.
Broderick P.
Gorlov I.P.
Gu J.
Eisen T.
Dong Q.
Zhang Q.
Vijayakrishnan J.
Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1.
Thorgeirsson T.E.
Geller F.
Sulem P.
Rafnar T.
Wiste A.
Magnusson K.P.
Manolescu A.
Thorleifsson G.
Ingason A.
A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.
5p15,
Chabrier A.
Byrnes G.
Lung cancer susceptibility locus at 5p15.33.
Webb E.
Matakidou A.
Qureshi M.
Chen W.V.
Common 5p15.33 and 6p21.33 variants influence lung cancer risk.
Stacey S.N.
Gudmundsson J.
Sigurdsson A.
Jakobsdottir M.
Helgadottir H.
Thorlacius S.
Aben K.K.
Sequence variants at the TERT-CLPTM1L locus associate with many cancer types.
and 6p21.
Lung cancer is classified into two main histologic groups: small cell lung cancer (SC) and non-small cell lung cancer; the latter includes adenocarcinoma (AD) and squamous cell carcinoma (SQ), along with rarer subtypes. Worldwide, adenocarcinoma is the most frequently identified histologic type, and the relative proportion of lung cancer due to this histology has steadily risen. Demographic, etiologic, clinical, and molecular characteristics of the lung cancer subtypes have been reported.
Gabrielson E.
Worldwide trends in lung cancer pathology.
Respirology. 2006; 11: 533-538
Although family history of lung cancer has been associated with histologic subtypes,
Gao Y.
Goldstein A.M.
Consonni D.
Pesatori A.C.
Wacholder S.
Tucker M.A.
Caporaso N.E.
Goldin L.
Landi M.T.
Family history of cancer and nonmalignant lung diseases as risk factors for lung cancer.
Int. J. Cancer. 2009; 125: 146-152
Hemminki K.
Inherited predisposition to early onset lung cancer according to histological type.
Ambrosone C.B.
Rao U.
Michalek A.M.
Cummings K.M.
Mettlin C.J.
Lung cancer histologic types and family history of cancer. Analysis of histologic subtypes of 872 patients with primary lung cancer.
Cancer. 1993; 72: 1192-1198
Sellers T.A.
Elston R.C.
Atwood L.D.
Rothschild H.
Lung cancer histologic type and family history of cancer.
Cancer. 1992; 69: 86-91
the inherited susceptibility factors that affect specific histologies are unknown.
We conducted a GWAS in 5739 lung cancer cases and 5848 controls (National Cancer Institute [NCI] GWAS) to search for overall susceptibility variants and variants associated with specific histologic types and smoking status. We also conducted a meta-analysis of the NCI GWAS with summary data from ten additional studies, for a total of 13,300 primary lung cancer cases and 19,666 controls, all of European descent. Four of the ten studies provided information on histology for replication analyses; 3333 AD, 2589 SQ, and 1418 SC cases were analyzed overall.
The 11,587 subjects in the NCI GWAS were drawn from one population-based case-control study and three cohort studies (Table 1); specifically: the Environment and Genetics in Lung Cancer Etiology (EAGLE),
Rotunno M.
Bergen A.W.
Lubin J.H.
Alavanja M.
Morgan G.
Subar A.F.
Environment And Genetics in Lung cancer Etiology (EAGLE) study: an integrative population-based case-control study of lung cancer.
BMC Public Health. 2008; 8: e203
a population-based case-control study including 2100 primary lung cancer cases and 2120 healthy controls enrolled in Italy between 2002 and 2005; the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC),
The ATBC Cancer Prevention Study Group
The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance.
Ann. Epidemiol. 1994; 4: 1-10
a randomized primary prevention trial including 29,133 male smokers enrolled in Finland between 1985 and 1993; the Prostate, Lung, Colon, Ovary Screening Trial (PLCO),
Hayes R.B.
Sigurdson A.
Moore L.
Peters U.
Huang W.Y.
Pinsky P.
Reding D.
Gelmann E.P.
Rothman N.
Pfeiffer R.M.
Methods for etiologic and early marker investigations in the PLCO trial.
Mutat. Res. 2005; 592: 147-154
a randomized trial including 150,000 individuals enrolled in ten U.S. study centers between 1992 and 2001; and the Cancer Prevention Study II Nutrition Cohort (CPS-II),
Calle E.E.
Rodriguez C.
Jacobs E.J.
Almon M.L.
Chao A.
McCullough M.L.
Feigelson H.S.
Thun M.J.
The American Cancer Society Cancer Prevention Study II Nutrition Cohort: rationale, study design, and baseline characteristics.
including over 183,000 subjects enrolled by the American Cancer Society between 1992 and 2001 across all U.S. states. Analyses stratified by histology in the NCI GWAS included 1730 AD cases, 1400 SQ cases, 678 SC cases, and groups of other histological types or of mixed histologies. These studies were approved by the individual institutional review boards of each location, and each subject gave his or her informed consent for participation.
Table 1Studies Included in the Genome-wide Association Analysis of Lung Cancer
No. of Subjects
Illumina HumanHap Chips
NCI GWAS
Environment and Genetics in Lung Cancer Etiology study.
1920 1979 Italy Population-based case-control 550K, 610QUAD
ATBC
Alpha-Tocopherol, Beta-Carotene Cancer Prevention study.
1732 1271 Finland Cohort 550K, 610QUAD
PLCO
Prostate, Lung, Colon, Ovary screening trial.
1390 1924 10 US Centers Cohort–Cancer Prevention Trial 317K+240S, 550K, 610QUAD
CPS-II
Cancer Prevention Study II nutrition cohort.
697 674 All US States Cohort 550K, 610QUAD, 1M
TOTAL 5739 5848
UK 1978 1438 UK Hospital-based cases, birth cohort controls 550K
Central Europe 1837 2432 Romania, Hungary, Slovakia, Poland, Russia, Checz Rep. Multicenter hospital-based case-control 317K, 370Duo
Texas 1154 1137 Texas, USA Hospital-based case-control 317K
DeCODE Genetics 719 6030 Iceland Population-based case-control 317K, 370Duo
HGF Germany
Helmholtz-Gemeinschaft Deutscher Forschungszentren Lung Cancer GWAS.
506 480 Germany Population-based case-control (<50 years) 550K
Carotene and Retinol Efficacy Trial cohort.
397 393 6 US Centers Cancer Prevention Trial 370Duo
HUNT2/Tromso
North Trondelag Health Study 2 / Tromsø IV.
394 382 Norway Population-based case-control 370Duo
Canada 332 505 Greater Toronto area Hospital-based case-control 317K
France 135 146 Paris and Caen areas Hospital-based case-control 370Duo
Estonia 109 874 Estonia Hospital-based case-control 317K, 370Duo
Grand Total 13300 19666
a Environment and Genetics in Lung Cancer Etiology study.
b Alpha-Tocopherol, Beta-Carotene Cancer Prevention study.
c Prostate, Lung, Colon, Ovary screening trial.
d Cancer Prevention Study II nutrition cohort.
e Helmholtz-Gemeinschaft Deutscher Forschungszentren Lung Cancer GWAS.
f Carotene and Retinol Efficacy Trial cohort.
g North Trondelag Health Study 2 / Tromsø IV.
The meta-analysis included all of the NCI GWAS data plus summary data from ten additional studies contributing 7561 cases and 13,818 controls (Table 1): (1) the UK study from the Institute for Cancer Research,
including lung cancer cases from the Genetic Lung Cancer Predisposition Study established in 1999 and controls from the 1958 birth cohort;
Power C.
Elliott J.
Cohort profile: 1958 British birth cohort (National Child Development Study).
Int. J. Epidemiol. 2006; 35: 34-41
(2) the International Agency for Research on Cancer (IARC) study in central Europe,
a hospital-based case-control study conducted in the Czech Republic, Hungary, Poland, Romania, Russia, and Slovakia between 1998 and 2002; (3) the Texas case-control study,
including cases newly diagnosed at the University of Texas M.D. Anderson Cancer Center since 1991 and controls from the Kelsey-Seybold clinics (the GWAS included only smokers and cases with non-small cell lung cancer); (4) the population-based case-control study from deCODE Genetics in Iceland,
including all Icelandic subjects originally recruited for different genetic studies between 1996 and 2007 at deCODE Genetics and lung cancer cases recruited from the Icelandic Cancer Registry since 1998; (5) the Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF) lung cancer GWA study,
Sauter W.
Rosenberger A.
Beckmann L.
Kropp S.
Mittelstrass K.
Timofeeva M.
Wolke G.
Steinwachs A.
Scheiner D.
Meese E.
Matrix metalloproteinase 1 (MMP1) is associated with early-onset lung cancer.
Cancer Epidemiol. Biomarkers Prev. 2008; 17: 1127-1135
including lung cancer cases diagnosed at ≤ 50 years from the LUng Cancer in the Young (LUCY) study, a multicenter study within 31 German hospitals, and the Heidelberg lung cancer study, a hospital-based case-control study conducted by the German Cancer Research Center (DKFZ) (controls were selected from the Cooperative Health Research in the Region of Augsburg [KORA]); (6) the Carotene and Retinol Efficacy Trial (CARET) cohort,
Omenn G.S.
Goodman G.
Thornquist M.
Grizzle J.
Rosenstock L.
Barnhart S.
Balmes J.
Cherniack M.G.
Cullen M.R.
Glass A.
The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers.
Cancer Res. 1994; 54: 2038s-2043s
including smokers with a smoking history of at least 20 pack-years enrolled in six U.S. centers between 1983 and 1994; (7) the HUNT2/Tromso study, including lung cancer cases and controls from the North Trondelag Health Study (HUNT 2),
Holmen J.M.K.
Kruger O.
Langhammer A.
Lingaas Holmen T.
Bratberg G.H.
The Nord-Trøndelag Health Study 1995-97 (HUNT 2): Objectives, contents, methods and participation.
Norweg. J. Epidemiol. 2003; 13: 19-32
a population-based study conducted between 1995 and 1997 in North Trondelag County, and the Tromsø IV population-based study conducted in Tromsø County between 1994 and 1995; 8) the lung cancer study from Canada,
including lung cancer cases recruited at the University of Toronto and the Samuel Lunenfeld Research Institute between 1997 and 2002 and GWAS controls randomly selected from family medicine clinics; 9) the lung cancer study from France,
Feyler A.
Voho A.
Bouchardy C.
Kuokkanen K.
Dayer P.
Hirvonen A.
Benhamou S.
Point: myeloperoxidase –463G–> a polymorphism and lung cancer risk.
a hospital-based case-control study including smoking cases and controls recruited between 1988 and 1992 in ten French hospitals; and 10) the lung cancer study from Estonia, a hospital-based case-control study including lung cancer cases enrolled between 2002 and 2006 in Estonian hospitals and controls randomly selected from the Estonian Genome Project population-based cohort.
Nelis M.
Esko T.
Magi R.
Zimprich F.
Zimprich A.
Karachanak S.
Pischakova T.
Balascak I.
Peltonen L.
Genetic structure of Europeans: a view from the North-East.
PLoS ONE. 2009; 4: e5472
Three studies (the Texas,
deCODE,
and HGF German
studies) also contributed summary data from genome-wide scans stratified by histology, including 1138 AD, 578 SQ, and 210 SC cases. The UK study
contributed data on the top single nucleotide polymorphisms (SNPs) of chromosome 5p15.33 by histology. These four studies contributed 1603 AD, 1189 SQ, and 740 SC cases to the meta-analysis by histology for this locus.
In both the NCI GWAS and the studies in the meta-analysis, the lung cancer diagnosis was based on clinical criteria and confirmed by pathology reports from surgery, biopsy, or cytology samples in approximately 95% of cases and on clinical history and imaging for the remaining 5%. Tumor histology was coded according to the International Classification of Diseases for Oncology. In analyses stratified by histology, only adenocarcinoma, squamous cell carcinoma, and small cell carcinoma cases were included. All mixed subtypes or other histologies were excluded. Overall, between 10% and 50% of all diagnoses from the NCI GWAS were centrally reviewed by expert lung pathologists from NCI.
The NCI GWAS scan was conducted at two institutions: the Center for Inherited Disease Research (CIDR), which genotyped all EAGLE and 1675 PLCO subjects, and the Core Genotyping Facility (CGF), NCI, which genotyped ATBC, CPS-II, and the remaining PLCO subjects. Controls from the Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer scan
Yeager M.
Orr N.
Jacobs K.B.
Kraft P.
Minichiello M.J.
Fearnhead P.
Yu K.
Chatterjee N.
Genome-wide association study of prostate cancer identifies a second risk locus at 8q24.
were also included.
EAGLE samples and 1675 PLCO samples were genotyped at CIDR, as part of the Gene Environment Association Studies Initiative (GENEVA) funded through the National Human Genome Research Institute, with the use of Illumina HumanHap550v3_B BeadChips (Illumina, San Diego, CA, USA). Data were released for 5620 of 5727 (98%) samples, including 32 blind duplicates (concordance was 99.993%); these were genotyped with 124 HapMap controls (66 CEU; 58 YRI). Allele cluster definitions per SNP were determined with the use of the Illumina BeadStudio Genotyping Module version 3.1.14 and the combined intensity data from 95% of the samples. The resulting cluster definitions were used on all samples. Genotypes were not called if the quality threshold (Gencall score) was below 0.15. Genotypes were released by CIDR for 560,505 (99.83% of attempted) SNPs. Genotypes were not released for SNPs not called by BeadStudio or for those with call rates less than 85%, more than one HapMap replicate error, more than a 3% (autosomal) or 5% (X chromosome) difference in call rate between genders, or more than 0.5% male AB frequency for the X chromosome. The mean non-Y chromosome SNP call rate and mean sample call rate were each 99.8% for the CIDR data set.
Similar procedures were followed at CGF for the ATBC, CPSII, and PLCO cohorts with the use of three Illumina platforms: the HumanHap550K, the HumanHap610, and HumanHap 1 Million chips. All genotyped samples passed quality control metrics at CGF. After removal of assay and locus as a result of low completion rates, genotypes for each sample that appeared in duplicate were merged to form consensus genotypes for each subject. There were 12,111 study subjects available for subsequent analysis. Table S1, available online, shows the distribution of subjects by study and phenotype after application of quality control (QC) metrics. Figure S1 shows the cluster plot for the most notable SNP, rs2736100.
A total of 221 pairs of samples were identified with >70% genotype concordance rate. Among them, 189 pairs were expected duplicates and had genotype concordance rates > 99.9%. There were 12 unexpected duplicates (cross or within studies) with >99.97% concordance rates. We evaluated the pairwise concordance on the basis of the entire set and observed 40 pairs of subjects with over 60% of concordant genotypes (genotype concordance > 60%). Exclusions are listed in Table S2. Deviations from Hardy-Weinberg proportions (HWP) were assessed in controls. Expected and observed p values were calculated with the use of the uniform distribution for all loci and the exact test, respectively. Autosomal SNPs with minor allele frequencies (MAFs) >5% and completion rates >95% were included. Deviation from HWP was minimal, and only loci with extremely low p values (p < 10−7) for each QC group were excluded from further analyses (Table S3). A quantile-quantile (Q-Q) plot of the p values per study is shown in Figure S2.
To assess population structure, we estimated imputed continental ancestry by using the STRUCTURE program,
Pritchard J.K.
Stephens M.
Donnelly P.
Inference of population structure using multilocus genotype data.
with a set of 12,898 autosomal SNPs with low local background linkage disequilibrium (LD) (pairwise r2 < 0.004 measured in the population of European ancestry for any pair of SNPs less than 500 kb apart)
Li Q.
Hunter D.J.
Hoover R.N.
Chanock S.
Population substructure and control selection in genome-wide association studies.
(Figure S3). Genotypes from the three HapMap populations (Build 22 for HapMap II with MAF > 5%)
The International HapMap Project
were used as reference populations. The number of inferred clusters ("K" parameter) was set to 3 for CEU, YRI, and JPT+CHB samples representing populations of European, African, and Asian origin, respectively. Eighteen subjects were detected as having less than 80% European ancestry and were excluded.
Principal component analysis (PCA) for each study group (excluding subjects with less than 80% European ancestry, unexpected duplicates, and potential relative pairs) was performed with the same informative 12,898 SNPs with the use of the EIGENSTRAT program
Price A.L.
Patterson N.J.
Plenge R.M.
Weinblatt M.E.
Shadick N.A.
Reich D.
Principal components analysis corrects for stratification in genome-wide association studies.
(Figures S4A–S4D). After adjustment for significant principal components (PCs) in each study, comparison of observed and expected distributions showed no evidence for large-scale inflation of the association test statistics (inflation factor λ = 1.03, 103, 1.01, and 1.01 in EAGLE, PLCO, CPS-II, and ATBC, respectively), excluding the possibility of significant hidden population substructure. Q-Q plots for each NCI study are shown in Figures S5A–S5D.
After excluding 183 subjects for the reasons described above (summarized in Table S2) and 337 subjects with incomplete phenotype data, we report analyses on 515,922 SNPs in 5739 lung cancer cases and 5848 controls (NCI GWAS, Table 1).
Comparable QC procedures were conducted at each institution that provided summary results for the meta-analysis.
For the genome-wide analysis of the NCI GWAS, we used unconditional logistic regression to derive a per-allele odds ratio (OR) and an associated 1 degree of freedom (df) association test adjusted for age in five-year intervals (defined as age at diagnosis or interview for the case-control study and as baseline age for cohort studies), gender, study (EAGLE, PLCO, ATBC, ACS), and four PCs for population stratification within studies (see description of PC analysis below). In additional analyses, we adjusted for smoking status (current, former, never), cigarettes smoked per day (≤ 10, 11–20, 21–30, 31–40, 41+), duration in 10 yr intervals, and number of years since quitting (1–5, 6–10, 11–20, 21–30, 30+) for former smokers (subjects who quit smoking at least 6 mo before participating in the study). The analyses with single and multiple SNPs stratified by histology, smoking status, and decade of birth were conducted with the use of the same models. Tests for interaction between a SNP (coded as a continuous variable) and smoking status or birth decade (coded with the use of dummy variables) were performed with Wald tests with the use of multiple dfs.
For the meta-analysis with other studies, we obtained per-allele ORs and standard errors from each study. Because only summary data were available, we conducted the meta-analysis in two separate groups: "Set 1 SNPs" included a core of 279,698 SNPs that were available across all studies; and "Set 2 SNPs" included 197,647 SNPs that were available only for a subset of the studies that used the HumanHap500 or denser genomic platforms or provided summary data on imputed SNPs. We obtained meta-analysis estimates of per-allele ORs and associated p values by using the weighted Z-score method under a fixed effect model.
Higgins J.P.
Thompson S.G.
Quantifying heterogeneity in a meta-analysis.
Stat. Med. 2002; 21: 1539-1558
Tests for heterogeneity by study were performed with the use of the QE statistics, assuming a random effect model. For testing of heterogeneity across histologic subtypes, we reported the smallest p values obtained from pairwise case-case analyses between the subtypes after adjustment for multiple testing with the use of the Bonferroni correction. All odds-ratios were reported with respect to the minor allele in the pooled set of controls from all studies that contributed to the meta-analysis.
For adjustment of population stratification, we used the same set of 12,898 autosomal informative SNPs
used for QC. We conducted PCA in each of the four study groups (EAGLE, PLCO, ATBC, and CPS-II) separately.
For each study group, we identified among the top ten PCs the ones on which lung cancer cases and controls were not distributed evenly (the Wilcoxon rank-sum test p < 0.1), and adjusted them as continuous covariates nested within each study group. We selected two PCs for PLCO and one for each EAGLE and ATBC. No PCs were selected for the CPS-II study. Of note, we replicated the major analyses by using PCs obtained from all SNPs and found virtually identical results (data not shown).
Genome-wide analysis of the NCI GWAS confirmed previously reported findings on 5p15, 15q25, and 6p21, but did not conclusively identify novel susceptibility loci for lung cancer risk. Similar results were obtained in the overall meta-analysis combining the NCI GWAS with results from the ten additional studies, for a total of over 30,000 subjects (Figure 1 and Table S5).
Figure 1"Manhattan Plot" of Meta-Analysis Results for Lung Cancer Susceptibility Loci
Genome-wide association results for 13,300 primary lung cancer cases and 19,666 controls. −Log10 p values plotted against the chromosomal positions are depicted. "Set 1 SNPs" includes the core of 279,698 SNPs that were available across all studies. "Set 2 SNPs" includes 197,647 SNPs that were available only for a subset of the studies that used HumanHap500 or denser genomic platforms or provided summary data on imputed SNPs. The plot has been truncated at p < 10−10. There were 37 additional SNPs with lower p values, which are included in the list of the top 200 SNPs reported in Table S5.
The analysis of the locus on the 5p15.33 region
provided notable findings. In the overall analysis of the NCI GWAS, the most prominent SNPs were rs4635969 (OR = 0.87, 95% confidence interval [CI] = 0.82–0.93, p = 9.80 × 10−5), followed by rs31489 in CLPTM1L (also named CCR9 [MIM 612585]) (OR = 0.90, 95% CI = 0.86–0.95, p = 2.80 × 10−4) and rs2736100 in TERT (MIM 187270) (OR = 1.09, 95% CI = 1.03–1.15, p = 0.001) (Table 2). rs2736100 showed discrepant results by smoking status (Table 2), which reflected different associations across histologies. In fact, this locus showed remarkable differences by histology (Figure 2). The rs2736100 SNP was associated only with AD (OR = 1.23, 95% CI = 1.13–1.33, p = 3.02 × 10−7), but not the other histologic types (OR = 1.01, p = 0.84 and OR = 1.00, p = 0.93, for SQ and SC, respectively; p = 0.001, test for heterogeneity across histologies corrected for multiple comparisons). The risk estimates were not altered by the adjustment for smoking and were consistent across categories of smoking intensity and decade of birth (data not shown). The analysis by smoking status (Table 2) revealed that the SNP was significantly associated with risk of adenocarcinoma in both smokers and those who had never smoked.
Table 2Association of Selected SNPs on 5p15 and 15q25 Loci with Lung Cancer Risk Overall and by Histologic Types and Smoking Status
Marker,
NCBI dbSNP identifier.
Allele,
Major allele, minor allele.
Chromosome and NCBI Human genome Build 36 location.
Gene neighborhood within 20 kb upstream and 10 kb downstream of SNP.
Minor allele frequency in controls/cases.
Overall NCI Data
Adenocarcinoma NCI Data
Squamous Cell Carcinoma NCI Data:
Small Cell Carcinoma NCI Data:
1d.f. Wald test.
OR, per-allele odds ratio; CI, 95% confidence interval.
SNPs on Chromosome 5p15
rs2736100, (T,G), 1339516, TERT, 0.499/0.466 NCI_Smoking Unadjusted 0.001 1.09 (1.03, 1.15) 3.02 × 10−7 1.23 (1.13,1.33) 0.84 1.01 (0.93, 1.10) 0.93 1.00 (0.90, 1.13)
NCI_Current smokers 0.41 1.03 (0.96-1.11) 0.001 1.23 (1.09, 1.39) 0.37 0.95 (0.85, 1.06) 0.77 0.98 (0.85, 1.12)
NCI_Former smokers 0.02 1.11 (1.02, 1.22) 0.01 1.17 (1.03, 1.33) 0.13 1.13 (0.97, 1.31) 0.81 1.03 (0.81, 1.30)
NCI_Never smokers 0.002 1.34 (1.11, 1.61) 0.01 1.35 (1.07, 1.71) 0.33 0.74 (0.40, 1.35) 0.18 1.95 (0.70, 5.23)
Meta-analysis Unadjusted 1.60 × 10-10 1.12 (1.08, 1.16) 3.74 × 10-14 1.24 (1.17, 1.31) 0.69 0.99 (0.93, 1.05) 0.48 0.97 (0.89, 1.05)
rs31489, (C,A), 1395714, CLPTM1L, 0.411/0.385 NCI_Smoking Unadjusted 2.80 × 10-4 0.90 (0.86, 0.95) 0.067 0.93 (0.86, 1.00) 8.51 × 10-5 0.84 (0.77, 0.91) 0.089 0.90 (0.80, 1.01)
NCI_Current smokers 0.008 0.90 (0.83-0.97) 0.21 0.92 (0.82, 1.05) 0.0003 0.81 (0.73, 0.91) 0.22 0.92 (0.80, 1.05)
NCI_Never smokers 0.37 0.92 (0.77, 1.10) 0.45 0.92 (0.73, 1.15) 0.41 0.77 (0.41, 1.44) 0.76 1.15 (0.47, 2.85)
Meta-analysis Unadjusted 1.56 × 10−10 0.89 (0.86, 0.92) 0.005 0.92 (0.87, 0.98) 1.39 × 10−5 0.87 (0.81, 0.92) 0.024 0.91 (0.83, 0.99)
rs4635969, (C,T), 1361552, TERT, CLPTM1L, 0.199/0.184 NCI_Smoking Unadjusted 9.80 × 10−5 0.87 (0.82, 0.93) 5.49 × 10−5 0.81 (0.73, 0.90) 0.031 0.88 (0.79, 0.99) 0.055 0.86 (0.74, 1.00)
NCI_Current smokers 0.08 0.92 (0.83, 1.01) 0.02 0.82 (0.70, 0.96) 0.12 0.89 (0.77, 1.03) 0.20 0.89 (0.74, 1.06)
NCI_Former smokers 0.001 0.83 (0.74, 0.93) 0.006 0.80 (0.68, 0.94) 0.20 0.88 (0.72, 1.07) 0.11 0.77 (0.56, 1.06)
Meta-analysis Unadjusted 2.15 × 10−8 0.88 (0.84, 0.92) 6.39 × 10−6 0.83 (0.77, 0.90) 0.005 0.88 (0.80, 0.96) 0.20 0.92 (0.80, 1.05)
SNPs on Chromosome 15q25
rs12914385, (C,T), 76685778, CHRNA3, 0.386/0.452 NCI_Smoking Unadjusted 5.24 × 10−27 1.34 (1.27, 1.42) 3.93 × 10−14 1.36 (1.25, 1.47) 5.23 × 10−12 1.36 (1.24, 1.48) 3.76 × 10−8 1.38 (1.23, 1.55)
NCI_Current smokers 6.12 × 10−18 1.41 (1.31, 1.53) 2.88 × 10−8 1.42 (1.25, 1.61) 2.12 × 10−8 1.38 (1.23, 1.55) 4.28 × 10−7 1.43 (1.25, 1.65)
NCI_Former smokers 6.11 × 10−10 1.34 (1.22, 1.47) 5.65 × 10−7 1.38 (1.22, 1.57) 2.92 × 10−5 1.39 (1.19, 1.62) 0.05 1.27 (1.00, 1.61)
Meta-analysis Unadjusted 2.75 × 10−38 1.30 (1.25, 1.36) 3.32 × 10−18 1.31 (1.23, 1.40) 8.72 × 10−13 1.30 (1.21, 1.40) 2.31 × 10−9 1.37 (1.24, 1.52)
rs1051730, (C,T), 76681394, CHRNA5,CHRNA3, 0.348/0.413 NCI_Smoking Unadjusted 3.63 × 10−25 1.33 (1.26, 1.41) 4.21x10−14 1.36 (1.26, 1.47) 1.93x 10−9 1.31 (1.20, 1.43) 6.70 × 10−8 1.38 (1.23, 1.55)
NCI_Current smokers 1.30 × 10−17 1.42 (1.31, 1.53) 1.03x10−8 1.44 (1.27, 1.63) 4.7x10−7 1.34 (1.20, 1.50) 2.58 × 10−7 1.45 (1.26, 1.67)
NCI_Former smokers 3.66 × 10−8 1.30 (1.19, 1.43) 8.05x10-7 1.38 (1.21, 1.57) 0.0005 1.32 (1.13, 1.54) 0.13 1.20 (0.95, 1.54)
rs8034191, (T,C), 76593078, LOC123688, 0.352/0.414 NCI_Smoking Unadjusted 6.19 × 10−20 1.29 (1.22, 1.36) 1.61 × 10−10 1.30 (1.20, 1.40) 1.10 × 10−7 1.26 (1.16, 1.38) 1.31 × 10−5 1.29 (1.15, 1.45)
NCI_Former smokers 1.52 × 10−7 1.29 (1.17, 1.41) 1.33 × 10−5 1.33 (1.17, 1.51) 0.0004 1.32 (1.13, 1.54) 0.10 1.22 (0.96, 1.56)
Meta-analysis Unadjusted 2.18 × 10-46 1.29 (1.25, 1.34) 1.46 × 10−15 1.29 (1.21, 1.37) 3.37 × 10−9 1.25 (1.16, 1.34) 4.49 × 10−7 1.31 (1.18, 1.45)
Bold font indicates genome-wide significant results
Overall NCI Data: 5848 controls (2384 current, 2041 former,1402 never smokers), 5739 cases (3410 current, 1946 former, 362 never smokers). Meta-analysis: 19666 controls, 13300 cases
Adenocarcinoma NCI Data: 5848 controls (2384 current, 2041 former,1402 never smokers), 1730 cases (786 current, 731 former, 203 never smokers). Meta-analysis: 14933 controls, 3333 cases
Squamous Cell Carcinoma NCI Data: 5848 controls (2384 current, 2041 former,1402 never smokers), 1400 cases (953 current, 422 former, 23 never smokers). Meta-analysis: 14933 controls, 2589 cases
Small Cell Carcinoma NCI Data: 5848 controls (2384 current, 2041 former,1402 never smokers), 678 cases (516 current, 152 former, 9 never smokers). Meta-analysis: 13796 controls, 1418 cases
Most notable SNPs from the NCI GWAS and SNPs identified as relevant for lung cancer risk in previous studies are shown. The lung cancer cases in the Overall analyses include adenocarcinomas, squamous cell carcinomas, small cell carcinomas, and other groups of different histologic types or mixed histologies. The Overall meta-analyses include four NCI GWAS studies plus ten additional studies; the meta-analyses in the three major histologic types include four NCI GWAS studies plus four replication studies for the SNPs on chromosome 5p15 and three replication studies for the SNPs on chromosome 15q25. Results for each SNP are shown in this order: Top row (NCI_Smoking Unadjusted), results from the NCI GWAS data adjusted for age in five-year intervals (defined as age-at-diagnosis/interview for case-control study and age at baseline for cohort study), gender, study (EAGLE, PLCO, ATBC, CPS-II) and four principal components for population stratification within studies (two for PLCO, and one each for EAGLE and ATBC). Adjustment for the same variables plus smoking status (current, former, never), cigarettes smoked per day (≤10, 11–20, 21–30, 31–40, 41+), duration in ten-year intervals and number of years since quitting (1–5, 6–10, 11–20, 21–30, 30+) for former smokers showed virtually identical results (data not shown). Second row (NCI_Current smokers), results from the NCI GWAS data restricted to current smoker subjects, adjusted for the same variables of the top row. Third row (NCI_Former smokers), results from the NCI GWAS data restricted to former smoker subjects who quit smoking > 6 months prior to the study, adjusted for the same variables of the top row. Fourth row (NCI_Never smokers), results from the NCI GWAS data restricted to never smoker subjects who smoked < 100 cigarettes in their lifetime, adjusted for the same variables of the top row. Bottom row (Meta-analysis Unadjusted), results from the meta-analysis combining NCI GWAS data and ten additional studies, unadjusted models.
a NCBI dbSNP identifier.
b Major allele, minor allele.
c Chromosome and NCBI Human genome Build 36 location.
d Gene neighborhood within 20 kb upstream and 10 kb downstream of SNP.
e Minor allele frequency in controls/cases.
f 1d.f. Wald test.
g OR, per-allele odds ratio; CI, 95% confidence interval.
Figure 2Results of Association Analyses and LD Block for the 5p15.33 Locus by Histology
Association results are shown in the top panel for the NCI GWAS. Results of the meta-analysis combining the NCI GWAS and the additional four studies for rs2736100 in the adenocarcinoma histologic type are indicated by the purple diamond. Red circles indicate adenocarcinoma, blue triangles indicate squamous cell carcinoma, and green circles indicate small cell carcinoma. At the bottom, pairwise LD is depicted for 65 SNPs with minor allele frequency >5% in the 5p15.33 region extending from 1204161 to 1496199. The LD among pairs of SNPs was characterized on the basis of the square of the correlation coefficient (r2) with the use of EAGLE and PLCO controls of a European background (1997 from EAGLE and 859 from PLCO, totaling 2856 unrelated individuals). Regions with high r2 values are red, and regions with low r2 values are light yellow. The shade lightens with decreasing r2. The purple bar indicates the approximate location of the TERT gene.
In the NCI controls, rs2736100 is not in LD with other tested SNPs in the region (Figure 2), with the exception of rs2853676, which is in modest LD (r2 = 0.25, D′ = 0.82) and showed a similar pattern of association (OR = 1.16, p = 3.44 × 10−4; OR = 0.95, p = 0.30; and OR = 1.06, p = 0.41 for AD, SQ, and SC, respectively). In contrast, rs4635969 and rs31489 were associated with lung cancer risk across histology groups (Table 2). The previously reported SNPs in CLPTM1L, e.g., rs4975616, rs402710, and rs401681, which are in LD with rs31489 (r2 = 0.74, 0.63, and 0.85, respectively), showed associations similar to rs31489 (data not shown). rs31489 and rs4635969 are moderately correlated (r2 = 0.35, D′ = 0.95), but not in LD with rs2736100 (r2 = 0.03, D′ = 0.20 for rs31489; r2 = 0.07, D′ = 0.49 for rs4635969). In a multivariate model including the main effects of these three SNPs simultaneously, we found statistically independent associations with AD for both rs4635969 and rs2736100 (OR = 0.81, p = 0.002; OR = 1.21, p = 2.60 × 10−5) but not for rs31489 (OR = 1.03, p = 0.42). Only rs31489 was associated with SQ (OR = 0.82, p = 8.50 × 10−4) and no SNPs were associated with SC (data not shown) in the multivariate model.
In the meta-analysis, rs2736100 was the most notable SNP for lung cancer risk overall (OR = 1.12, 95% CI = 1.08–1.16, p = 1.60 × 10−10), followed by the same set of SNPs observed in the NCI GWAS (Table 2, larger list in Table S5). In analyses by histology, risk associated with rs2736100 was accounted for by cases with adenocarcinoma in each replication study (p < 0.05 in each study; p = 0.59, test for heterogeneity across studies) (Figure 3). Other histologies exhibited no association. In the meta-analysis combining the NCI GWAS data with the data from the Texas, deCODE, HGF, and UK studies, this SNP had OR = 1.24, 95% CI = 1.17–1.31, p = 3.74 × 10−14 for AD versus OR = 0.99, p = 0.69 and OR = 0.97, p = 0.48, for SQ and SC, respectively (Table 2).
Figure 3Forest Plot Showing Associations between the rs2736100 SNP and Lung Cancer Risk Both Overall and by Histologic Types
Left panel: (A) Association between rs2736100 and lung cancer risk in each study included in the NCI GWAS and in each additional study contributing to the meta-analysis. Right panel: (B) Association between rs2736100 and risk of adenocarcinoma, (C) squamous cell carcinoma, and (D) small cell carcinoma in the NCI GWAS and in each additional study contributing to the meta-analysis, stratified by histology. Individual studies (boxes) are plotted against the individual effect sizes (ORs). The size of the boxes is inversely proportioned to the variance. Horizontal lines indicate 95% CIs. The dashed vertical line in each panel shows the value for no effect (OR =1.0).
These findings provide evidence that the previously identified association of the rs2736100 variant on 5p15.33 with lung cancer risk
is confined to one histologic type, adenocarcinoma. Rs2736100 is located in intron 2 of TERT and, on the basis of the ESPERR score, lies within a putative regulatory region.
Taylor J.
Tyekucheva S.
King D.C.
Hardison R.C.
Chiaromonte F.
ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements.
TERT is a ribonucleoprotein that extends TTAGGG nucleotide repeats at the telomere, which shorten with each cell division. Telomere shortening is associated with increased genomic instability and, consequently, increased risk of cancer development.
Feldser D.M.
Hackett J.A.
Greider C.W.
Telomere dysfunction and the initiation of genome instability.
Nat. Rev. Cancer. 2003; 3: 623-627
In cancer cells, reactivated TERT is linked to cellular proliferation and abnormal telomere maintenance.
Fernandez-Garcia I.
Ortiz-de-Solorzano C.
Montuenga L.M.
Telomeres and telomerase in lung cancer.
J. Thorac. Oncol. 2008; 3: 1085-1088
Other studies have suggested that perturbations of TERT may contribute to the pathogenesis of lung adenocarcinoma. TERT expression has been reported to be significantly lower in adenocarcinoma than in any other histological type,
Lantuejoul S.
Soria J.C.
Moro-Sibilot D.
Morat L.
Veyrenc S.
Lorimier P.
Brichon P.Y.
Sabatier L.
Brambilla C.
Brambilla E.
Differential expression of telomerase reverse transcriptase (hTERT) in lung tumours.
Br. J. Cancer. 2004; 90: 1222-1229
and its reexpression may indicate progression from bronchiolo-alveolar carcinoma to adenocarcinoma.
Salon C.
Telomerase expression in lung preneoplasia and neoplasia.
Int. J. Cancer. 2007; 120: 1835-1841
viel-Ronen S.
Lau S.K.
da Cunha S.G.
Zhu C.Q.
Strumpf D.
Jurisica I.
Lam W.L.
Tsao M.S.
Genomic markers for malignant progression in pulmonary adenocarcinoma with bronchioloalveolar features.
Proc. Natl. Acad. Sci. 2008; 105: 10155-10160
TERT has been reported to promote epithelial proliferation,
Choi J.
Southworth L.K.
Sarin K.Y.
Venteicher A.S.
Ma W.
Chang W.
Cheung P.
Jun S.
Artandi M.K.
Shah N.
TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program.
whereas telomere maintenance has been implicated in the progression from KRAS-activated adenoma to adenocarcinoma in murine models.
Sweet-Cordero A.
Tseng G.C.
You H.
Douglass M.
Huey B.
Albertson D.
Jacks T.
Comparison of gene expression and DNA copy number changes in a murine model of lung cancer.
Genes Chromosomes Cancer. 2006; 45: 338-348
rs2736100 was recently found in association with lung cancer risk in two populations, with suggestive stronger associations in adenocarcinoma cases, female cases, and case individuals who had never smoked.
Jin G.
Xu L.
Shu Y.
Tian T.
Liang J.
Xu Y.
Wang F.
Dai J.
Hu Z.
Common genetic variants on 5p15.33 contribute to risk of lung adenocarcinoma in a Chinese population.
Carcinogenesis. 2009; 30: 987-990
Spitz M.R.
Houlston R.S.
Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study.
Cancer Res. 2009; 69: 6633-6641
Interestingly, rs2736100 has been reported to be associated with susceptibility to sporadic idiopathic pulmonary fibrosis (IPF),
Mushiroda T.
Wattanapokayakit S.
Takahashi A.
Nukiwa T.
Kudoh S.
Ogura T.
Taniguchi H.
Kubo M.
Kamatani N.
Nakamura Y.
A genome-wide association study identifies an association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis.
J. Med. Genet. 2008; 45: 654-656
Tsakiri K.D.
Cronkhite J.T.
Kuan P.J.
Xing C.
Raghu G.
Weissler J.C.
Rosenblatt R.L.
Shay J.W.
Garcia C.K.
Adult-onset pulmonary fibrosis caused by mutations in telomerase.
whereas rare mutations in TERT and consequent shorter telomeres are responsible for familial IPF.
Armanios M.Y.
Chen J.J.
Cogan J.D.
Alder J.K.
Ingersoll R.G.
Markin C.
Lawson W.E.
Xie M.
Vulto I.
Phillips III, J.A.
Telomerase mutations in families with idiopathic pulmonary fibrosis.
IPF is a lethal disease characterized by massive fibrotic changes and thickening of the alveolar walls in the lung. Members of IPF families frequently develop lung adenocarcinoma, suggesting that these two diseases share a common etiology.
Torres F.
DiMaio J.M.
Kinch L.N.
Grishin N.V.
Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer.
Am. J. Hum. Genet. 2009; 84: 52-59
Furthermore, telomerase dysfunction has been linked to leukemia, bone marrow failure, and cancer predisposition,
Vulliamy T.J.
Marrone A.
Knight S.W.
Walne A.
Mason P.J.
Dokal I.
Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation.
Blood. 2006; 107: 2680-2685
Yamaguchi H.
Calado R.T.
Ly H.
Kajigaya S.
Baerlocher G.M.
Chanock S.J.
Lansdorp P.M.
Young N.S.
Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia.
Regal J.A.
Hills M.
Yewdell W.T.
Dalmazzo L.F.
Zago M.A.
Hogge D.
Estey E.H.
Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia.
and other SNPs in the TERT-CLPTM1L region have been found in association with multiple cancer types,
suggesting that this region possesses a fundamental key for cancer development. rs2736100 and other SNPs in the locus are close to the location of known mutations that compromise telomerase activity (Figure 4) and may be in LD with mutations that have yet to be identified. Complete sequencing of this locus in adenocarcinoma patients would enable a more comprehensive understanding of the variants associated with this signal.
Figure 4Location of SNPs and Mutations in the TERT Gene
Exon and intron organization of the TERT gene, including the locations of rs2736100, rs2853676, and the known mutations (red asterisks) that compromise telomerase activity.
The NCI GWAS also refined other previously identified susceptibility loci.
The strongest evidence for association with lung cancer risk overall and with each histology group was observed for the 15q25.1 locus.
(nicotinic acetylcholine receptor genes), beginning with rs12914385 in CHRNA3 (MIM 118503) (OR = 1.34, 95% CI = 1.27–1.42, p = 5.24 × 10−27) (Table 2; top SNPs with p < 0.0001 in each histologic group are shown in Tables S6–S8). In the meta-analysis including the NCI GWAS and summary results from ten studies, the SNP with the lowest p value was rs1051730 in CHRNA5 (MIM 118505) (OR = 1.31, 95% CI = 1.27–1.36, p = 1.91 × 10−51), whereas rs12914385 had an OR = 1.30, 95% CI = 1.25–1.36, p = 2.75 × 10−38 (Table 2; a longer SNP list in given in Table S5). The same SNPs were also strongly associated with all major histology groups (Table 2).
There were 20 SNPs at this locus with p < 10−7 and 15 after adjustment for multiple smoking variables, suggesting that the association of these SNPs with lung cancer risk is not entirely explained by the association with smoking or that residual confounding by smoking cannot be completely ruled out. In the analysis of the NCI GWAS stratified by smoking status (Table 2), SNPs on 15q25 showed a very strong association in current and former smokers but no association in those who had never smoked, as previously observed in some,
Amos C.
Lin J.
The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer.
J. Natl. Cancer Inst. 2008; 100: 1552-1556
but not all,
studies. The interaction between these SNPs and smoking status was borderline significant (p = 0.07, p = 0.07, and p = 0.04 for rs12914385, rs1051730, and rs8034191, respectively).
We conducted an analysis stratified by decade of birth (<1930, 1930–1939, 1940–1949, and >1950) to explore whether the complex changes in cigarette composition and population trends in cigarette smoking affected the association between this locus and lung cancer risk. Most subjects in our study were born in the 1930s–1940s and began smoking approximately 15–20 years after birth. Thus, smokers were affected by the progressive adoption of cigarette filters and alterations in tar, nicotine, and nitrosamine content in cigarettes that began in the 1950s.
Hoffmann D.
Djordjevic M.V.
Hoffmann I.
The changing cigarette.
Prev. Med. 1997; 26: 427-434
For the top SNPs on 15q25, we observed a trend of increasing lung cancer risk with more recent decades of birth both overall and in each histology group, with the exception of the SQ cases (Table 3). Because widespread cigarette smoking generally began a few years later in Europe than in the U.S., we stratified the analyses between American (PLCO and CPS-II) and European (EAGLE and ATBC) studies. As expected, the American studies showed a slightly stronger association (data not shown).
Table 3Association of Selected SNPs on 15q25 Loci with Lung Cancer Risk by Decade of Birth in the NCI GWAS
< 1930 (No. of Controls = 1749)
1930–1939 (No. of Controls = 2113)
1940–1949 (No. of Controls = 696)
1950+ (No. of Controls = 190)
No. of Cases
1 d.f. Wald test.
P-value of interaction between SNPs and decade of birth in the association with lung cancer risk overall and in each histology stratum. 1d.f. Wald test (decade of birth coded as 0,1,2,3).
SmokAdj
rs12914385
Overall Smok.Unadj 2202 6.94 × 10−8 1.29 (1.18–1.41) 2173 6.94 × 10−12 1.35 (1.24–1.47) 594 2.49 × 10−5 1.42 (1.20–1.66) 155 2.60 × 10−5 1.94 (1.42–2.64) 0.02
Overall Smok.Adjust 2202 1.95 × 10−5 1.25 (1.13–1.38) 2173 5.11 × 10−7 1.28 (1.16–1.41) 594 2.08 × 10−4 1.44 (1.19–1.74) 155 3.91 × 10−4 1.98 (1.36–2.88) 0.04
Adenocarc. Smok.Adjust 541 0.012 1.21 (1.04–1.42) 683 8.33 × 10−5 1.31 (1.15–1.50) 270 0.004 1.42 (1.12–1.80) 84 0.001 2.10 (1.33–3.32) 0.03
Squamous Smok.Adjust 596 6.75 × 10−5 1.36 (1.17–1.58) 582 0.002 1.27 (1.09–1.47) 120 0.096 1.35 (0.95–1.92) 17 0.16 1.75 (0.80–3.85) 0.92
Small Cell Smok.Adjust 268 0.042 1.23 (1.01–1.50) 265 0.002 1.37 (1.12–1.67) 70 0.001 2.02 (1.31–3.09) 15 0.043 2.59 (1.03–6.51) 0.10
rs1051730
Overall Smok.Unadj 2202 9.26 × 10−7 1.27 (1.15–1.39) 2173 2.32 × 10−11 1.35 (1.23–1.47) 594 2.41 × 10−5 1.42 (1.21–1.68) 155 6.75 × 10−6 2.08 (1.51–2.86) 0.009
Squamous Smok.Adjust 596 9.27 × 10−4 1.29 (1.11–1.51) 582 0.002 1.26 (1.09–1.47) 120 0.32 1.20 (0.84–1.72) 17 0.053 2.23 (0.99–5.05) 0.79
Small Cell Smok.Adjust 268 0.11 1.18 (0.96–1.44) 265 0.002 1.38 (1.13–1.70) 70 7.02 × 10−4 2.12 (1.37–3.28) 15 0.018 3.23 (1.22–8.53) 0.02
Overall Smok.Unadj 2202 1.13 × 10−5 1.23 (1.12–1.35) 2173 2.60 × 10−8 1.23 (1.12–1.35) 594 2.70 × 10−5 1.42 (1.20–1.67) 155 1.10 × 10−5 2.01 (1.47–2.74) 0.007
Overall Smok.Adjust 2202 0.002 1.18 (1.06–1.30) 2173 5.67 × 10−5 1.22 (1.11–1.35) 594 5.73 × 10−4 1.40 (1.16–1.70) 155 1.56 × 10−4 2.09 (1.43–3.06) 0.01
Adenocarc. Smok.Adjust 541 0.13 1.13 (0.96–1.31) 683 0.001 1.25 (1.09–1.43) 270 0.002 1.45 (1.14–1.84) 84 0.005 1.92 (1.22–3.02) 0.01
Squamous Smok.Adjust 596 0.006 1.23 (1.06–1.43) 582 0.007 1.23 (1.06–1.43) 120 0.39 1.17 (0.82–1.67) 17 0.064 2.04 (0.96–4.35) 0.67
Small Cell Smok.Adjust 268 0.24 1.13 (0.92–1.38) 265 0.005 1.33 (1.09–1.63) 70 0.004 1.89 (1.23–2.91) 15 0.039 2.60 (1.05–6.44) 0.05
Most notable SNPs from the NCI GWAS and SNPs identified as relevant for lung cancer risk in previous studies are shown. The lung cancer cases in the Overall analyses include adenocarcinomas, squamous cell carcinomas, small cell carcinomas, and other groups of different histologic types or mixed histologies. Smoking Unadjusted results are adjusted for age in five-year intervals (defined as age-at-diagnosis/interview for case-control study and age at baseline for cohort study), gender, study (EAGLE, PLCO, ATBC, CPS-II), decade of birth (<1930, 1930–1940, 1940+, MISSING) and four principal components for population stratification within studies (two for PLCO, and one each for EAGLE and ATBC). Smoking Adjusted, results are adjusted for the same variables as above plus smoking status (current, former, never), cigarettes smoked per day (≤10, 11–20, 21–30, 31–40, 41+), duration in ten-year intervals and number of years since quitting (1–5, 6–10, 11–20, 21–30, 30+) for former smokers.
a 1 d.f. Wald test.
b OR, per-allele odds ratio; CI, 95% confidence interval.
c P-value of interaction between SNPs and decade of birth in the association with lung cancer risk overall and in each histology stratum. 1d.f. Wald test (decade of birth coded as 0,1,2,3).
One possible explanation for the increasing risk in more recent decades of birth is that the association of chromosome 15q25 SNPs with lung cancer risk is mediated in part by the increasing nitrosamine content in cigarettes over the second half of the 20th century.
Hecht S.S.
Tobacco smoke carcinogens and lung cancer.
J. Natl. Cancer Inst. 1999; 91: 1194-1210
Lally C.A.
Flannery J.T.
Flanders W.D.
Heath Jr., C.W.
Cigarette smoking and changes in the histopathology of lung cancer.
Carcinogenic nitrosamines are thought to bind to the nicotinic receptor,
Schuller H.M.
Orloff M.
Tobacco-specific carcinogenic nitrosamines. Ligands for nicotinic acetylcholine receptors in human lung cancer cells.
Biochem. Pharmacol. 1998; 55: 1377-1384
and carriers of the 15q25 locus are exposed to a higher internal dose of nitrosamines per cigarette than are noncarriers.
Le Marchand L.
Derby K.S.
Murphy S.E.
Hatsukami D.
Carmella S.G.
Tiirikainen M.
Wang H.
Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine.
No clear trend by decade of birth was observed for squamous cell carcinoma, possibly because this histologic type is more strongly associated with polycyclic aromatic hydrocarbons than with nitrosamines.
Sivaraman L.
Pierce L.
Seifried A.
Lum A.
Wilkens L.R.
Lau A.F.
Associations of CYP1A1, GSTM1, and CYP2E1 polymorphisms with lung cancer suggest cell type specificities to tobacco carcinogens.
However, these findings may be affected by small numbers in subgroups and should be further explored.
A recent study from the UK reported that the 6p21.33 locus is associated with lung cancer risk,
and a suggestive association for another SNP in the region (rs4324798 on 6p22.1) had been previously shown.
In the meta-analysis, SNPs at this locus were associated with lung cancer risk (Table S4). However, the association varied by study and was weak in the NCI GWAS and in the studies used in replicating the analysis by histology (Table S4). These SNPs are located near the major histocompatibility complex and thus could be markers for differences in population substructure.
In this study including over 30,000 subjects, no new genomic regions associated with lung cancer risk were identified. This contrasts with studies of other cancer types, such as breast, colon, and prostate cancers, which observed multiple common susceptibility loci in similar or smaller sample sizes.
Cox D.G.
Hankinson S.E.
Hutchinson A.
A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1).
Pittman A.M.
Di Bernardo M.C.
Lubbe S.
Chandler I.
Sullivan K.
Peneg S.
Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer.
Eeles R.A.
Kote-Jarai Z.
Giles G.G.
Olama A.A.
Guy M.
Jugurnauth S.K.
Mulholland S.
Leongamornlert D.A.
Edwards S.M.
Morrison J.
Multiple newly identified loci associated with prostate cancer susceptibility.
It is plausible that additional genetic variation for smoking-related cancers will be revealed through the investigation of interaction with tobacco smoking or structural variants. Our findings are based on subjects of European descent only; further work is necessary for the exploration of whether additional loci or different variants in the same loci are associated with lung cancer risk in distinct populations.
In conclusion, we have established that a locus on chromosome 5p15.33 is distinctly associated with risk of lung adenocarcinoma and not with the other major histologic types, providing evidence of histology-specific germ-line susceptibility for lung cancer risk. Defining the distinct hereditary contribution to histological subtypes and their interplay with tobacco smoking is a step on the pathway to the molecular characterization of cancer and could lead to improved measures for early detection or prevention.
The authors wish to thank: the participants and collaborators of EAGLE (listed on the EAGLE website); the staff of the Core Genotyping Facility—specifically Chenwei Liu, Amy Hutchinson, Aurelie Vogt, and Belynda Hicks; the National Center for Biotechnology for assistance with data cleaning; Justin Paschall and Mike Feolo for data manipulation; Teri Manolio and Bruce Weir for the GENEVA initiative; Adam Risch of Information Management Services, Inc. for database support; all participants in the CPS-II Nutrition Cohort; the LUCY-consortium (detail in Sauter et al. 2008
); the KORA study group and H. Dienemann, P. Drings, and the staff at the Thoraxklinik Heidelberg for the German study; the participants of the Nord Trondelag Study and the Tromso Study in Norway; and Steve Narod and Frances Shepherd for the Canadian study. K.S., P.S., G.T., and T.R. are employees and shareholders of deCODE Genetics. A list of funding agencies can be found in the Supplemental Data.
Document S1. Supplemental Acknowledgments, Five Figures, and Four Tables
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Table S5. Results of Meta-Analysis Including NCI GWAS Data and Data from Ten Additional GWASs
Table S6. Top SNPs in the Adenocarcinoma Cases from the NCI GWAS
Table S7. Top SNPs in the Squamous Cell Carcinoma Cases from the NCI GWAS
Table S8. Top SNPs in the Small Cell Carcinoma Cases from the NCI GWAS
The URLs for data presented herein are as follows:
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), http://atbcstudy.cancer.gov
Cancer Prevention Study overview, http://www.cancer.org/docroot/RES/content/RES_6_2_Study_Overviews.asp
Cancer Genetic Markers of Susceptibility (CGEMS) portal, http://cgems.cancer.gov/
Core Genotyping Facility (CGF), http://cgf.nci.nih/gov/
CGF sample handling and quality control, http://cgf.nci.nih.gov/operations/sample-handling.html
dbGaP, http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gap
EIGENSTRAT, http://genepath.med.harvard.edu/∼reich/EIGENSTRAT.htm
The Environment and Genetics in Lung Cancer Etiology (EAGLE), http://eagle.cancer.gov
ESPERR score, http://genome.ucsc.edu
The Estonian Genome Project, www.geenivaramu.eeresources/groups/ed/programs/plco
GENEVA data set, http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gap
Genotype Library and Utilities (GLU), http://code.google.com/p/glu-genetics/
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/
The Prostate, Lung, Colon, Ovary Screening Trial (PLCO), http://prevention.cancer.gov/programs
SNP500Cancer, http://snp500cancer.nci.nih.gov/
STRUCTURE, http://pritch.bsd.uchicago.edu/structure.html
Tagzilla, http://tagzilla.nci.nih.gov/
Accepted: September 22, 2009
Received in revised form: September 4, 2009
DOI: https://doi.org/10.1016/j.ajhg.2009.09.012
© 2009 The American Society of Human Genetics. Published by Elsevier Inc.
Landi et al.
The American Journal of Human GeneticsJune 10, 2011
(The American Journal of Human Genetics 85, 679–691; November 13, 2009)


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EE is a relatively new mobile network to hit the UK centre stage. Combining the vast Orange network with the sizeable T-Mobile, they have quickly become the largest network in the UK, which is pretty good work considering how long some of the other networks have been kicking about. So what is their secret to success? Well, simply put, EE know how to get themselves out there. They know how to get recognised. How many of us use a two for one code every Wednesday to go see the latest film in the cinema or get two Pizza Express pizzas for the price of one? The answer to that is evident as Wednesday is now the day where you need to book to see a film and eat at Pizza Express because crowds of EE'ers flock there after work.
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