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April 10, 2019 Movies » Movie Reviews & Stories
Florida Film Festival programmers balance quality and variety in choosing the best
By Cameron Meier
It sounds like a joke: How do you whittle 2,015 submitted films down to just 184? The punchline: carefully.
But for Florida Film Festival Programming Director Matthew Curtis and Programming Coordinator Tim Anderson, it's no joke. It's their job.
"It's not easy," Curtis understates. "You know, it's something that we kind of have an innate sense of how to balance a program, how to order a program, what we like in each section of the festival. ... One of the tag lines long ago of the festival was 'films for everyone.' And we've always prided ourselves on having as eclectic and diverse a slate as possible. So it is a kind of juggling act and a balance. There are always really good films that fall by the wayside because we have too many of those type of films."
Speaking of pride, Curtis and Anderson brag that 47 percent of this year's films are directed by women, with one shorts program devoted exclusively to female directors. But just as they sometimes sacrifice quality to balance subjects, do they sacrifice quality to create other types of balance?
"No. It's the easiest no I'll ever have to answer," Anderson says. "Quality trumps everything. The fact that we keep breaking the record [of number of female filmmakers] is total happenstance. We didn't set out to do it. ... It is 100 percent happening organically."
But what about Florida flicks? After all, this is the Florida Film Festival. Well, everything being equal, Curtis and Anderson admit they might give extra credit to homegrown movies. But they also stress that this is an international event.
"Let's say everything was exactly identical about [two competing] movies, we'd be programming the one from Florida," Anderson says. "[But] your film [is accepted] based on its quality and not based on an ancillary item about it, which I think maybe is a misconception because we are called the Florida Film Festival: that somehow we're uniquely responsible for playing films that are made here. ... But like we would not sacrifice quality to put a female filmmaker ahead of a male filmmaker, we essentially would not necessarily sacrifice quality to put a Florida filmmaker above, you know, a filmmaker from Iowa. ... A lot of times it really breaks our heart."
Knowing they beat out filmmakers from around the globe surely made acceptance all the more gratifying for UCF professors Lisa Mills and Robert Cassanello, who co-directed Marching Forward. The world-premiere documentary explores segregation in 1960s Orlando and joins Pahokee (a coming-of-age documentary set in the Florida Everglades) as this year's "Florida Features."
And new to the festival in 2019 is "Sunshine & Swampland: New Florida Shorts," a collection of 10 Florida shorts, half receiving their world premiere. The program replaces "Best of Brouhaha," which was a favorite among locals because it included winners of the Enzian's monthly FilmSlam competitions. Its elimination was not without controversy, but Anderson says the change was made mostly to allow the festival to select the best films. (Other movies by filmmakers with Florida connections are scattered through the festival too, notably in the Midnight Shorts program.)
Helping Curtis and Anderson are their committee members, who work without pay, though they do receive perks, including free Enzian membership. One such volunteer, Kate Shults – filmmaker, curator and lecturer at the University of Central Florida – sits on the domestic narrative features and experimental shorts committees.
"Each committee is sent every single film submitted for that particular category, and we watch them all!" Shults says. "For about two to three months, I will watch 10 feature films every week. Some committees meet, watch and discuss the films together. Other committees work remotely, then have one very long meeting where we debate and fight for the films we feel strongly about programming.
"Unique and underrepresented perspectives are very important to me as a programmer. I look for films with stories that are subtle and complex. I like a film with a confident style that makes sense for the film and isn't just an unrevised copy of something else. But I think everyone can relate to the sentiment that when you see a good film, you just feel it. Guts and hearts are definitely part of the process."
Because Charles Sutter sits on both the documentary features and documentary shorts committees, he saw around 600 shorts and 280 features. And the toughest task, he says, was cutting those doc features down to a shortlist of just 25.
"This year was a strong year," says Sutter, who is both a filmmaker and online instructor for the LA Film School. "That makes sense when things are a little politically turbulent. Documentaries are more interesting."
But regardless of the quality in a given year, Sutter says the process is more a group effort than a personal crusade.
"I try not to make it about myself, like these are my tastes, this is what I want, this is what I think should be in the festival," he says. "In terms of coming up with those 25 movies that we can all agree on ... there are a couple of different kinds of criteria that we use to get there [such as] how well did this movie execute its own goals."
Though Curtis and Anderson rely on Shults, Sutter and another 19 people across nine committees, they watch about 600-700 films themselves. That's especially impressive considering Curtis has been involved since the festival's debut in 1992. So what keeps him going?
"I think I'm a fairly patient person and fairly even-keeled," Curtis says.
"Oh, God, he's very patient," Anderson interjects, adding that they both have more than their share of OCD.
"I get an awful amount of pleasure and take an incredible amount of pride in bringing the best films I can to this community," Curtis continues. "And I'm kind of really happy I've been given this opportunity to be in such a unique situation. You know, I still love it. And how many people can say that after doing the same job for decades?"
Tags: Movie Reviews & Stories
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Adopted on December 15, 1791, the Second Amendment of the Bill of Rights protects the right of the people to keep and bear arms. As the source of countless debates, this amendment has been saddled politically, however, time and time again the Supreme Court continues to uphold that this right belongs to individuals and is not to be infringed. George Washington himself is emblazoned on this medal with a declaration to those who would be armed in the defense of this nation, demanding discipline, which cannot be argued by any reasonable or rational person.
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GitHub - cmendible/AzureBus: Inspired by the simple EasyNetQ API, this library helps you get started with Microsoft Azure Service Bus or Service Bus 1.1 for Windows Server pub/sub and queues!
Inspired by the simple EasyNetQ API, this library helps you get started with Microsoft Azure Service Bus or Service Bus 1.1 for Windows Server pub/sub and queues!
Want to be notified of new releases in cmendible/AzureBus?
// Publish a sample message.
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CAN A WOMAN BE PROUD OF HER EFFECT ON MEN?
In my mid-20s, I was an active young woman who liked music, parties, good movies, and hoped to get married to a man who would love me for the rest of my days. But as years went by, I was increasingly unhappy with my life. After trying work as a secretary and a waitress, and two important relationships failed, I decided to go to college to study something I might really like to do: design clothing. I had liked sewing outfits for myself and others, and later earned good grades at the Fashion Institute of Technology, where I learned about some of the beautiful fabrics and garments of the past and present.
And she described how the phrase "It fits like a glove" is about that garment and you, but also says something so large about how reality can fit you. It never occurred to me to be grateful that the world provided materials to make clothing--like the earliest made of grass fibers, and later made of fabrics woven from spun threads--or to respect the people who made them.
I'll speak now of what I learned, and of a very good, very influential American designer of the early to mid 20th Century, Claire McCardell. And as I talk about how women can use clothes and fashion to be proud of our effect on men, I also have to say that it is horrible and unnecessary that millions of people in our rich nation can't afford to have decent, attractive, well-made clothing to wear!
1. What Interferes With Being Proud of Our Effect on Men?
My answer was, "Superior." And I came to see that that hurtful desire began early in my life. There were times, for instance, when after shopping for a new holiday dress and shoes, my mother would ask me to "model" them for my father, and to thank him. But what was more important to me was how he would say "Ohhhh, you look beautiful" than being grateful for his hard work which enabled me to have them.
Clothing should be a means of relating ourselves accurately to the outside world, or showing ourselves honestly....[but] people so often use clothes really to hide who they are and to put forth something that will impress and fool people; that is contempt, and is a big reason people are excessive about clothes.
I feel so described by these sentences! There were times I had great pleasure in finding or making an outfit that had me feel "This is me!" And I once stayed up all night to make an outfit for my sister to wear for a special occasion, when she didn't have money to buy one.
But many times I used clothing to impress and fool men, without knowing how much it made me ashamed. Women the world over need to know what Miss Reiss writes further in her commentary: "And, of course, women have used clothes as weapons, to weaken men."
When out on a date, I often dressed in a flirtatious manner in some of the daring clothes of the day: tight tops and hot pants, or a low-cut jumpsuit. One summer my boyfriend, John, and I drove to Canada to see the Montreal Expo. After visiting several exhibits, I was surprised when he said he thought my outfit was too revealing, and that he was uncomfortable with how other men were looking at me. I dismissed his feeling as being old-fashioned: I was a modern, liberated woman, and thought: "If men can't keep up with evolution and accept woman's new freedom of expression, it's their problem." But I wasn't proud of this attitude because I was looking for a cheap victory as I arranged to turn men's heads toward me, and not at the exhibits of countries from around the world. And as I think of that outfit now, I see it did not have a beautiful relation of the opposites of tightness and looseness, hidden and shown, and didn't encourage people's respect for women.
Today, many styles are even more revealing, such as skimpy tops showing bare torsos, and the low cut pants I see on girls in the high school where I work. Many of these states of undress are promoted by music videos and designers as the most avant garde fashions But with all the bold and surprised-how-they-stay-on kinds of garments women wear, it is simply a fact of reality that when we use anything—money, education, love, or clothing— to have contempt for the world and people, we have to be ashamed.
Aesthetic Realism certainly doesn't tell people how to dress, or say women should look like prudes. But it does teach that we have an ethical unconscious, and we judge ourselves for how fair we are to the world, in everything we do. This knowledge is more precious than gold--what women and clothing designers are hoping for.
and like himself for how he is pleased? Because most men don't.
It means so much to me to that I had been learning to see a man as representing the universe when I first met Jeffrey Williams, who is now my husband. While working on this paper, he reminded me of how I told him then that I hoped to dress in a way that would have people feel the world looked good to them. He felt it important for me to relate what a good effect hearing this had on him--that he had never heard anything like it, and would never forget it.
In the 1920's, the new direction in fashions also affected a young woman, who became one of the first designers promoted as having "The American Look": Claire McCardell. And as I say some of why her work is still widely respected, I'm not in any way saying that this is the style women should follow to feel proud of their effect on men, but as a means of illustrating the Aesthetic Realism principles I've described.
I use a book about her life and work, Claire McCardell: Defining Modernism, written by Kohle Yohannan and Nancy Wolfe in conjunction with F.I.T. Born May 24, 1905 in Frederick, Maryland, Claire McCardell grew up in privileged surroundings, and was affected early by the fashions her mother had made by a personal dressmaker.
After attending a local college in Maryland for two years, she finally convinced her parents to send her to New York City to study fashion design in the spring of 1925. This happens to be the same time that Eli Siegel's article on the new styles appeared in The Baltimore American, and I wouldn't be surprised if she read it.
It is this philosophy that led Ms. McCardell's designs to be loved by many thousands of women, and for her to be called "the designer for Mrs. America." She was also among the first designers to popularize separate, coordinated pieces, now called "sportswear", and was widely admired for creating practical, affordable, attractive styles--many of which are still popular today.
Diaper Suit, Vogue 1944 This is a magazine photo of the "Diaper Suit" first introduced by McCardell in the 1930s, but was not widely popular until the 1940s. While it may not appeal to every woman's figure or taste, I think it shows "the beauty of [a woman's] body with as little perceptible effort as possible." And it certainly has met the hopes of women for over 60 years now, as I saw styles just like it on the racks last spring.
swimsuit encourage a man to be more interested in the world, or have him focus exclusively on me?"
Claire McCardell will be remembered by students of fashion for many more innovations than I can show tonight, including her deep commitment to using America's mass-production capabilities to provide millions of women with stylish, affordable clothing. This is McCardell's own gouache rendering of her immensely popular day dress called "the Pop-over" of 1943: a denim, wrap-front with an attached oven mitt! And while women today don't usually wear a dress for chores, it could be asked: could we be proud of our affect on a man, children, or a roommate by going around in something looking fresh and energetic.
Eli Siegel is the historian and sociologist who did use fashions to see how the world changes, and to understand the deepest hopes of people, of women and men--and I am so glad he did!


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Home » NAA Sues CDC, Seeks Halt of Eviction Moratorium
NAA Sues CDC, Seeks Halt of Eviction Moratorium
The National Apartment Association (NAA) has joined a lawsuit filed by the New Civil Liberties Alliance (NCLA), challenging the U.S. Centers for Disease Control and Prevention's (CDC) overreaching eviction moratorium order. The complaint, Richard Lee Brown, et al. v. Secretary Alex Azar, et al., includes several plaintiffs alongside NAA who have been directly and irreparably damaged by the CDC order and have faced significant economic damages. NCLA has also requested a temporary restraining order, also known as a preliminary injunction, asking the court to stop the CDC from enforcing their unlawful order.
While the CDC has an inherent interest in slowing and preventing transmission of communicable disease, the eviction moratorium order does not fall under their purview and overrules state laws throughout the country that protect both protect rental housing providers and their residents. The lawsuit challenges the CDC's authority to enact such an order, as they have not identified an act of Congress that gives them this authority. Put simply, federal agencies do not have powers to waive state laws and the CDC has encroached on private property rights with no legal authority.
In many cases, rent debt from earlier in the pandemic has become uncollectable and the CDC order has limited housing owners and managers from providing contracted services to tenants who have paid their rent and paying financial obligations like taxes, mortgages, payroll and insurance. This jeopardizes the short- and long-term viability of the rental housing industry, and the CDC is not equipped to solve the housing crisis that they are creating. They do not have the authority or knowledge to insert themselves into property owner/resident regulations and housing policy that could devastate our nation's already limited housing supply, and the order tries to force a federal one-size-fits-all approach to a hyper-localized state and local issue.
Throughout the COVID-19 pandemic, NAA has advocated for direct, emergency rental assistance – a sustainable, responsible policy that will help keep Americans in their homes and ensure housing providers can pay their bills. However, because Congress and the Administration have failed to reach the agreement necessary to protect America's renters and housing providers from the certain damage of the CDC order, NAA had no choice but to take legal action.
In addition to this suit, NAA is committed to challenging the CDC's illegal order in a number of lawsuits in different areas of the country. NAA will keep members apprised as this rapidly evolving situation continues to develop. The rental housing industry should not be held solely responsible for solving our nation's housing crisis, which has been exacerbated in this pandemic, and government agencies should not trade one crisis for another.
Inauguration Activities Include Nationwide Building Lighting Ceremony to Honor Americans Lost to COVID-19.
The Presidential Inaugural Committee (PIC) is hosting a nationwide memorial to remember and honor the lives lost to COVID-19 on Tuesday, January...
Read Moreabout Inauguration Activities Include Nationwide Building Lighting Ceremony to Honor Americans Lost to COVID-19.
Learn More about Trending Issues in NAA's Policy Outlook
The National Apartment Association (NAA) is unveiling a new resource that includes insights from the NAA Government Affairs staff about...
Read Moreabout Learn More about Trending Issues in NAA's Policy Outlook
New Research Will Affect Industry Advocacy and Fair Housing Enforcement
As we all experienced in 2020, 2021 begins with more uncertainty in American life. Congress extended the CDC eviction moratorium order until...
Read Moreabout New Research Will Affect Industry Advocacy and Fair Housing Enforcement
NAA Joins Lawsuit Challenging CDC National Eviction Moratorium
ARLINGTON, VA | September 18, 2020 – The National Apartment Association (NAA) today joined the New Civil Liberties Alliance (NCLA) in their lawsu...
State of Play: Federal Eviction Moratorium Muddies State and Local Landscape
The public health crisis caused by COVID-19 and the policy response at all levels of government has severely affected the apartment industry,...
Trump Signs Executive Order on Housing, No Eviction Moratorium
On August 8, President Trump signed four executive actions directing federal agencies to provide additional relief to those affected by the COVID-19...
CDC Issues Guidance, Apartment Industry Concerns Heard
On the evening of October 9, the U.S. Centers for Disease Control and Prevention (CDC) issued answers to frequently asked questions to supplement...
CDC Eviction Moratorium Update
On September 1, 2020, the U.S. Centers for Disease Control and Prevention (CDC) filed an order in the Federal Register to temporarily...
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Sanders, Warren spar over disputed remark about chances of a woman defeating Trump
John Whitesides and Tim Reid
DES MOINES — Elizabeth Warren and Bernie Sanders disagreed in a Democratic presidential debate on Tuesday over whether he once told her a woman could not win the White House in 2020, underlining an emerging rift between the progressive allies as the first voting nears.
After days of tensions between the fellow U.S. senators, friends and liberal standard-bearers, who agreed early in the campaign not to attack each other, Sanders emphatically denied he ever made the remark, saying it was "incomprehensible" he could have said such a thing in a private 2018 meeting with her.
Warren confirmed the comment and said she disagreed with Sanders, but quickly pivoted to the broader question of whether a woman could be elected president.
"Bernie is my friend and I am not here to try to fight with Bernie. But look, this question about whether or not a woman can be president has been raised and it's time for us to attack it head-on," Warren said.
The dispute brought questions about gender, sexism and electability back into the spotlight in the campaign, almost four years after Democrat Hillary Clinton failed in her bid to become the first woman president, in an upset loss to Republican Donald Trump.
Warren pointed out the men on the stage had collectively lost 10 elections, while the two women on the stage – she and U.S. Senator Amy Klobuchar – had won each election they had contested.
"I have won every race, every place, every time, I have won in the reddest of districts, I have won in the suburban areas, in the rural areas," Klobuchar said, pointing to the 2018 election of women governors in conservative states as further evidence a woman can win the White House this year.
The rare clash between Warren and Sanders came as recent opinion polls show her trailing him nationally and in early nominating states just weeks before Iowa voters kick off the Democratic nominating race on Feb. 3.
The debate also featured sharp exchanges between Sanders and former Vice President Joe Biden on foreign policy and trade as the top Democrats made their case to voters assessing an unsettled presidential field with no clear front-runner.
The debate was the seventh in the race to find a November election challenger to Trump. Polls show an extremely tight race among Biden, Sanders, Warren and former South Bend, Indiana, Mayor Pete Buttigieg.
Sanders, a longtime antiwar advocate who voted against the 2002 authorization of war in Iraq, criticized Biden for supporting the war and said they heard the same arguments from officials in former President George W. Bush's administration before coming to different conclusions.
"I thought they were lying, I did not believe them for a moment," Sanders said. "I did everything I could to prevent that war. Joe saw things differently."
Biden, a former chairman of the Senate Foreign Relations Committee who touts his security credentials, acknowledged the vote "was a big, big mistake" and said that as President Barack Obama's vice president, he worked to bring the troops home.
"It was a mistake to trust that they weren't going to go to war," Biden said of the Bush administration. "It was a mistaken vote, but I think my record overall on everything we have done, I'm prepared to compare it to anybody's on this stage."
'FUNDAMENTAL DIFFERENCE' ON TRADE
On trade, Sanders said he and Biden had "a fundamental difference" on the worth of regional free trade agreements like Trump's new agreement with Mexico and Canada, called the USMCA, which Sanders opposes and Biden backs.
"I don't know that there's any trade agreement that the senator would ever think made any sense," Biden said.
Sanders said the agreements "were written for one reason alone, and that is to increase the profits of large multinational corporations."
With surveys showing a virtual tie in Iowa and a largely undecided electorate, all the candidates face mounting pressure to make an impression.
The debate stage was the least crowded since the debates began in June, with the Democratic National Committee's toughened polling and fundraising requirements to qualify eliminating other candidates.
Entrepreneur Andrew Yang, an Asian American who participated in last month's seven-candidate debate, did not make the cut this time, leaving an all-white field of debaters in a party that prides itself on diversity.
Billionaire activist Tom Steyer had qualified for the debate late after a spending surge in Nevada and South Carolina produced strong poll showings that helped him make the cut.
The Iowa debate was the first of four to be held in slightly more than a month as the first four states kick off the voting in February. The next debate will be Feb. 7 in New Hampshire, followed by debates on Feb. 19 in Nevada and Feb. 25 in South Carolina. (Reporting by John Whitesides and Tim Reid; Additional reporting by Michael Martina, Ginger Gibson and Amanda Becker; Editing by Soyoung Kim and Peter Cooney)


A young man longs to test himself in ways his comfortable suburban life will not permit.
A north wood's rabbit hunt becomes a crucible in which a man examines the course his life has taken.
A woman's memories of childhood abuse threatens her marriage.
A businessman uses his youthful love of baseball to remake his life.
An old man visits the scene of a story that has haunted him throughout his life.
Reflecting the unique insights of an engineer who began writing fiction late in life, these and the other stories in Donald Lystra's SOMETHING THAT FEELS LIKE TRUTH take us on a page-turning journey through the American heartland to as far away as Paris. In fierce but tender prose, Lystra writes about ordinary people navigating life's difficult boundaries---of age and love and family---and somethings finding redemption in face face of searing regret. Although spanning half a century, these are timely stories that speak about the limits we place on ourselves, both from fear and for the sake of those we love, and of our willingness to confront change.
SEASON OF WATER AND ICE is the unforgettable story of two young people confronting life during a tumultuous few months of 1957. In quiet but searing prose, it explores the timeless issues of love and family, the destructive forces to which these ideals are exposed, and the healing powers which can restore them.
Reflecting the political and social climate of the 1950s, Season of Water and Ice is underscored by themes of independence and obligation, love and sexuality, courage and surrender.
"Lystra's graceful prose is evocative of place and time....This is a rich and satisfying read."
"The north woods of Michigan in 1957 proves rich emotional ground for Lystra's quietly impressive debut novel."
"This is a love story of a most unusual kind....There is a kind of innocence...that has not been so effectively portrayed since Salinger invented Holden Caulfield. Lystra's style is spare and direct and yet profoundly evocative....An absolutely stunning debut."


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Godfather of Soul vs. Bad Boys of Rock
The T.A.M.I. (Teenage Awards Music Intenational) Show was a concert documentary that combined footage from two concerts held in Santa Monica, California in October 1964. The concerts were attended mostly by local high school students, who had been given free tickets to the show, and were headlined by a mix of white pop and rock-and-roll artists and black R&B and soul musicians.
One of the most celebrated performances in the concerts was that of James Brown and his band, the Famous Flames. There had been a backstage conflict just moments earlier between Brown and the Rolling Stones over who would go last. The Stones prevailed, and Brown, before going onstage, supposedly said, "Watch this, y'all."
Watch it here.
James Brown's performance
in its most thrilling, compressed, erotic, explosive form, just eighteen minutes long, is also arguably the most electrifying performance in the history of postwar American music.
. . . The Stones had come to the States from England determined to play black R. & B. for a mainly white audience that did not know its Son House from its Howlin' Wolf. They were already stars, and the T.A.M.I. producers had them scheduled to close the show. James Brown did not approve. "Nobody follows James Brown!" he kept telling the show's director, Steve Binder. Mick Jagger himself was hesitant. He and Keith Richards were boys from Kent [England] with an unusual obsession with American blues. They knew what Brown could do. In Santa Monica, they watched him from the wings, just twenty feet away, and, as they did, they grew sick with anxiety.
Brown, who had played the Chitlin Circuit for years, was genuinely incensed that the producers would put him on before pallid amateurs (in his mind) like the Stones. His performance, he later admitted, was a cutting contest that he refused to lose. As Brown puts it in his memoir, "James Brown: The Godfather of Soul," "We did a bunch of songs, nonstop, like always. . . . I don't think I ever danced so hard in my life, and I don't think they'd ever seen a man move that fast." . . .
Brown [said] that the T.A.M.I. performance was the "highest energy" moment of his career: "I danced so hard my manager cried. But I really had to. What I was up against was pop artists—I was R. & B. I had to show 'em the difference, and believe me, it was hard. . . It's a Holiness feeling—like a Baptist thing . . . It's a spiritual-background thing. You're involved and you don't want to quit. That's the definition of soul, you know. Being involved and they try to stop you and you just don't want to stop."
. . . [Keith] Richards would eventually say that the very idea of following James Brown was the biggest mistake of the Stones' careers.
You can see the results here.
In the 1991 Irish film "The Commitments," set in the working-class neighborhood of North Dublin in the 1960s, an Irish soul fan tries to put together an American-style soul band. He shows his skeptical bandmembers a clip of James Brown's T.A.M.I. performance, and tells them that, as the "Blacks of Europe," they should be able to relate:
cross-cultural encounters, cultural appropriation, James Brown, MUS 113, R&B, Rock, Soul, Uncategorized


Here is a gorgeous, attractive and soft teddy bear basket that can impress anyone who receives it.
Here is a gorgeous, attractive and soft teddy bear basket that can impress anyone who receives it. Be it friendship day, your anniversary, valentine's day or someone's birthday, this gift is bound to steal the heart of the recipient. Not only that, this special addition is also going to enhance the aesthetics of any space where you keep it by making it clutter-free and more organised. So pamper your loved and dear ones with this amazing teddy bear basket today.


Today is the birthday of Alexandra Isles, the original "Victoria Winters" on DARK SHADOWS. It's usually not the kind of occasion I'd recognize here, but a photo crossed my desk involving the former actress that's just too good to not share.
It's nice to see that Alexandra turned out to be such a happy, well-adjusted person given the sketchy characters she grew up with.
The CHS scores two Rondo nominations!


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Home » Fairfax County, VA News » Police: Teen's ex-boyfriend says…
Police: Teen's ex-boyfriend says he strangled her in Fairfax Co. park
Dan Friedell
At a preliminary hearing, Nebuyu Ebrahim told a detective that he expected to have an argument with his ex-girlfriend Jholie Moussa that January afternoon, but the encounter turned deadly.
WASHINGTON — Jholie Moussa was missing for two weeks in January before her body was finally found Jan. 26 in a shallow grave covered with leaves close to a walking path in Fairfax County's Woodland Park.
Now, according the recent testimony of county police detective Brian Byerson, police know how she got there.
Nebuyu Ebrahim, Moussa's 17-year-old ex-boyfriend who was arrested and charged with her murder over the summer, told Byerson Friday at a preliminary hearing that he expected to have an argument with his ex-girlfriend that January afternoon, but when Moussa stumbled, he grabbed her and placed her in a chokehold.
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At that point, according to the detective's testimony reported by The Washington Post, Moussa lost consciousness and Ebrahim, now 18, choked her two more times to ensure she was dead.
The hearing took place in juvenile court, but the judge decided to forward the first-degree murder case on to a grand jury who will consider Ebrahim an adult. If he is found guilty, he could face life in prison.
Earlier this year, Moussa's aunt, Veronica Eyenga, told WTOP that knowing more about what happened to her niece on the day of her death doesn't make things easier. "If anything, it just makes it harder because now we're learning facts and details that we just never wanted to ever imagine in our lives," she said.
Eyenga started a nonprofit called Not a Runaway, whose aim is to help provide resources for teens who may be in abusive relationships.
WTOP's John Domen contributed to this report.
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RESEARCH DESIGN AND METHODS
Genetics| July 08 2009
A Systematic Meta-Analysis of Genetic Association Studies for Diabetic Retinopathy
Sotoodeh Abhary;
Sotoodeh Abhary
1Department of Ophthalmology, Flinders Medical Centre and Flinders University, Bedford Park, SA, Australia;
Alex W. Hewitt;
Alex W. Hewitt
2Centre for Eye Research Australia, Melbourne University, Melbourne, Victoria, Australia.
Kathryn P. Burdon;
Kathryn P. Burdon
Jamie E. Craig
Corresponding author: Jamie Craig, jamie.craig@flinders.edu.au.
Diabetes 2009;58(9):2137–2147
https://doi.org/10.2337/db09-0059
Sotoodeh Abhary, Alex W. Hewitt, Kathryn P. Burdon, Jamie E. Craig; A Systematic Meta-Analysis of Genetic Association Studies for Diabetic Retinopathy. Diabetes 1 September 2009; 58 (9): 2137–2147. https://doi.org/10.2337/db09-0059
Diabetic retinopathy is a sight-threatening microvascular complication of diabetes with a complex multifactorial pathogenesis. A systematic meta-analysis was undertaken to collectively assess genetic studies and determine which previously investigated polymorphisms are associated with diabetic retinopathy.
All studies investigating the association of genetic variants with the development of diabetic retinopathy were identified in PubMed and ISI Web of Knowledge. Crude odds ratios (ORs) and 95% CIs were calculated for single nucleotide polymorphisms and microsatellite markers previously investigated in at least two published studies.
Twenty genes and 34 variants have previously been studied in multiple cohorts. The aldose reductase (AKR1B1) gene was found to have the largest number of polymorphisms significantly associated with diabetic retinopathy. The z−2 micro satellite was found to confer risk (OR 2.33 [95% CI 1.49–3.64], P = 2 × 10−4) in type 1 and type 2 diabetes and z+2 to confer protection (0.58 [0.36–0.93], P = 0.02) against diabetic retinopathy in type 2 diabetes regardless of ethnicity. The T allele of the AKR1B1 promoter rs759853 variant is also significantly protective against diabetic retinopathy in type 1 diabetes (0.5 [0.35–0.71], P = 1.00 × 10−4), regardless of ethnicity. These associations were also found in the white population alone (P < 0.05). Polymorphisms in NOS3, VEGF, ITGA2, and ICAM1 are also associated with diabetic retinopathy after meta-analysis.
Variations within the AKR1B1 gene are highly significantly associated with diabetic retinopathy development irrespective of ethnicity. Identification of genetic risk factors in diabetic retinopathy will assist in further understanding of this complex and debilitating diabetes complication.
Diabetic retinopathy is a sight-threatening microvascular complication of diabetes. Global population–based data indicate that it is the fifth most common cause of blindness in the world, accounting for ∼4.8% of global blindness (1). Diabetic retinopathy is a leading cause of blindness in industrialized countries (1), and its significance is likely to increase with increasing frequency of diabetes (2). Diabetic retinopathy is defined by the presence of retinal microvascular lesions. Early retinal changes include microaneurysms, hemorrhages, hard exudates, cotton wool spots, intraretinal microvascular abnormalities, and venous beading. These clinical features occur in nonproliferative diabetic retinopathy (NPDR). Growth of abnormal new blood vessels that frequently lead to preretinal and vitreous hemorrhage are the principal hallmarks of proliferative diabetic retinopathy (PDR). Visual impairment in diabetic retinopathy occurs secondary to preretinal or vitreous hemorrhage and diabetic maculopathy (either macular edema or macular ischemia) (3).
The prevalence of diabetic retinopathy is higher in type 1 diabetic patients, with sight-threatening retinopathy reported to be up to 2.5 times more common than in those with type 2 diabetes (4). Conversely, the incidence of macular edema has been reported to be up to two times higher among those with type 2 diabetes (5).
The pathogenesis of diabetes is believed to be multifactorial, with genetic risk factors playing a fundamental role. Recent genome-wide association studies have identified several genetic loci involved in the pathogenesis of both type 1 diabetes and type 2 diabetes (6,7). Pathogenesis of diabetic retinopathy is complex, also having a multifactorial biochemical pathogenesis, primarily because of altered glucose metabolism (8). Glycemic control (9,10) and the duration of diabetes (11,12) have been identified through large longitudinal prospective studies as being major risk factors for the development of diabetic retionopathy. However, genetic factors are also likely to account for the susceptibility to this blinding disease as well as the differences in diabetic retinopathy incidence between individuals with type 1 and type 2 diabetes. It has become evident through familial aggregation studies that susceptibility to complications of diabetes such as diabetic retinopathy also have a heritable component independent of glycemic control and duration of diabetes. The Diabetes Control and Complications Trial revealed a familial tendency for severe diabetic retinopathy in type 1 and type 2 diabetes (13). These findings were also replicated in Mexican Americans (14,15) and other familial risk studies (16,17), independent of associated environmental risk factors. There have been numerous studies investigating candidate genes for diabetic retinopathy susceptibility in subjects of various ethnicities.
The aim of this systematic meta-analysis was to analyze all published studies that investigated the association between genetic risk factors and the development of diabetic retinopathy and met specified inclusion criteria. We sought to determine which of the previously investigated genetic variants are significantly associated with the development of diabetic retinopathy in type 1 or type 2 diabetes and to examine the strength of these associations.
Literature search and data collection.
A systematic literature search was performed to identify all studies published between January 1990 and August 2008 that investigated the association of genetic variants with the development of any form of diabetic retinopathy. The PubMed database (National Center for Biotechnology Information; NCBI), ISI Web of Knowledge (version 4.5), and the Cochrane Library were explored independently by two authors using the following keyword strings: "genetic" AND "diabetic retinopathy" and "gene" AND "diabetic retinopathy." All retrieved publications were reviewed and compared and studies written in English that contained sufficient case (subjects with diabetes and diabetic retinopathy) and control (subjects with diabetes but without the complication of diabetic retinopathy) subjects' genotype information, such as allele or genotype frequency, were included. The reference list of each relevant publication was also examined to identify additional studies appropriate for inclusion in the meta-analysis. Polymorphisms were included in the meta-analysis if a minimum of two studies had assessed association with diabetic retinopathy development.
Data analysis.
Data were entered into a database and statistical analyses performed using RevMan software (version 4.2; Oxford, U.K.) and SPSS (version 16.0; SPSS, Chicago, IL). Data extraction and data entry was performed independently by two of the authors (S.A. and A.W.H.) and compared. Independent review and resolution by a senior investigator (K.P.B. and J.E.C.) was sought if disagreement between the reviewers occurred.
Ensemble (http://www.ensembl.org/index.html) and dbSNP (http://www.ncbi.nlm.nih.gov/SNP/) were used to locate rs# identifiers for the genetic variants. When an rs# identifier could not be located, the most commonly used name for that specific variant or single nucleotide polymorphism (SNP) was selected. All rs# identifiers were confirmed independently by a senior investigator (K.P.B.).
Analyses were performed for all cases with any form of diabetic retinopathy compared with all diabetic subjects without diabetic retinopathy (control subjects). Subanalysis was subsequently undertaken for NPDR and PDR where possible. Major and minor allele frequencies were calculated from the available genetic data of all reported variants in the included studies and odds ratios (ORs) and 95% CIs were calculated. The allelic association of microsatellite markers was also investigated, whereby the risk conferred by each allele was compared against all other alleles as well as against specific alleles. The Der Simonian and Laird random-effects model was used (18,19). This model utilizes weights that incorporate both within-study and between-study variance. Heterogeneity between studies was calculated as the inverse variance estimate. To minimize genetic heterogeneity, subanalysis was performed for all cohorts of white origin and for datasets in which heterogeneity remained; outlying studies were then removed in a stepwise fashion until homogeneity was achieved (20). For the purpose of this study, white ancestry was defined as being of European descent. Studies including subjects of white and nonwhite ancestry have had their cohorts divided and analyzed individually. Funnel plots were constructed in Revman and Egger's test (21) applied in Stata (version 10.1; Stata, College Station, TX) to investigate for publication bias. A P value of <0.05 was considered statistically significant in all analyses, except for publication bias (Egger's test), where a P value of <0.1 (22) was considered as statistically significant. No adjustments were made for multiple testing.
There were 702 publications identified. Of these, 160 were specific to genetic polymorphisms and the development of diabetic retinopathy (Fig. 1). Twelve of these studies were in a language other than English and were excluded, and a final total of 82 studies were suitable for inclusion as a result of having presented sufficient case and control genotype information. There were 196 polymorphisms identified, with 34 of these having adequate genotype data for inclusion in the meta-analysis. Visual inspection of the funnel plots revealed a symmetrical inverted V shape and Egger's test did not detect significant publication bias (P > 0.1) for all polymorphisms examined by more than five studies (supplementary Fig. 1, available in an online appendix at http://diabetes.diabetesjournals.org/cgi/content/full/db09-0059/DC1).
Flow chart of study selection process and included studies.
Seven polymorphisms were investigated by more than five studies and are discussed in detail (Table 1). Details of their study design are provided in supplementary Table 1. Forty-eight studies were included in the analyses for the seven polymorphisms, 20 (42%) of which included subjects of white ancestry (Table 2). Heterogeneity was eliminated in the subanalyses of studies with participants of white ancestry without the requirement of removal of outlying studies, indicating that ethnicity is a major source of heterogeneity generally.
Meta-analysis of genetic variants and risk for diabetic retinopathy in type 1 diabetes, type 2 diabetes, and both types of diabetes regardless of participant's ethnicity
Gene .
Variant .
Risk allele .
Comparison .
Type of diabetes .
Total case subjects with risk allele (%) .
Total control subjects with risk allele (%) .
Weight .
OR (95% CI) .
SE .
Number of studies .
χ2 .
References .
ACE INS/DEL at intron 16 287 base pair deletion No diabetic retinopathy vs. any diabetic retinopathy Type 1 651 (55) 458 (52) 32.76 1.06 (0.88–1.27) 0.09 6 3.67 0.5402 (S1–S6)
Type 2 986 (44) 931 (43) 67.24 1.01 (0.89–1.15) 0.06 7 2.67 0.866 (S3) (S7–S12)
Total 1,637 (47) 1,389 (45) 100.00 1.03 (0.93–1.14) 0.05 13 6.51 0.6249
No diabetic retinopathy vs. NPDR Type 2 276 (35) 438 (36) 100.00 0.91 (0.75–1.12) 0.10 3 1.51 0.3786 (S9) (S10) (S12)
No diabetic retinopathy vs. PDR Type 1 387 (60) 220 (55) 48.63 1.19 (0.77–1.86) 0.23 4 8.01 0.4355 (S1) (S2) (S4) (S5)
Type 2 221 (41) 438 (36) 51.37 1.12 (0.89–1.42) 0.12 3 0.21 0.3237 (S9) (S10) (S12)
Total 608 (51) 658 (40) 100.00 1.17 (0.94–1.44) 0.11 7 8.55 0.1515
NPDR vs. PDR Type 1 120 (64) 72 (45) 17.02 2.21 (1.44–3.39) 0.22 1 0 0.0003 (S4)
Type 2 353 (45) 481 (41) 82.98 1.12 (0.92–1.35) 0.1 6 4.75 0.2512 (S9) (S10) (S12–S15)
Total 473 (49) 553 (41) 100.00 1.25 (0.95–1.65) 0.14 7 12.77 0.1064
NOS3 rs3138808 393 base pair insertion No diabetic retinopathy vs. any diabetic retinopathy Type 1 21 (11) 42 (22) 9.91 0.43 (0.24–0.76) 0.29 1 0.00 0.0036 (S16)
Type 2 498 (21) 705 (26) 90.09 0.93 (0.74–1.17) 0.12 7 13.63 0.5408 (S17–S23)
No diabetic retinopathy vs. NPDR Type 1 21 (11) 42 (22) 32.47 0.43 (0.24–0.76) 0.29 1 0.00 0.0036 (S16)
Type 2 95 (20) 116 (24) 67.53 0.53 (0.12–2.46) 0.78 2 22.10 0.421 (S17) (S23)
Total 116 (17) 158 (24) 100.00 0.5 (0.19–1.31) 0.49 3 22.99 0.157
No diabetic retinopathy vs. PDR Type 2 43 (17) 116 (24) 100.00 0.42 (0.05–3.69) 1.11 2 28.95 0.4341 (S17) (S23)
NPDR vs. PDR Type 2 43 (17) 95 (20) 100.00 0.79 (0.42–1.5) 0.33 2 2.61 0.4723 (S17) (S23)
VEGF rs2010963 G No diabetic retinopathy vs. any diabetic retinopathy Type 2 1,204 (55) 1,144 (59) 100.00 0.86 (0.7–1.05) 0.10 7 14.65 0.1407 (S22) (S24–S29)
No diabetic retinopathy vs. NPDR Type 2 242 (53) 328 (65) 100.00 0.62 (0.48–0.81) 0.14 3 1.93 0.0005 (S24) (S28) (S29)
No diabetic retinopathy vs. PDR Type 2 212 (56) 643 (59) 100.00 0.8 (0.6–1.06) 0.14 4 0.92 0.1166 (S24) (S26) (S28) (S29)
NPDR vs. PDR Type 2 211 (56) 242 (53) 100.00 1.32 (0.99–1.76) 0.15 3 0.81 0.0559 (S24) (S28) (S29)
AKR1B1 rs759853 T No diabetic retinopathy vs. any diabetic retinopathy Type 1 114 (29) 149 (45) 33.33 0.49 (0.36–0.68) 0.16 3 0.02 <0.0001 (S30–S32)
Type 2 508 (34) 460 (26) 66.67 1.16 (0.98–1.36) 0.08 5 3.96 0.0885 (S33–S36)
Total 622 (33) 609 (29) 100.00 0.9 (0.66–1.22) 0.16 8 25.19 0.4857
No diabetic retinopathy vs. NPDR Type 1 8 (27) 28 (43) 14.13 0.49 (0.19–1.27) 0.48 1 0.00 0.143 (S32)
Type 2 175 (43) 147 (39) 85.87 1.17 (0.88–1.55) 0.15 2 0.09 0.2945 (S33)
Total 183 (42) 175 (39) 100.00 1.02 (0.7–1.5) 0.20 3 3.00 0.9099
No diabetic retinopathy vs. PDR Type 1 7 (25) 28 (43) 12.07 0.45 (0.17–1.21) 0.50 1 0.00 0.1144 (S32)
Type 2 123 (35) 147 (39) 87.93 0.84 (0.6–1.19) 0.18 2 1.19 0.3285 (S33)
NPDR vs. PDR Type 1 7 (25) 8 (27) 6.65 0.92 (0.28–2.98) 0.60 1 0.00 0.8848 (S32)
Type 2 123 (35) 175 (43) 93.35 0.76 (0.47–1.2) 0.24 2 1.95 0.2364 (S33)
AKR1B1 (CA)n dinucleotide repeat z No diabetic retinopathy vs. any diabetic retinopathy Type 1 344 (36) 313 (32) 39.83 1.09 (0.89–1.35) 0.11 6 5.24 0.3945 (S30) (S32) (S37–S40)
Type 2 436 (29) 612 (25) 60.17 1.04 (0.70–1.57) 0.21 9 46.91 0.8330 (S36) (S41–S48)
Total 780 (32) 925 (27) 100.00 1.05 (0.81–1.35) 0.13 15 52.88 0.7264
z No diabetic retinopathy vs. NPDR Type 1 25 (41) 20 (31) 28.59 1.55 (0.75–3.23) 0.37 1 0.00 0.2366 (S32)
Type 2 97 (27) 81 (37) 71.41 0.65 (0.45–0.94) 0.19 2 0.03 0.0215 (S48) (S42)
z No diabetic retinopathy vs. PDR Type 1 132 (43) 147 (37) 37.17 1.29 (0.95–1.75) 0.15 2 0.30 0.0979 (S39) (S32)
Type 2 179 (31) 171 (38) 62.83 0.77 (0.59–1.00) 0.13 4 1.63 0.0482 (S48) (S41–S43)
z NPDR vs. PDR Type 1 25 (41) 20 (31) 28.59 1.55 (0.75–3.23) 0.37 1 0.00 0.2366 (S32)
Z−2 No diabetic retinopathy vs. any diabetic retinopathy Type 1 362 (37) 261 (27) 41.98 1.95 (1.04–3.66) 0.32 6 40.66 0.0367 (S30) (S32) (S37–S40)
Type 2 385 (26) 171 (7) 58.02 2.64 (1.39–5.01) 0.33 9 69.93 0.0029 (S36) (S41–S48)
Total 747 (30) 432 (13) 100.00 2.33 (1.49–3.64) 0.23 15 120.27 0.0002
Z−2 No diabetic retinopathy vs. NPDR Type 1 22 (36) 23 (35) 22.71 1.03 (0.50–2.13) 0.37 1 0.00 0.9400 (S32)
Type 2 137 (38) 55 (25) 77.29 1.87 (1.29–2.71) 0.19 2 0.20 0.0010 (S48) (S42)
Total 159 (38) 78 (28) 100.00 1.64 (1.14–2.35) 0.18 3 2.26 0.0075
Z−2 No diabetic retinopathy vs. PDR Type 1 41 (24) 35 (23) 24.74 1.18 (0.69–2.01) 0.27 2 0.31 0.5363 (S32) (S40)
Type 2 173 (30) 85 (19) 75.26 1.64 (1.21–2.22) 0.16 4 2.50 0.0016 (S48) (S41–S43)
Z−2 NPDR vs. PDR Type 1 19 (18) 12 (14) 18.52 1.39 (0.64–3.04) 0.40 1 0.00 0.4076 (S40)
z+2 No diabetic retinopathy vs. any diabetic retinopathy Type 1 153 (16) 224 (23) 40.68 0.58 (0.36–0.93) 0.24 6 18.16 0.0243 (S30) (S32) (S37–S40)
z+2 No diabetic retinopathy vs. NPDR Type 1 7 (12) 13 (20) 22.07 0.52 (0.19–1.40) 0.51 1 0.00 0.1955 (S32)
Total 41 (10) 42 (15) 100.00 0.66 (0.41–1.05) 0.24 3 0.36 0.0820
z+2 No diabetic retinopathy vs. PDR Type 1 48 (16) 70 (18) 38.34 0.84 (0.50–1.40) 0.26 2 1.26 0.4971 (S39) (S32)
Type 2 82 (14) 98 (22) 61.66 0.62 (0.39–0.99) 0.24 4 4.71 0.0464 (S41–S43) (S48)
z+2 NPDR vs. PDR Type 1 7 (12) 13 (20) 22.07 0.52 (0.19–1.40) 0.51 1 0.00 0.1955 (S32)
All variants have been examined by a minimum of five studies. Subanalyses have been performed for NPDR and PDR if data were available. References are preceded with S as they correlate with the online supplementary appendix.
Meta-analysis of genetic variants and risk for diabetic retinopathy in patients with type 1 diabetes, type 2 diabetes, and both types of diabetes, for studies of white populations
ACE INS/DEL at intron 16 287 base pair deletion No diabetic retinopathy vs. any diabetic retinopathy Type 1 651 (55) 458 (52) 50.735 1.06 (0.88–1.27) 0.09 6 3.67 0.5402 (S1–S6)
Type 2 504 (53) 501 (54) 49.265 0.99 (0.83–1.19) 0.09 4 1.43 0.9182 (S7) (S8) (S10) (S3)
Total 1,155 (54) 959 (53) 100 1.02 (0.9–1.16) 0.07 10 5.35 0.7157
No diabetic retinopathy vs. PDR Type 1 387 (60) 220 (55) 76.8488 1.19 (0.77–1.86) 0.23 4 8.01 0.4355 (S1) (S2) (S4) (S5)
Type 2 75 (53) 78 (49) 23.1512 1.14 (0.73–1.79) 0.23 1 0.00 0.5617 (S10)
Total 462 (59) 298 (53) 100 1.19 (0.86–1.66) 0.17 5 8.11 0.2995
NPDR vs. PDR Type 1 120 (64) 72 (45) 33.9165 2.21 (1.44–3.39) 0.22 1 0.00 0.0003 (S4)
Type 2 156 (54) 224 (50) 66.0835 1.23 (0.9–1.67) 0.16 2 0.83 0.1905 (S10) (S14)
Total 276 (58) 296 (49) 100 1.52 (1–2.32) 0.22 3 5.55 0.0509
NOS3 rs3138808 393 base pair insertion No diabetic retinopathy vs. any diabetic retinopathy Type 1 21 (11) 42 (22) 47.0284 0.43 (0.24–0.76) 0.29 1 0.00 0.0036 (S16)
Type 2 123 (22) 58 (21) 52.9716 1.09 (0.77–1.55) 0.18 1 0.00 0.6248 (S21)
VEGF rs2010963 G No diabetic retinopathy vs. any diabetic retinopathy Type 2 387 (55) 247 (62) 100 0.83 (0.65–1.07) 0.13 2 0.43 0.1601 (S27) (S28)
AKR1B1 rs759853 T No diabetic retinopathy vs. any diabetic retinopathy Type 1 99 (29) 121 (46) 45.1355 0.5 (0.35–0.71) 0.18 2 0.01 0.0001 (S30) (S31)
Type 2 324 (42) 202 (41) 54.8645 1.05 (0.83–1.33) 0.12 2 0.91 0.6756 (S33)
Total 423 (38) 323 (43) 100 0.76 (0.5–1.16) 0.22 4 12.83 0.2061
AKR1B1 (CA)n dinucleotide repeat z No diabetic retinopathy vs. any diabetic retinopathy Type 1 277 (42) 247 (39) 75.2466 1.11 (0.88–1.39) 0.117 3 0.88 0.3785 (S30) (S37) (S39)
Type 2 79 (32) 67 (42) 24.7534 0.66 (0.44–1.00) 0.21 1 0.00 0.05 (S42)
z No diabetic retinopathy vs. PDR Type 1 107 (43) 127 (38) 51.9056 1.24 (0.89–1.74) 0.17 1 0.00 0.2008 (S39)
Total 186 (38) 194 (39) 100 0.92 (0.5–1.70) 0.314 2 5.42 0.7872
z−2 No diabetic retinopathy vs. any diabetic retinopathy Type 1 226 (34) 167 (27) 74.1019 1.83 (0.85–3.95) 0.393 3 15.42 0.1238 (S30) (S37) (S39)
Total 323 (36) 210 (27) 100 1.80 (1.06–3.06) 0.271 4 15.89 0.0301
z−2 No diabetic retinopathy vs. PDR Type 1 87 (35) 121 (36) 52.3594 0.96 (0.68–1.35) 0.175 1 0.00 0.8023 (S39)
z+2 No diabetic retinopathy vs. any diabetic retinopathy Type 1 103 (16) 159 (25) 76.3483 0.51 (0.25–1.06) 0.372 3 12.85 0.0722 (S39)
Type 2 28 (12) 24 (15) 23.6517 0.73 (0.41–1.31) 0.299 1 0.00 0.2958 (S42)
Total 131 (15) 183 (23) 100 0.56 (0.32–0.97) 0.282 4 13.71 0.039
z+2 No diabetic retinopathy vs. PDR Type 1 41 (17) 57 (17) 63.9459 0.97 (0.62–1.50) 0.224 1 0.00 0.8814 (S30) (S37) (S39)
Total 69 (14) 81 (17) 100 0.87 (0.62–1.24) 0.179 2 0.56 0.455
Subanalyses were performed for NPDR and PDR if data were available. References are preceded with S as they correlate with the online supplementary appendix.
Data on the remaining 27 SNPs analyzed in the current study, which have been examined by a minimum of two and maximum of five cohorts, are presented in Table 3. The rs2910964 SNP of the α2β1 integrin (ITGA2) gene (OR 1.65 [95% CI 1.26–2.15], P = 2 × 10−4) and rs13306430 of the intercellular cell adhesion molecule 1 (ICAM1) gene (0.56 [0.39–0.81], P = 1.70 × 10−3) were significantly associated with diabetic retinopathy, both being examined in type 2 diabetes only and by two studies in each case.
Pooled ORs for 27 SNPs and risk for diabetic retinopathy in type 1 diabetes, type 2 diabetes, and both types of diabetes
AGTR1 rs5186 C No diabetic retinopathy vs. any diabetic retinopathy Type 1 98 (29) 200 (33) 73.99 0.82 (0.61–1.10) 0.15 2 1.87 0.1852 (S6; S12)
Type 2 22 (4) 46 (5) 34.26 0.73 (0.43–1.22) 0.26 1 0.00 0.2251 (S12)
Total 142 (14) 246 (15) 100.00 0.8 (0.62–1.03) 0.13 3 2.05 0.0788
ITGA2 rs2910964 A No diabetic retinopathy vs. any diabetic retinopathy Type 2 258 (46) 137 (34) 100.00 1.65 (1.26–2.15) 0.14 2 0.05 0.0002 (S49; S50)
ADRB3 rs4994 C No diabetic retinopathy vs. any diabetic retinopathy Type 1 62 (7) 12 (10) 48.01 0.73 (0.38–1.39) 0.33 1 0.00 0.3320 (S51; S52)
Type 2 49 (27) 34 (15) 51.99 2.16 (1.32–3.51) 0.25 1 0.00 0.0020 (S51; S52)
No diabetic retinopathy vs. NPDR Type 1 27 (7) 12 (10) 47.68 0.71 (0.35–1.44) 0.36 1 0.00 0.3420 (S51; S52)
No diabetic retinopathy vs. PDR Type 1 35 (7) 12 (10) 48.89 0.74 (0.37–1.47) 0.35 1 0.00 0.3892 (S51; S52)
NPDR vs. PDR Type 1 35 (7) 27 (7) 61.48 1.04 (0.62–1.76) 0.27 1 0.00 0.8706 (S51; S52)
AGT rs4762 C No diabetic retinopathy vs. any diabetic retinopathy Type 1 111 (55) 189 (63) 37.28 0.73 (0.51–1.05) 0.18 1 0.00 0.0875 (S6; S12)
Type 2 90 (14) 161 (17) 62.72 0.84 (0.63–1.11) 0.14 1 0.00 0.2102 (S6; S12)
APOE ϵ2/ϵ3/ϵ4 ϵ2 No diabetic retinopathy vs. any diabetic retinopathy Type 1 21 (14) 19 (10) 19.55 1.46 (0.75–2.83) 0.34 1 0.00 0.2620 (S53; S54)
Type 2 223 (10) 51 (11) 80.45 1.05 (0.76–1.45) 0.17 2 0.05 0.7681 (S53; S54)
Total 244 (11) 70 (11) 100.00 1.12 (0.84–1.5) 0.15 3 0.81 0.4470
FGF2 rs41456044 A No diabetic retinopathy vs. PDR Type 2 31 (5) 47 (5) 100.00 1.19 (0.74–1.91) 0.24 2 0.27 0.4672 (S55; S56)
FGF2 rs308395 G No diabetic retinopathy vs. PDR Type 2 90 (14) 131 (13) 100.00 1.08 (0.81–1.45) 0.15 2 0.29 0.5882 (S55; S56)
NOS3 rs1799983 G No diabetic retinopathy vs. any diabetic retinopathy Type 2 393 (30) 478 (24) 100.00 1.11 (0.94–1.31) 0.08 4 1.69 0.2279 (S17-S20)
NOS3 rs41322052 C No diabetic retinopathy vs. any diabetic retinopathy Type 1 105 (42) 106 (42) 25.37 1.01 (0.71–1.44) 0.18 1 0.00 0.9525 (S57)
Type 2 313 (27) 334 (24) 74.63 1.04 (0.75–1.45) 0.17 3 4.33 0.7956 (S17; S19)
No diabetic retinopathy vs. PDR Type 1 105 (42) 106 (42) 77.27 1.01 (0.71–1.44) 0.18 1 0.00 0.9525 (S57)
SLC2A1 rs841853 XbaI- No diabetic retinopathy vs. any diabetic retinopathy Type 1 227 (35) 142 (64) 66.08 0.41 (0.13–1.23) 0.57 2 8.27 0.1118 (S58; S59)
HLA DR1–8 DR1 No diabetic retinopathy vs. any diabetic retinopathy Type 1 45 (14) 40 (15) 100.00 0.99 (0.62–1.56) 0.2359 2 0.2 0.9506 (S60; S61)
HLA DR1–8 DR7 No diabetic retinopathy vs. any diabetic retinopathy Type 1 39 (12) 38 (14) 100.00 0.59 (0.10–3.60) 0.9247 2 1.86 0.5658 (S60; S61)
ICAM1 rs13306430 G No diabetic retinopathy vs. any diabetic retinopathy Type 2 150 (36) 89 (50) 100.00 0.56 (0.39–0.81) 0.18 2 0.01 0.0017 (S62; S63)
MTHFR rs1801133 T No diabetic retinopathy vs. any diabetic retinopathy Type 2 318 (44) 405 (37) 100.00 1.39 (0.99–1.94) 0.17 4 8.34 0.0563 (S35; S64–S66)
NPY rs16139 C No diabetic retinopathy vs. any diabetic retinopathy Type 2 26 (9) 16 (5) 100.00 2.62 (0.9–7.61) 0.54 2 1.38 0.0759 (S67; S68)
PAI-1 rs1799768 5G No diabetic retinopathy vs. any diabetic retinopathy Type 2 355 (44) 252 (45) 100.00 1.06 (0.85–1.32) 0.11 3 0.00 0.6017 (S10; S35; S69)
PON1 rs662 G No diabetic retinopathy vs. any diabetic retinopathy Type 2 310 (54) 175 (48) 100.00 0.99 (0.44–2.27) 0.42 2 8.48 0.9896 (S69; S70)
PON2 rs7493 G No diabetic retinopathy vs. any diabetic retinopathy Type 1 192 (57) 191 (49) 54.02 1.37 (1.03–1.84) 0.15 1 0.00 0.0322 (S70; S71)
PPARG rs1801282 G No diabetic retinopathy vs. any diabetic retinopathy Type 1 33 (13) 108 (14) 29.35 0.85 (0.56–1.29) 0.21 1 0.00 0.4413 (S72-S75)
Type 2 124 (14) 273 (16) 70.65 0.83 (0.62–1.11) 0.15 4 3.33 0.2135 (S72-S75)
AGER rs1800624 A No diabetic retinopathy vs. any diabetic retinopathy Type 2 361 (33) 112 (18) 100.00 1.89 (0.53–6.75) 0.65 3 46.09 0.3271 (S76-S78)
No diabetic retinopathy vs. NPDR Type 2 217 (37) 60 (12) 100.00 2.94 (0.46–18.76) 0.95 2 26.55 0.2540 (S76; S78)
No diabetic retinopathy vs. PDR Type 2 67 (26) 93 (20) 100.00 0.93 (0.62–1.38) 0.20 2 0.88 0.7055
AGER rs1800625 C No diabetic retinopathy vs. any diabetic retinopathy Type 2 125 (13) 94 (15) 100.00 0.94 (0.7–1.27) 0.15 3 0.32 0.7035 (S76; S78)
No diabetic retinopathy vs. PDR Type 2 35 (14) 76 (15) 100.00 0.99 (0.64–1.55) 0.23 2 0.99 0.9803 (S76; S78)
VDR rs10735810 C No diabetic retinopathy vs. any diabetic retinopathy Type 1 207 (40) 86 (34) 57.59 1.27 (0.93–1.74) 0.16 1 0.00 0.1282 (S79)
Type 2 85 (50) 169 (47) 42.41 1.15 (0.8–1.66) 0.19 1 0.00 0.4415 (S80)
VEGF rs25648 T No diabetic retinopathy vs. any diabetic retinopathy Type 2 86 (16) 56 (14) 100.00 1.48 (0.42–5.19) 0.64 2 9.06 0.5363 (S22; S24)
VEGF rs1570360 A No diabetic retinopathy vs. any diabetic retinopathy Type 2 78 (12) 81 (13) 100.00 0.93 (0.67–1.3) 0.17 2 0.22 0.6740 (S24; S25)
VEGF rs3095039 T No diabetic retinopathy vs. any diabetic retinopathy Type 2 86 (16) 52 (13) 100.00 1.1 (0.47–2.62) 0.44 2 4.47 0.8230 (S24; S29)
No diabetic retinopathy vs. NPDR Type 2 45 (14) 52 (13) 100.00 0.97 (0.33–2.85) 0.55 2 5.03 0.9560 (S24; S29)
NPDR vs. PDR Type 2 41 (18) 45 (14) 100.00 1.22 (0.76–1.96) 0.24 2 1.01 0.4146 (S24; S29)
VEGF rs35569394 -2549DEL No diabetic retinopathy vs. any diabetic retinopathy Type 1 73 (58) 68 (52) 46.01 1.25 (0.77–2.04) 0.25 1 0.00 0.3724 (S81)
Type 2 252 (65) 81 (45) 53.99 2.28 (1.59–3.26) 0.18 1 0.00 1.0 × 10.5 (S82)
VEGF rs699947 A No diabetic retinopathy vs. any diabetic retinopathy Type 2 204 (29) 280 (29) 100.00 1.01 (0.56–1.83) 0.30 2 7.61 0.9741 (S25; S26)
All SNPs have been examined by a minimum of two and maximum of five studies. Subanalyses have been performed for NPDR and PDR if data were available. References are preceded with S as they correlate with the online supplementary appendix.
ACE.
The gene encoding ACE is located on chromosome 17q23. Six studies examined the insertion/deletion (INS/DEL) polymorphism in intron 16 of the ACE gene in patients with type 1 diabetes, and seven studies in patients with type 2 diabetes were included in the meta-analysis. The 287 base pair deletion was treated as the risk variant, and there was no statistically significant association with this polymorphism and the development of any form of diabetic retinopathy (Table 1).
Ten studies of subjects with white origin were subanalyzed for all diabetic retinopathy comparisons. The 287 base pair deletion was not found to be significantly associated with any diabetic retinopathy or its subtypes in type 1 or type 2 diabetes (Table 2).
Aldose reductase (AKR1B1).
The aldo-keto reductase family 1 member B1 (AKR1B1) gene (also known as ALR) is located on chromosome 7q35. Associations of two AKR1B1 SNPs with diabetic retinopathy have been reported in the literature: the promoter SNP rs759853 and the (CA)n microsatellite polymorphism located 5′ of the AKR1B1 gene. Six studies have examined the association between the AKR1B1 (CA)n microsatellite with diabetic retinopathy in type 1 and nine studies in type 2 diabetes (Table 1). The three most commonly investigated AKR1B1 variants (z, z+2, and z−2) in the literature were included for analysis.
There was a significant association with the z−2 allele and the development of any diabetic retinopathy (OR 2.33 [95% CI 1.49–3.64], P = 2 × 10−4). Subanalyses revealed a significant association between the z−2 allele and diabetic retinopathy in patients with type 2 diabetes (2.64 [1.39–5.01], P = 2.9 × 10−3), with weaker but statistically significant association also being found for patients with type 1 diabetes (1.95 [1.04–3.66], P = 0.04). A significant association was also found in the NPDR and PDR subgroups.
No statistically significant association was found between the z allele and the development of diabetic retinopathy overall (OR 1.05 [95% CI 0.81–1.35], P = 0.73). However, in the subanalysis for type of diabetic retinopathy, the z allele was significantly protective against NPDR development in type 2 diabetes (0.65 [0.45–0.94], P = 0.02). A significant difference between NPDR and PDR development for the presence of z allele was found also in type 2 diabetes (0.65 [0.45–0.94], P = 0.02). Similarly, the z+2 allele was found to be significantly protective against the development of diabetic retinopathy (0.58 [0.36–0.93], P = 0.02).
Only four studies examining the AKR1B1 (CA)n microsatellite have included subjects of white ancestry (Table 2), with the majority of studies including subjects of only Asian ancestry. In the analyses of studies of white origin, only the z−2 (OR 1.80 [95% CI 1.06–3.06], P = 0.03) and z+2 (0.56 [0.32–0.97], P = 0.04) polymorphisms remained significantly associated with diabetic retinopathy, with the z−2 allele conferring risk and z+2 conferring protection against diabetic retinopathy.
Three studies examined the association of a second AKR1B1 polymorphism (promoter SNP rs759853) with diabetic retinopathy in type 1 diabetes and five studies in type 2 diabetes (Table 1). The T allele was considered the risk variant. Interestingly, analyses revealed protection against diabetic retinopathy with the T allele in type 1 diabetes (OR 0.49 [95% CI 0.36–0.68], P < 1.00 × 10−4). There was no statistically significant association between diabetic retinopathy and rs759853 in type 2 diabetes. However, a borderline association between NPDR and PDR was found (0.73 [0.54–0.99], P = 0.04).
Four studies investigating the AKR1B1 rs759853 included subjects of white ancestry. A significant protection of the T allele against diabetic retinopathy in type 1 diabetes (OR 0.5 [95% CI 0.35–0.71], P = 1.00 × 10−4) remained. Insufficient studies were available for subanalysis of diabetic retinopathy subtypes.
Vascular endothelial growth factor.
The vascular endothelial growth factor (VEGF) gene is located on chromosome 6p12. Six VEGF polymorphisms were included in this meta-analysis, with the rs2010963 polymorphism being the most frequently studied. No studies examining this polymorphism in type 1 diabetes and diabetic retinopathy were located. Seven studies examining this polymorphism in type 2 diabetes and diabetic retinopathy were included in the analyses (Table 1). The G allele has been considered as the risk variant. A significant association between patients with no diabetic retinopathy and those with NPDR (OR 0.62 [95% CI 0.48–0.81], P = 5.0 × 10−4) was identified, yet no significant differences were found between NPDR and PDR development. Meta-analysis revealed no significant association between the VEGF polymorphisms: rs25648, rs1570360, rs3095039, rs35569394, or rs699947 and any type of diabetic retinopathy (Table 3).
Only two studies of participants were available for inclusion in the subanalysis for white ancestry (Table 2). No statistically significant association of the VEGF rs2010963 polymorphism with diabetic retinopathy was found (OR 0.83 [95% CI 0.65–1.07], P = 0.16) and insufficient studies were available for diabetic retinopathy subtype analyses.
Endothelial nitric oxide synthase.
The endothelial nitric oxide synthase (NOS3) gene is located on chromosome 7q35–36. Three NOS3 SNPs (rs1799983, rs41322052, and rs3138808) met the inclusion criteria for meta-analysis. The rs3138808 variant has been the most commonly examined NOS3 diabetic retinopathy polymorphism, and the 393 base pair insertion has been classified as the risk variant. One study examining this polymorphism and diabetic retinopathy in type 1 diabetes and seven studies in type 2 diabetes were included in the analysis (Table 1). There was no statistically significant association between rs3138808 and any form of diabetic retinopathy. Additionally, no significant association between any form of diabetic retinopathy and the rs1799983 (OR 1.11 [95% CI 0.94–1.31], P = 0.23) or rs41322052 (1.06 [0.85–1.33], P = 0.60) were identified (Table 3).
Only two studies were available to be included in the subanalysis for subjects of white ancestry (Table 2). No statistically significant association was found with the NOS3 rs3138808 polymorphism and diabetic retinopathy development (OR 0.71 [95% CI 0.28–1.75], P = 0.45) and insufficient studies were available for diabetic retinopathy subtype analysis.
Diabetic retinopathy remains one of the leading causes of blindness in the developed world (1). There is strong evidence for a genetic component in the development of diabetic retinopathy, independent of other established risk factors (13,,,–17). Despite a large number of candidate gene studies on diabetic retinopathy, the genetic evidence thus far for an association with the development of or severity of diabetic retinopathy has been conflicting. This is largely accounted for by varying participant ethnicity, study design, differences in retinopathy grading scales, and in particular suboptimal power.
The current meta-analysis comprehensively assesses the risk of diabetic retinopathy in relation to every published candidate gene meeting inclusion criteria. Eighty-two studies examining 20 genes and 34 SNPs were analyzed. Pathways involved in the pathogenesis of diabetic retinopathy relevant to the genes with the most studied polymorphisms in this meta-analysis are described in detail below.
Renin-angiotensin system.
ACE is involved in the conversion of angiotensin I to angiotensin II (ATII). ATII mediates its hemodynamic effects through signaling via angiotensin type 1 (AT1) and type 2 (AT2) receptors. Vascular remodeling and proliferation occurs mainly via the AT1 receptor (23). All components of the renin-angiotensin system (RAS) have been shown to be expressed in the retina (24). The physiologic effects of ATII in the eye include the regulation of intraocular blood flow and pressure, promotion of capillary growth, enhancing vascular permeability, increasing oxidative stress, and the regulation of cell growth via the expression of various growth factors including VEGF, insulin-like growth factor, and platelet-derived growth factor (23).
Clinical evidence also supports the role for the RAS system in diabetic retinopathy pathogenesis. The EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes (EUCLID) trial provided evidence for lisinopril, an ACE inhibitor, decreasing the progression of diabetic retinopathy by 50% (25). In addition, animal studies have shown that ACE inhibitors and AT1 receptor blockers can prevent retinal neovascularization (26).
The ACE INS/DEL polymorphism in intron 16 had the largest number of subjects to be genotyped for any polymorphism and the largest number of studies to include participants of white ancestry. Three-quarters of the studies included participants of white ancestry. There was no statistically significant association of the INS/DEL polymorphism of the ACE gene with diabetic retinopathy or diabetic retinopathy subtypes in type 1, type 2, or combined diabetes. This is consistent with the findings of the majority of the included studies examining this polymorphism in this meta-analysis. Two other meta-analyses have examined the association of the INS/DEL of the ACE gene with diabetic retinopathy development. Fujisawa et al. (27) examined 12 studies, including type 1 and type 2 diabetic subjects. Wiwanitkit (28) examined four studies and included type 2 diabetic subjects only. Both analyses also found no statistically significant association with this polymorphism and the development of diabetic retinopathy.
Polyol pathway.
Aldose reductase (ALR) is a rate-limiting enzyme of the polyol pathway, which catalyzes NADPH-dependent reduction of glucose to sorbitol. This pathway leads to the intracellular accumulation of sorbitol and is primarily active under hyperglycemic conditions (29). Several mechanisms have been proposed to explain the pathogenesis of diabetic microvascular complications, including the induction of osmotic stress and the activation of protein kinase C as well as pathogenic vascular and hemodynamic alterations (8). ALR has been identified in human pericytes, which exhibit an active polyol pathway (30). Animal studies have shown that cultured mural cells from the retinal capillaries of adult rhesus monkeys undergo cellular degeneration after exposure to high glucose levels, with ALR being isolated from these mural cells (31). The sorbitol pathway is also biologically plausible as it is involved in the selective degeneration of human mural cells in NPDR (32). Induced hyperglycemia in dogs with galactosemia has similarly shown retinal vascular changes including microaneurysm formation, degeneration of retinal pericytes, retinal hemorrhages, and nonperfused or acellular vessels (33).
The AKR1B1 gene had the largest number of studies examining the relationship of its polymorphisms to diabetic retinopathy development, regardless of ethnicity. The z−2 microsatellite showed the most significant association with diabetic retinopathy, especially in type 2 diabetes, conferring risk also in PDR and NPDR subtypes. The z+2 and z microsatellite conferred protection against overall diabetic retinopathy and NPDR, respectively, and both were protective against PDR when compared with NPDR in type 2 diabetes. The majority of studies included in this meta-analysis have individually reported a risk for diabetic retinopathy with the z−2 microsatellite; however, the z microsatellite was not found to be statistically significant by most studies, with only a fifth of the studies individually reporting z+2 to be protective against diabetic retinopathy. The vast majority of studies have included participants of non-white ancestry; however, those of white ancestry found the z−2 microsatellite to confer risk and z+2 to confer protection against overall diabetic retinopathy in combined diabetes.
The T allele of the AKR1B1 promoter SNP rs759853 conferred protection against diabetic retinopathy in type 1 diabetes of any ancestry and also of white ancestry alone. This protection against diabetic retinopathy in type 1 diabetes has also been found in the individual studies examining this polymorphism.
VEGF.
VEGF is a multifunctional cytokine that promotes angiogenesis and is a potent mediator of microvascular permeability. Diabetic microvascular changes in the retina lead to hypoxia, a stimulator of VEGF production (34). VEGF has been found to have a significant role in the development of diabetic retinopathy by inducing hyperpermeability of retinal vessels, breakdown of the blood–retinal barrier, and neovascularization in PDR (35,–37). Complications such as retinal edema and blinding vitreous hemorrhage arise as a result of the abnormal barrier function of vessels and the growth of new vessels, which are fragile and prone to rupture.
VEGF protein expression has been shown to be influenced by genetic variation in the VEGF gene (38). VEGF levels in the vitreous of patients with PDR are significantly elevated when compared with the vitreous of diabetic eyes without PDR and control subjects without diabetes (39,40). VEGF inhibition has been shown to result in a marked reduction in retinal neovascularization (41) and prevention of the blood–retinal barrier breakdown (42), further supporting its role in diabetic retinopathy development.
The VEGF gene had the largest number of individual SNPs examined in relation to diabetic retinopathy. Of these six polymorphisms, the G variant of the rs2010963 polymorphism was found to significantly protect against the development of NPDR in type 2 diabetes but not with overall diabetic retinopathy development. In keeping with the findings of this meta-analysis, the majority of studies reported no statistically significant association of this polymorphism with any diabetic retinopathy development in type 2 diabetes, regardless of ethnicity.
NO pathway.
Endothelial NO synthase (eNOS) is an enzyme produced by endothelial cells. NO derived from eNOS is a key endogenous vasodilator (43). It is also believed to be important in the promotion of angiogenesis and regulation of VEGF expression (44). A low concentration of eNOS is believed to be necessary to maintain endothelial function (45) with experimental deficiency of eNOS shown to significantly decrease retinal neovascularization in a mouse model (46). Aqueous NO levels have also been found to play an important role in the progression of diabetic retinopathy, with levels significantly higher in active PDR (47). Similarly, NO levels have been found to be significantly elevated in PDR vitreous when compared with nondiabetic subjects (48), making the eNOS gene (NOS3) a biologically plausible candidate for susceptibility to diabetic retinopathy development.
The NOS3 rs3138808 polymorphism was the most studied polymorphism, and the majority of studies included participants of nonwhite ancestry. No statistically significant association was found with diabetic retinopathy development regardless of ethnicity and for whites alone, consistent with the findings of the majority of the included studies. All other NOS3 polymorphisms did not show statistically significant associations with the development of diabetic retinopathy.
Data on the remaining 27 SNPs examined by a minimum of two and maximum of five studies revealed the rs2910964 SNP of the ITGA2 gene and rs13306430 of the ICAM1 gene to be significantly associated with diabetic retinopathy. Both of these variants were examined in type 2 diabetes only and by the minimum allowable two studies each. Unless further replicative studies are undertaken, the importance of these genes in diabetic retinopathy may remain unclear. Zintzaras et al. (49) performed a meta-analysis of five studies examining the link between the C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene and development of diabetic retinopathy in type 2 diabetes. Unlike our results, a borderline association between C677T transition and the risk of development diabetic retinopathy (OR 1.39 [95% CI 1.05–1.83], P = 0.08) was reported.
Because of the publication deadline for included studies, some polymorphisms, such as those recently reported in the erythropoietin gene (50), were unable to be included in the meta-analysis as further studies have not as yet been reported. The definition of diabetic retinopathy requires the minimum of microaneurysm presence in a diabetic individual (34); however, several definitions and criteria exist for the subclassification of diabetic retinopathy and preferences have been variable among included studies, with many studies defining diabetic retinopathy without the use of standardized scales. Additionally, confounding factors such as glycemic control have not been adjusted for in calculation of the ORs of polymorphisms included in this meta-analysis, as this information provided by included studies have often been incomplete and nonstandardized definitions were used. Therefore, these are accepted as limitations of this meta-analysis, with some being implicit in the meta-analysis concept when dealing with a large number of studies with different design and reporting style.
In conclusion, this meta-analysis has found that sequence variation within the AKR1B1 gene are the most significantly associated with diabetic retinopathy development among those genes qualifying for inclusion. This result supports more detailed research into the role of the AKR1B1 gene in diabetic retinopathy to determine which variants are causally associated and their mechanism of action. Genetic research on diabetic retinopathy susceptibility has the potential for a direct positive impact on patient management by ultimately altering screening regimes in an individualized manner for a disease that is of major and increasing public health concern. Although much work has focused on dissecting the genetics of diabetes itself, considerably less has been conducted into the molecular mechanisms leading to its specific complications, including diabetic retinopathy and its subtypes. Although NPDR and PDR are commonly subanalyzed in genetic studies, very few studies have reported on genetic associations with the common subtype of macular edema, that is a frequent cause of visual disability in diabetic subjects. This is an area that requires further exploration. Future genetic studies should also include genome-wide association studies to identify diabetic retinopathy susceptibility loci that have not been previously considered as candidates to assist with a better understanding of the pathogenesis of this debilitating sight-threatening diabetes complication.
This research was supported by a grant from the Ophthalmic Research Institute of Australia. K.P.B. is a Peter Doherty Fellow of the National Health and Medical Research Council of Australia (NHMRC) and J.E.C. is an NHMRC Practitioner Fellow.
No other potential conflicts of interest relevant to this article were reported.
We acknowledge Richard Woodman for his statistical advice and expertise.
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Possible involvement of nitric oxide in the progression of diabetic retinopathy
Ophthalmologica
Kociok
Heimann
Elevated vitreous nitric oxide levels in patients with proliferative diabetic retinopathy
Zintzaras
Chatzoulis
Karabatsas
Stefanidis
The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: a meta-analysis
J Hum Genet
Kaminoh
Tinkham
Zabriskie
Zeng
Ronquillo
Sadda
Jorde
Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications
Supplemental Table- xls file
Supplemental Figure and Appendix- doc file


text:
(→Example 3: Assurance contracts)
To do this, a protocol similar to one proposed by hashcoin can be used:
To do this, the following protocol can be used. This protocol relies upon a '''different''' behavior of nLockTime to the original design. Starting around 2013 time-locked transactions were made non standard and no longer enter the memory pool, thus cannot be broadcast before the timelock expires. When the behaviour of nLockTime is restored to the original design from Satoshi, a variant of this protocol is required which is discussed below.
# Request a public key from the access point.
# Create, but do not sign, a transaction (T1) that sets up a payment of (for example) 10 BTC to an output requiring both the access point's public key and one of your own to be used. The value to be used is chosen as an efficiency tradeoff.
# Create, but do not sign, another transaction (T2) that has two outputs, one to the access point's key and another that goes back to you. The initial value is 0.001 BTC to the access point and the rest back to you. Use a sequence number of zero on the input and a lock time in the future (e.g., 1 day).
# Send both unsigned transactions to the access point. It sees that T1 and T2 are of the expected form and signs T2. It hands T2 back to you.
# Check that T2 is signed correctly, sign T1 and T2. Send them to the access point, which broadcasts them, thus locking in the agreement. Note that T2 won't get included into a block for at least one day, unless it's replaced by a newer transaction, as determined by the sequence numbers.
# Each time you want 10kb of data quota, sign a new version of T2 with a higher sequence number, the same lock time, and adjust the outputs so more value is allocated to the access point, and send it. The AP sees that the output sizes are correct, signs it, and keeps it (does not broadcast).
This continues until the session ends, or the 1-day period is getting close to expiry. The AP broadcasts the last transaction it saw, replacing the original that was pending. Once the lock time passes, the value transfer is committed. Alternatively, if the session end is negotiated cleanly, the user can sign a transaction that's final (sequence number of UINT_MAX), which signals that no more data quota will be purchased, allowing instant commitment of the transaction.
# Create a public key (K1). Request a public key from the server (K2).
# Create and sign but do not broadcast a transaction (T1) that sets up a payment of (for example) 10 BTC to an output requiring both the server's public key and one of your own to be used. A good way to do this is use OP_CHECKMULTISIG. The value to be used is chosen as an efficiency tradeoff.
# Create a refund transaction (T2) that is connected to the output of T1 which sends all the money back to yourself. It has a time lock set for some time in the future, for instance a few hours. Don't sign it, and provide the unsigned transaction to the server. By convention, the output script is "2 K1 K2 2 CHECKMULTISIG"
# The server signs T2 using its public key K2 and returns the signature to the client. Note that it has not seen T1 at this point, just the hash (which is in the unsigned T2).
# The client verifies the servers signature is correct and aborts if not.
# The client then creates a new transaction, T3, which connects to T1 like the refund transaction does and has two outputs. One goes to K1 and the other goes to K2. It starts out with all value allocated to the first output (K1), ie, it does the same thing as the refund transaction but is not time locked. The client signs T3 and provides the transaction and signature to the server.
# The server verifies the output to itself is of the expected size and verifies the client's provided signature is correct.
# When the client wishes to pay the server, it adjusts its copy of T3 to allocate more value to the server's output and less to its ow. It then re-signs the new T3 and sends the signature to the server. It does not have to send the whole transaction, just the signature and the amount to increment by is sufficient. The server adjusts its copy of T3 to match the new amounts, verifies the signature and continues.
Mike Hearn is working on an implementation of this protocol in bitcoinj. Please [mailto:mike@plan99.net contact him] for more information.
The lock time and sequence numbers avoid an attack in which the AP provides connectivity, and then the user [[double-spending|double-spends]] the output back to themselves using the first version of TX2, thus preventing the cafe from claiming the bill. If the user does try this, the TX won't be included right away, giving the access point a window of time in which it can observe the TX broadcast, and then broadcast the last version it saw, overriding the user's attempted double-spend.


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