***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading , despite our best efforts to improve the design and analysis of studies . Mendelian r and omization-the r and om assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures . The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies . Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian r and omization and are described . The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study , that polymorphisms may have several phenotypic effects associated with disease , the lack of suitable polymorphisms for study ing modifiable exposures of interest , and canalization-the buffering of the effects of genetic variation during development . Nevertheless , Mendelian r and omization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to underst and ing and preventing the adverse effects on human health of modifiable exposures Genetic variation in vitamin D – related genes has not been investigated comprehensively and findings are equivocal . We studied the association between polymorphisms across the entire vitamin D receptor ( VDR ) gene and genes encoding for vitamin D activating enzyme 1-α-hydroxylase ( CYP27B1 ) and deactivating enzyme 24-hyroxylase ( CYP24A1 ) and prostate cancer risk among middle-aged men using a population -based case-control study design . DNA sample s and survey data were obtained from incident cases ( n = 630 ) , 40 to 64 years old , identified through the Seattle-Puget Sound Surveillance , Epidemiology , and End Results cancer registry from 1993 to 1996 and from r and om controls ( n = 565 ) of similar age without a history of prostate cancer . We selected and genotyped tag single-nucleotide polymorphisms to predict common variants across VDR ( n = 22 ) , CYP27B1 ( n = 2 ) , and CYP24A1 ( n = 14 ) . Haplotypes of VDR and CYP24A1 were not associated with prostate cancer risk . In the genotype analysis , homozygotes at two VDR loci ( rs2107301 and rs2238135 ) were associated with a 2- to 2.5-fold higher risk of prostate cancer compared with the homozygote common allele [ odds ratio , 2.47 ( 95 % confidence interval , 1.52 - 4.00 ; P = 0.002 ) and 1.95 ( 95 % confidence interval , 1.17 - 3.26 ; P = 0.007 ) , respectively ; P value corrected for multiple comparisons for VDR = 0.002 ] . We found no evidence that the two associated VDR single-nucleotide polymorphisms were modified by age at diagnosis , prostate cancer aggressiveness , first-degree family history of prostate cancer , or vitamin D intake . Genotypes of CYP27B1 and CYP24A1 were not associated with prostate cancer risk . Our findings suggest that polymorphisms in the VDR gene may be associated with prostate cancer risk and , therefore , that the vitamin D pathway might have an etiologic role in the development of prostate cancer . ( Cancer Epidemiol Biomarkers Prev 2007;16(10):1990–9 Determination of the relevance of both dem and ing classical epidemiologic criteria for control selection and robust h and ling of population stratification ( PS ) represents a major challenge in the design and analysis of genome-wide association studies ( GWAS ) . Empirical data from two GWAS in European Americans of the Cancer Genetic Markers of Susceptibility ( CGEMS ) project were used to evaluate the impact of PS in studies with different control selection strategies . In each of the two original case-control studies nested in corresponding prospect i ve cohorts , a minor confounding effect due to PS ( inflation factor λ of 1.025 and 1.005 ) was observed . In contrast , when the control groups were exchanged to mimic a cost-effective but theoretically less desirable control selection strategy , the confounding effects were larger ( λ of 1.090 and 1.062 ) . A panel of 12,898 autosomal SNPs common to both the Illumina and Affymetrix commercial platforms and with low local background linkage disequilibrium ( pair-wise r 2<0.004 ) was selected to infer population substructure with principal component analysis . A novel permutation procedure was developed for the correction of PS that identified a smaller set of principal components and achieved a better control of type I error ( to λ of 1.032 and 1.006 , respectively ) than currently used methods . The overlap between sets of SNPs in the bottom 5 % of p-values based on the new test and the test without PS correction was about 80 % , with the majority of discordant SNPs having both ranks close to the threshold . Thus , for the CGEMS GWAS of prostate and breast cancer conducted in European Americans , PS does not appear to be a major problem in well- design ed studies . A study using suboptimal controls can have acceptable type I error when an effective strategy for the correction of PS is employed Abstract Objective : The hormone 1,25-dihydroxyvitamin D ( 1,25(OH)2D ) promotes prostate epithelial cell differentiation in vitro and thus , several groups have hypothesized that men who systemically have lower levels of 1,25(OH)2D may be at increased risk for prostate cancer . To address this hypothesis , we evaluated the association of circulating concentrations of 1,25(OH)2D and its precursor 25-hydroxyvitamin D ( 25(OH)D ) with subsequent risk of prostate cancer . Methods : Prostate cancer cases were 460 men in the Health Professionals Follow-up Study who were diagnosed through 1998 after providing a blood specimen in 1993/95 . 90.2 % of the cases were organ confined or had minimal extraprostatic extension . An equal number of controls who had had a screening PSA test after blood draw  were individually matched to cases on age , history of a PSA test before blood draw , and time of day , season , and year of blood draw .  Plasma 1,25(OH)2D and 25(OH)D concentrations  were determined by radio-immunosorbant assay blindly to case – control status . Odds ratios ( OR ) of prostate cancer and 95 % confidence intervals ( CI ) were estimated from conditional logistic regression models mutually adjusting for quartiles of 1,25(OH)2D and 25(OH)D concentrations and for suspected prostate cancer risk factors . Quartile cutpoints were determined separately by season of blood draw using the distributions among controls . Results : Mean concentrations of 1,25(OH)2D and 25(OH)D were slightly , but not statistically significantly ( p= 0.06 and 0.20 , respectively ) , higher in cases ( 34.3 ± 7.1 pg/ml and 24.6 ± 7.7 ng/ml , respectively ) than in controls ( 33.5 ± 7.1 pg/ml and 23.9 ± 8.2 ng/ml , respectively ) . The OR of prostate cancer comparing men in the top to bottom quartile of 1,25(OH)2D was 1.25 ( 95 % CI : 0.82–1.90 , p-trend = 0.16 ) . For 25(OH)D the OR of prostate cancer comparing the top and bottom quartiles was 1.19 ( 95 % CI : 0.79–1.79 , p-trend = 0.59 ) . These findings did not vary by level of the other metabolite , age at diagnosis , family history of prostate cancer , or factors that are thought to influence 25(OH)D levels . Conclusion : In this prospect i ve study , we did not observe an inverse association between plasma concentrations of 1,25(OH)2D or 25(OH)D and incident prostate cancer , although we can not rule out potential effects at later stages of the disease Background In conventional epidemiology confounding of the exposure of interest with lifestyle or socioeconomic factors , and reverse causation whereby disease status influences exposure rather than vice versa , may invali date causal interpretations of observed associations . Conversely , genetic variants should not be related to the confounding factors that distort associations in conventional observational epidemiological studies . Furthermore , disease onset will not influence genotype . Therefore , it has been suggested that genetic variants that are known to be associated with a modifiable ( nongenetic ) risk factor can be used to help determine the causal effect of this modifiable risk factor on disease outcomes . This approach , mendelian r and omization , is increasingly being applied within epidemiological studies . However , there is debate about the underlying premise that associations between genotypes and disease outcomes are not confounded by other risk factors . We examined the extent to which genetic variants , on the one h and , and nongenetic environmental exposures or phenotypic characteristics on the other , tend to be associated with each other , to assess the degree of confounding that would exist in conventional epidemiological studies compared with mendelian r and omization studies . Methods and Findings We estimated pairwise correlations between nongenetic baseline variables and genetic variables in a cross-sectional study comparing the number of correlations that were statistically significant at the 5 % , 1 % , and 0.01 % level ( α = 0.05 , 0.01 , and 0.0001 , respectively ) with the number expected by chance if all variables were in fact uncorrelated , using a two-sided binomial exact test . We demonstrate that behavioural , socioeconomic , and physiological factors are strongly interrelated , with 45 % of all possible pairwise associations between 96 nongenetic characteristics ( n = 4,560 correlations ) being significant at the p < 0.01 level ( the ratio of observed to expected significant associations was 45 ; p-value for difference between observed and expected < 0.000001 ) . Similar findings were observed for other levels of significance . In contrast , genetic variants showed no greater association with each other , or with the 96 behavioural , socioeconomic , and physiological factors , than would be expected by chance . Conclusions These data illustrate why observational studies have produced misleading cl aims regarding potentially causal factors for disease . The findings demonstrate the potential power of a methodology that utilizes genetic variants as indicators of exposure level when study ing environmentally modifiable risk factors Operating through the vitamin D receptor ( VDR ) , vitamin D inhibits prostate cancer growth and increases insulin-like growth factor binding protein ( IGFBP ) expression , suggesting that the vitamin D and insulin-like growth factor ( IGF ) regulatory systems may operate together to affect prostate cancer . Among 191 newly diagnosed prostate cancer cases and 304 r and omly selected population controls in Shanghai , China , we found no significant association between the BsmI or FokI VDR gene polymorphisms and prostate cancer risk . However , we found that among men with the ff FokI genotype , those in the highest tertile of plasma IGFBP-3 had a decreased risk versus those in the lowest tertile ( odds ratio , 0.14 ; 95 % confidence interval , 0.04 - 0.56 ; P(trend ) < 0.01 ) , whereas among men with the FF and Ff genotypes , IGFBP-3 was not associated with risk . Similarly , IGFBP-1 was inversely associated with prostate cancer risk only among men with the ff FokI genotype ( odds ratio , 0.25 ; 95 % confidence interval , 0.07 - 0.85 ; P(trend ) = 0.02 ) . No such FokI genotype-specific effects were observed for IGF-I or IGF-II . Our findings in a low-risk population suggest that the IGF and vitamin D regulatory systems may interact to affect prostate cancer risk . Larger studies are needed to confirm these findings and clarify the underlying mechanisms 
    Output:
    
Our finding provides some support for the hypothesis that low levels of vitamin D may increase the risk of prostate cancer progression