***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: We have studied the effect of common mutations ( 677C-->T and 1298A-->C ) of the  methylenetetrahydrofolate reductase ( MTHFR ) gene  in sixty-six healthy French subjects , aged 27 - 47 years .  Serum folate , vitamin B12 , and plasma total homocysteine  were measured as well as the specific activity of MTHFR  in lymphocytes . The frequency of subjects homozygous for the 677TT genotype was 18 % , and that of those homozygous for the 1298CC genotype was 12.5 % . The frequency of individuals heterozygous for both mutations was 23.5 % . The 1298A-->C mutation was associated with decreased MTHFR specific activity in subjects with both 677CC and 677CT genotypes . This activity was 60 % for the 677CC/1298AC genotype and 52 % for the 677CC/1298CC genotype when compared with the MTHFR specific activity of the 677CC/1298AA genotype . Heterozygotes for both mutations ( 677CT/1298AC genotype ) had 36 % of the reference specific activity . Although homocysteine levels in 677TT and 1298CC genotype subjects were higher than for other genotypes , no significant differences were observed among different genotypes . This may be due to high serum folate level in our sample s , and suggests that folate therapy may be useful to prevent hyperhomocysteinaemia in homozygous mutant subjects BACKGROUND Methylenetetrahydrofolate reductase ( MTHFR ; EC 1.7.99.5 ) supplies the folate needed for the metabolism of homocysteine . A reduction in MTHFR activity , as occurs in the homozygous state for the 677C-->T ( so-called thermolabile ) enzyme variant ( TT genotype ) , is associated with an increase in plasma total homocysteine ( tHcy ) . OBJECTIVE In vitro studies suggest that the reduced activity of thermolabile MTHFR is due to the inappropriate loss of its riboflavin cofactor . We investigated the hypothesis that MTHFR activity in the TT genotype group is particularly sensitive to riboflavin status . DESIGN We studied tHcy and relevant B-vitamin status by MTHFR genotype in a cross-sectional study of 286 healthy subjects aged 19 - 63 y ( median : 27 y ) . The effect of riboflavin status was examined by dividing the sample into tertiles of erythrocyte glutathionine reductase activation coefficient , a functional index of riboflavin status . RESULTS Lower red blood cell folate ( P = 0.0001 ) and higher tHcy ( P = 0.0082 ) concentrations were found in the TT group than in the heterozygous ( CT ) or wild-type ( CC ) groups . However , these expected relations in the total sample were driven by the TT group with the lowest riboflavin status , whose mean tHcy concentration ( 18.09 micromol/L ) was almost twice that of the CC or CT group . By contrast , adequate riboflavin status rendered the TT group neutral with respect to tHcy metabolism . CONCLUSIONS The high tHcy concentration typically associated with homozygosity for the 677C-->T variant of MTHFR occurs only with poor riboflavin status . This may have important implication s for governments considering new fortification policies aim ed at the prevention of diseases for which this genotype is associated with increased risk The effectiveness of additional food folate in improving folate status in humans is uncertain particularly in people with the common genetic variant ( 677 C-->T ) in the methylenetetrahydrofolate reductase ( MTHFR ) gene . To examine the effect of a doubling of food folate consumption on folate status response variables , women ( n=32 ; 18 - 46 years ) with the MTHFR 677 CC or TT genotype consumed either 400 ( n=15 ; 7 CC and 8 TT ) or 800 ( n=17 ; 8 CC and 9 TT ) microg/day of dietary folate equivalents ( DFE ) derived exclusively from naturally occurring food folate for 12 weeks . A repeated measures two-factor ANOVA was used to examine the effect of the dietary treatment , the MTHFR C677 T genotype and their interactions on serum folate , RBC folate and plasma total homocysteine ( tHcy ) during the last 3 weeks of the study . Consumption of 800 microg DFE/day result ed in serum folate concentrations that were 67 % ( P=.005 ) higher than consumption of 400 microg DFE/day ( 18.6+/-2.9 vs. 31.0+/-2.7 nmol/L , respectively ) and RBC folate concentrations that were 33 % ( P=.001 ) higher ( 1172+/-75 vs. 1559+/-70 nmol/L , respectively ) . Serum folate ( P=.065 ) and RBC folate ( P=.022 ) concentrations were lower and plasma tHcy was higher ( P=.039 ) in women with the MTHFR 677 TT genotype relative to the CC genotype . However , no genotype by dietary treatment interaction was detected . These data suggest that a doubling of food folate intake will lead to marked improvements in folate status in women with the MTHFR 677 CC or TT genotype Objective To determine an optimal population red blood cell ( RBC ) folate concentration for the prevention of neural tube birth defects . Design Bayesian model . Setting Data from two population based studies in China . Participants 247 831 participants in a prospect i ve community intervention project in China ( 1993 - 95 ) to prevent neural tube defects with 400 μg/day folic acid supplementation  and 1194 participants in a population based r and omized trial ( 2003 - 05 ) to evaluate the effect of folic acid supplementation on blood folate concentration among Chinese women of reproductive age . Intervention Folic acid supplementation ( 400 μg/day ) . Main outcome measures Estimated RBC folate concentration at time of neural tube closure ( day 28 of gestation ) and risk of neural tube defects . Results Risk of neural tube defects was high at the lowest estimated RBC folate concentrations ( for example , 25.4 ( 95 % uncertainty interval 20.8 to 31.2 ) neural tube defects per 10 000 births at 500 nmol/L ) and decreased as estimated RBC folate concentration increased . Risk of neural tube defects was substantially attenuated at estimated RBC folate concentrations above about 1000 nmol/L ( for example , 6 neural tube defects per 10 000 births at 1180 ( 1050 to 1340 ) nmol/L ) . The modeled dose-response relation was consistent with the existing literature . In addition , neural tube defect risk estimates developed using the proposed model and population level RBC information were consistent with the prevalence of neural tube defects in the US population before and after food fortification with folic acid . Conclusions A threshold for “ optimal ” population RBC folate concentration for the prevention of neural tube defects could be defined ( for example , approximately 1000 nmol/L ) . Population based RBC folate concentrations , as a biomarker for risk of neural tube defects , can be used to facilitate evaluation of prevention programs as well as to identify sub population s at elevated risk for a neural tube defect affected pregnancy due to folate insufficiency INTRODUCTION Methylenetetrahydrofolate reductase ( MTHFR ) C677 T is involved in folate and homocysteine metabolism . Disruption in the activity of this enzyme will alter their levels in the body . METHODOLOGY This study assessed MTHFR C677 T polymorphism and its relationship with serum homocysteine and B-vitamins levels in a sample of Chinese and Malays subjects in UPM , Serdang . One hundred subjects were r and omly selected from among the university population .  Folate , vitamin B12 , B6 , and homocysteine levels were determined using  MBA , ECLIA  , and  HPLC  , respectively . PCR coupled with HinfI digestion was used for detection of MTHFR C677 T polymorphism . RESULTS The frequency of T allele was higher in the Chinese subjects ( 0.40 ) compared to the Malay ( 0.14 ) . Folate , vitamin B12 and B6 levels were highest in the wild genotype in both ethnic groups . Subjects with heterozygous and homozygous genotype showed the highest homocysteine levels . The serum folate and homocysteine were mainly affected by homozygous genotype . CONCLUSION MTHFR C677 T polymorphism plays an important role in influencing the folate and homocysteine metabolism BACKGROUND The association between blood homocysteine concentration and the risk of cardiovascular disease ( CVD ) remains controversial , but few studies have examined the association between MTHFR C677 T ( a proxy for high homocysteine concentration ) and death from CVD . OBJECTIVE The objective was to examine associations of MTHFR C677 T , a proxy for high homocysteine concentrations , with CVD mortality and with all-cause mortality in a national representative prospect i ve cohort of the US adult population before the introduction of m and atory folic acid fortification of flour .  DESIGN We used Mendelian r and omization to examine the association of MTHFR C677 T with  cause-specific mortality in 5925 participants by accessing the NHANES III ( 1991 - 1994 ) Linked Mortality File ( through 2006 ) . RESULTS A comparison of homozygotes at baseline showed that individuals with a TT genotype had a 2.2-μmol/L higher homocysteine and a 1.4-ng/mL lower folate concentration , respectively , than did those with a CC genotype . The TT genotype frequency varied from 1.2 % ( 95 % CI : 0.7 , 2.0 ) in non-Hispanic blacks and 11.6 % ( 95 % CI : 9.6 , 14.0 ) in non-Hispanic whites to 19.4 % ( 95 % CI : 16.7 , 22.3 ) in Mexican Americans . After adjustment for ethnic group and other CVD risk factors , the MTHFR C677 T TT genotype was associated with significantly lower CVD mortality ( HR : 0.69 ; 95 % CI : 0.50 , 0 . 95 ) but had no significant effect on all-cause mortality ( HR : 0.79 ; 95 % CI : 0.59 , 1.05 ) . After stratification by period of follow-up , the inverse association of MTHFR with CVD mortality was significant only in the period after introduction of m and atory folic acid fortification . CONCLUSION The inverse association of MTHFR with CVD mortality was unexpected and highlights the need for caution in interpretation of Mendelian r and omization studies , which , like other observational studies , can be influenced by chance , bias , or confounding BACKGROUND The methylenetetrahydrofolate reductase ( MTHFR ) genotype is associated with modification of disease and risk of neural tube defects . Plasma and red blood cell ( RBC ) folate and plasma homocysteine concentrations change in response to daily intakes of folic acid supplements , but no large-scale or population -based r and omized trials have examined whether the MTHFR genotype modifies the observed response . OBJECTIVE We sought to determine whether the MTHFR 677C→T genotype modifies the response to folic acid supplementation during and 3 mo after discontinuation of supplementation . DESIGN Northern Chinese women of childbearing age were enrolled in a 6-mo supplementation trial of different folic acid doses : 100 , 400 , and 4000 μg/d and 4000 μg/wk  . Plasma and RBC folate and plasma homocysteine concentrations were measured at baseline ; after 1 , 3 , and 6 mo of supplementation ; and 3 mo after discontinuation of supplementation . MTHFR genotyping was performed to identify a C→T mutation at position 677 ( n = 932 ) . RESULTS Plasma and RBC folate and homocysteine concentrations were associated with MTHFR genotype throughout the supplementation trial , regardless of folic acid dose . MTHFR TT was associated with lower folate concentrations , and the trend of TT < CC was maintained at even the highest doses . Folic acid doses of 100 μg/d or 4000 μg/wk did not reduce high homocysteine concentrations in those with the MTHFR TT genotype . CONCLUSION MTHFR genotype was an independent predictor of plasma and RBC folate and plasma homocysteine concentrations and did not have a significant interaction with folic acid dose during supplementation . This trial was registered at clinical trials.gov as NCT00207558 
    Output:
    
Meta- analysis results ( limited to the MA , the recommended population assessment method ) indicated a consistent percentage difference in S/P and RBC folate concentrations across MTHFR C677 T genotypes .
Lower blood folate concentrations associated with this polymorphism could have implication s for a population -level risk of neural tube defects