***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: A moderately elevated plasma total homocysteine ( tHcy ) , whether measured during fasting or post-methionine load ( PML ) , is increasingly being recognized as a risk factor for coronary artery diseases ( CAD ) . However , etiologies for moderately elevated plasma tHcy , particularly with regard to the role of genetic influence on plasma tHcy levels , are still not well understood . In the current investigation , we studied 1025 individuals with respect to the effect of the 68-bp insertion ( 844ins68 variant ) of the cystathionine beta-synthase ( CBS ) gene  , the A(2756)G transition of the B(12)-dependent methionine synthase ( MS ) gene and the C(677)T transition of the methylenetetrahydrofolate reductase ( MTHFR ) gene on fasting and 4 h PML tHcy . Of these individuals , 153 ( 14.9 % ) were heterozygous for the 68-bp insertion , 329 ( 32.1 % ) were heterozygous for the G(2756 ) allele and 122 ( 11.9 % ) were homozygous for the C(677)T transition . Individuals heterozygous for the insertion had significantly lower PML increase in tHcy concentrations , while individuals homozygous for the A(2756)G transition had significantly lower fasting tHcy levels . A 2-way ANOVA showed that there was no interaction between the 844ins68 and the A(2756)G transition for either fasting tHcy or PML increase in tHcy , confirming the fact that the effect of these two genotypes on plasma tHcy levels are additive . The effects are opposite but additive with the C(677)50 % of all individuals in this study carried polymorphic traits , which predisposed them to either higher or lower plasma tHcy concentrations , thus providing new evidence of the importance of genetic influences as determinants of tHcy levels Background : Determinants of one-carbon metabolism , such as folate and vitamin B12 , have been implicated in cancer development . Previous studies have not provided conclusive evidence for the importance of circulating concentrations of folate and vitamin B12 in prostate cancer etiology . The aim of the present study was to investigate the relationship between prostate cancer risk and circulating concentrations of folate and vitamin B12 in a large prospect i ve cohort . Methods : We analyzed circulating concentrations of folate and vitamin B12 in 869 cases and 1,174 controls , individually matched on center , age , and date of recruitment , nested within the European Prospect i ve Investigation into Cancer and Nutrition cohort .  Relative risks ( RR ) for prostate cancer were estimated using conditional logistic regression models . Results : Overall , no significant associations were observed for circulating concentrations of folate ( Ptrend = 0.62 ) or vitamin B12 ( Ptrend = 0.21 ) with prostate cancer risk . RRs for a doubling in folate and vitamin B12 concentrations were 1.03 [ 95 % confidence interval ( 95 % CI ) , 0.92 - 1.16 ] and 1.12 ( 95 % CI , 0.94 - 1.35 ) , respectively . In the subgroup of cases diagnosed with advanced stage prostate cancer , elevated concentrations of vitamin B12 were associated with increased risk ( RR for a doubling in concentration , 1.69 ; 95 % CI , 1.05 - 2.72 , Ptrend = 0.03 ) . No other subgroup analyses result ed in a statistically significant association . Conclusion : This study does not provide strong support for an association between prostate cancer risk and circulating concentrations of folate or vitamin B12 . Elevated concentrations of vitamin B12 may be associated with an increased risk for advanced stage prostate cancer , but this association requires examination in other large prospect i ve studies . ( Cancer Epidemiol Biomarkers Prev 2007;17(2):279–85 Methionine synthase ( MS ) encodes an enzyme that catalyzes the remethylation of homocysteine to methionine using a methyl group donated by 5-methyltetrahydrofolate , which is the major circulating form of folate in the body . Functional genetic variants of the MS may alter total homocysteine ( tHcy ) as well as folate levels which are independent risk factors for vascular disease . The influence of a common genetic polymorphism ( 2756A-->G , D919 G ) of the MS gene on plasma tHcy and folate levels and its relation to the risk of myocardial infa rct ion ( MI ) in a prospect i ve study of male physicians in the US was investigated . A nested case-control study was conducted within the Physicians ' Health Study which was originally design ed as a double-blind trial of aspirin and beta-carotene among 22071 US male physicians , aged 40 - 84 years in 1982 . Sixty-eight percent of participants also donated a blood sample .  The study included 387 incident MI case and 767 controls matched on age , smoking status , and time from r and omization in 6-month intervals . Individuals with GG genotype had a non-significant reduction of MI risk ( RR 0.51 , 95 % CI 0.17 - 1.16 ) compared to individuals with DD genotype after adjusting for MI risk factors . The MS polymorphism was associated with decreased tHcy ( 10.55 , 9.87 and 9.57 nmol/ml for DD , DG and GG genotypes , respectively ) and increased folate levels ( 3.95 , 3.78 , 7.31 ng/ml for DD , DG and GG genotypes , respectively ) only among controls but not cases . It was concluded that influence of the MS ( D919 G ) polymorphism on the plasma tHcy and folate levels is at most moderate , but should be further investigated in other large prospect i ve studies It has been proposed that folate and polymorphisms of the enzyme methylenetetrahydrofolate reductase ( MTHFR ) , which regulates influx of folate from DNA synthesis and repair to methylation reactions , are involved in the aetiology of cancer . To relate the MTHFR 677C→T and 1298A→C polymorphisms to the risk of prostate cancer , taking into consideration prospect i ve plasma levels of folate , vitamin B12 and homocysteine . The design was a case – control study of 223 prostate cancer cases and 435 matched controls nested within the population -based Northern Sweden Health and Disease Cohort . Neither the MTHFR 677C→T nor the MTHFR 1298A→C polymorphism was statistically significantly associated with the risk of prostate cancer in univariate analysis by conditional logistic regression . After adjustment for MTHFR 1298A→C , plasma folate , vitamin B12 , homocysteine , body mass index and smoking , the odds ratios were , for the 677 CT genotype , 1.52 [ 95 % confidence interval ( CI ) 1.02–2.26 ] , and for TT , 0.91 ( 95 % CI 0.41–2.04 ) . Our previously reported observation of a possible increase in the risk of prostate cancer at high plasma folate levels was attributable in this study to subjects having the MTHFR 677C→T polymorphism . We found that the MTHFR 677C→T polymorphism is not likely to have a major role in the development of prostate cancer , although it may possibly increase the risk in combination with high plasma folate levels . Further investigation in larger studies is warranted The role of folate metabolism in cancer development is a topic of much current interest , with maintenance of adequate folate status tending to show a protective effect . Aberrant methylation , primarily hypermethylation of certain genes including tumor suppressors , has been implicated in prostate cancer development . Folate , vitamin B12 and homocysteine are essential for methyl group metabolism and thus also for DNA methylation . We related plasma levels of these factors to prostate cancer risk in a prospect i ve study of 254 case subjects and 514 matched control subjects . Increasing plasma levels of folate and vitamin B12 were statistically significantly associated with increased prostate cancer risk , with an odds ratio of 1.60 ( 95 % CI = 1.03 - 2.49 ; p(trend ) = 0.02 ) for folate and 2.63 ( 95 % CI = 1.61 - 4.29 ; p(trend ) < 0.001 ) for vitamin B12 for highest vs. lowest quartile . Increasing plasma homocysteine levels were associated with a reduced risk of borderline significance ( OR = 0.67 ; 95 % CI = 0.43 - 1.04 ; p(trend ) = 0.08 ) . After adjustment for the other 2 plasma variables , body mass index and smoking , a statistically significant increased risk remained only for vitamin B12 ( OR = 2.96 ; 95 % CI = 1.58 - 5.55 ; p(trend ) = 0.001 ) . Adjusted OR for folate and homocysteine were 1.30 ( 95 % CI = 0.74 - 2.24 ; p(trend ) = 0.17 ) and 0.91 ( 95 % CI = 0.51 - 1.58 ; p(trend ) = 0.60 ) , respectively . Our results suggest that factors contributing to folate status are not protective against prostate cancer . On the contrary , vitamin B12 , associated with an up to 3-fold increase in risk , and possibly also folate , may even stimulate prostate cancer development . These findings are novel and should be explored further in future studies Suboptimal DNA repair capacity is a risk factor for cancer that may be modulated by dietary nutrient intake , and serine hydroxymethyltransferase ( SHMT ) participates in folate metabolism and synthesis of purines and pyrimidines needed for DNA repair . Therefore , we tested our hypothesis that genetic variants of the cytosolic SHMT ( SHMT1 ) gene are associated with lung cancer risk . In a hospital-based case-control study of 1032 non-Hispanic white lung cancer patients and 1145 matched cancer-free controls , we genotyped five common SHMT1 polymorphisms either in the promoter , exons , or 3'-untranslated regions . Although the genotype and allele frequency distribution of each SNP did not differ between cases and controls statistically significantly in the single-locus analysis , the rs638416 polymorphism in the promoter alone and the combined putative risk variant genotypes containing rs643333C , rs638416 G , rs1979277 T , rs3738 G , and rs1979276C were associated with altered risk . Those carrying the combined 3 + risk variant genotypes had an increased risk of lung cancer ( adjusted OR=1.65 , 95 % CI=1.05 - 2.57 , compared with those having 0 - 1 risk genotypes ; and OR=1.21 , 95 % CI=1.01 - 1.45 , compared with those having 0 - 2 risk genotypes ) . The risk was more pronounced among older individuals ( > 61 years ) or those having a low total folate intake or a high methionine intake . No evidence of interactions between the putative SHMT risk variant genotypes and the selected variables was found . These results suggest that SHMT1 variants may play a role in the etiology of lung cancer , and our findings need to be verified in larger prospect i ve studies Elevation in plasma homocysteine concentration has been associated with vascular disease and neural tube defects . Methionine synthase is a vitamin B(12)-dependent enzyme that catalyses the remethylation of homocysteine to methionine . Therefore , defects in this enzyme may result in elevated homocysteine levels . One relatively common polymorphism in the methionine synthase gene ( D919 G ) is an A to G transition at bp 2,756 , which converts an aspartic acid residue believed to be part of a helix involved in co-factor binding to a glycine . We have investigated the effect of this polymorphism on plasma homocysteine levels in a working male population ( n = 607 ) in which we previously described the relationship of the C677 T " thermolabile " methylenetetrahydrofolate reductase ( MTHFR ) polymorphism with homocysteine levels .  We found that the methionine synthase D919 G polymorphism is significantly ( P = 0.03 ) associated with homocysteine concentration , and the DD genotype contributes to a moderate increase in homocysteine levels across the homocysteine distribution ( OR = 1.58 , DD genotype in the upper half of the homocysteine distribution , P = 0.006 ) . Unlike thermolabile MTHFR , the homocysteine-elevating effects of the methionine synthase polymorphism are independent of folate and B(12 ) levels ; however , the DD genotype has a larger homocysteine-elevating effect in individuals with low B(6 ) levels . This polymorphism may , therefore , make a moderate , but significant , contribution to clinical conditions that are associated with elevated homocysteine PURPOSE To test a community population for the hypothesis that carcinogenesis is related to blood folate levels . METHODS Prospect i ve analysis of cancer mortality data for a coh 
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We found no effect of MTHFR 677C > T or any of the other alleles in dominant , recessive or additive models , or in comparing a/a versus A/A homozygous .
Neither did we find any difference in effects on advanced or localized cancers .
Our meta- analysis suggests that known common folate-pathway single nucleotide polymorphisms do not have significant effects on susceptibility to prostate cancer