Methylenetetrahydrofolate reductase variants associated with hypertension and cardiovascular disease interact with dietary polyunsaturated fatty acids to modulate plasma homocysteine in puerto rican adults.
ABSTRACT: Although methylenetetrahydrofolate reductase (MTHFR) genetic variants are associated with plasma homocysteine (Hcy) and cardiovascular disease (CVD), little is known whether dietary fatty acid intake modulates these associations. The goal was to examine the interaction of MTHFR variants with dietary fatty acids influencing plasma Hcy in 995 Boston Puerto Rican adults. We found that plasma Hcy concentration was negatively correlated with (n-3) PUFA intake (r = -0.117; P = 0.022), and the ratio of (n-3):(n-6) PUFA in the diet (r = -0.122; P = 0.009). Further, 2 functional MTHFR variants, 1298A>C and 677C>T, which are not in linkage disequilibrium in this population, were significantly associated with hypertension (OR = 1.72, P = 0.024, and OR = 1.60, P = 0.002, respectively). In addition, the 1298A>C variant was significantly associated with CVD (OR = 3.32; P = 0.030). Importantly, this variant exhibited significant interactions with intakes of total and (n-6) PUFA and the (n-3):(n-6) PUFA ratio of the diet. The plasma Hcy concentration of carriers of risk allele 1298C was greater than that of noncarriers only when participants had consumed a high-PUFA diet (>7.8% energy) but was not greater when they had low intake of PUFA (?7.8% energy). In addition, participants with combined genotypes of both SNP (677 TT with 1298 AC or CC) who consumed high levels of (n-3) PUFA (>0.66% energy) had lower plasma Hcy compared with those who had the same genotype and consumed low levels of (n-3) PUFA (?0.66% energy). Our study suggests that dietary PUFA intake modulates the effect of 2 MTHFR variants on plasma Hcy in Boston Puerto Rican adults.
Project description:OBJECTIVE:To investigate genetic and lifestyle factors and their interactions on plasma homocysteine (Hcy) concentrations in the Boston Puerto Rican population. DESIGN:Cross-sectional study. Plasma concentrations of Hcy, folate, vitamin B12 and pyridoxal phosphate were measured, and genetic polymorphisms were determined. Data on lifestyle factors were collected in interviews. SETTING:A population survey of health and nutritional measures. SUBJECTS:A total of 994 Puerto Rican men and women residing in the Boston metropolitan area. RESULTS:Smoking status was positively associated with plasma Hcy. Genetic polymorphisms MTHFR 677C?T, FOLH1 1561C?T, FOLH1 rs647370 and PCFT 928A?G interacted significantly with smoking for Hcy. MTHFR 1298A?C (P = 0·040) and PCFT 928A?G (P = 0·002) displayed significant interactions with alcohol intake in determining plasma Hcy. Subjects with PCFT 928GG genotype had significantly higher plasma Hcy concentrations compared with carriers of the A allele (AA+AG; P = 0·030) among non-drinking subjects. When consuming alcohol, GG subjects had lower plasma Hcy levels compared with AA+AG subjects. Physical activity interacted significantly with MTR 2756A?G in determining plasma Hcy (P for interaction = 0·002). Smoking interacted with physical activity for plasma Hcy (P for interaction = 0·023). CONCLUSIONS:Smoking and drinking were associated plasma Hcy concentrations. Genetic variants involved in folate metabolism further modify the effects of lifestyle on plasma Hcy.
Project description:Dietary n-3 polyunsaturated fatty acids (PUFAs) are associated with decreased plasma homocysteine (Hcy), an important biomarker for cardiovascular disease. The S-adenosylmethionine synthetase type-1 (MAT1A), an essential enzyme in the conversion of methionine to S-adenosylmethionine, plays a key role in homocysteine metabolism. This study investigated the interaction between dietary fatty acids and MAT1A genotypes on plasma Hcy concentrations among Boston Puerto Ricans.Plasma Hcy and MAT1A genotypes were determined in 994 subjects of the Boston Puerto Rican Health Study. Dietary fatty acid intakes were assessed by interviews using a questionnaire adapted from the NCI/Block food frequency form.In the cross-sectional analysis, genetic variant MAT1A 3U1510 displayed a significant interaction with dietary n-3:n-6 PUFA ratio in determining plasma Hcy (p-value for interaction = 0.025). 3U1510G homozygotes had significantly lower plasma Hcy concentration than major allele homozygotes and heterozygotes (AA + AG) (p-value for trend = 0.019) when the n-3:n-6 ratio was >0.09. Two other MAT1A variants, d18777 and i15752, also showed significant interactions with different constituents of dietary fat influencing Hcy concentrations. Furthermore, haplotypes consisting of three variants displayed a strong interaction with n3:n6 ratio influencing Hcy concentrations.Our results suggest that MAT1A genotypes appear to modulate effects of dietary fat on plasma Hcy.
Project description:The study was conducted to investigate potential association between MTHFR genotypes and diabetic peripheral neuropathy (DPN) in Puerto Ricans with type-2 diabetes mellitus (T2DM) treated with metformin. The prevalence of major MTHFR polymorphisms in this cohort was also ascertained.DNAs from 89 metformin-treated patients with T2DM and DPN were genotyped using the PCR-based RFLP assay for MTHFR677C>T and 1298A>C polymorphisms. Frequency distributions of these variants in the study cohort were compared to those reported for three reference populations (HapMap project) and controls (400 newborn specimens). Chi-square (or Fischer's exact) tests and odds ratios (OR) were used to assess association with DPN susceptibility risk (patients vs. controls) and biochemical markers (wild types vs. carriers).Sixty-seven percent (67%) of participants carry at least one of these MTHFR polymorphisms. No deviations from Hardy-Weinberg equilibrium were detected. The genotype and allele frequencies showed statistically significant differences between participants and controls (p<0.0001 and p=0.03, respectively). Results suggest that 1298A>C but not 677C>T is associated with DPN susceptibility in this cohort (p=0.018). Different patterns of allelic dissimilarities are observed when comparing our cohort vs. the three parental ancestries. After sorting individuals by their carrier status, no significant associations were observed between these genetic variants (independently or combined) and any of the biochemical markers (HbA1c, folate, vitamin B12, homocysteine).Prevalence of major MTHFR variants in Puerto Rican patients with T2DM is first time ever reported. The study provides further evidence on the use of this genetic marker as an independent risk factor for DPN.
Project description:<b><i>Objective:</i></b> Although genetic variants of key enzymes in the folic acid-methionine metabolic circulation, including methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) were thought to be related to the risk of recurrent pregnancy loss (RPL), the results of recent studies have been inconsistent. Therefore, the present retrospective case-control study was designed to explore whether the variants c.66A>G in <i>MTRR</i> and c.677C>T and c.1298A>C in <i>MTHFR</i> are associated with the susceptibility of RPL in Southeast Chinese women. <b><i>Materials and Methods:</i></b> In total, samples from 237 RPL patients and 618 healthy controls were collected and genotyped by fluorescent quantitative polymerase chain reaction. The frequencies of the variants were calculated and compared between the two groups. The relative risk of the various genotypes was further determined by calculating the odds ratio (OR) at a 95% confidence interval (CI). <b><i>Results:</i></b> A significant positive correlation was observed between the variants <i>MTHFR</i> c.677C>T, <i>MTHFR</i> c.1298A>C, <i>MTRR</i> c.66A>G, and RPL susceptibility (<i>MTHFR</i> c.677C>T, OR?=?0.74, 95% CI?=?0.58-0.95, <i>p</i>?=?0.02; <i>MTHFR</i> c.1298A>C, OR?=?1.39, 95% CI?=?1.09-1.77, <i>p</i>?=?0.008; <i>MTRR</i> c.66A>G, OR?=?1.38, 95% CI?=?1.10-1.73, <i>p</i>?=?0.006). Further analysis of the genotypic distributions of the three variants between the two groups showed that the <i>MTHFR</i> c.677C>T heterozygote was associated with lower RPL risk, while the <i>MTHFR</i> c.1298A>C variant and MTRR c.66A>G heterozygote were correlated with higher RPL risk (dominant model, <i>MTHFR</i> c.677C>T, OR?=?0.70, 95% CI?=?0.52-0.95, <i>p</i>?=?0.02; <i>MTHFR</i> c.1298A>C, OR?=?1.39, 95% CI?=?1.03-1.88, <i>p</i>?=?0.032; <i>MTRR</i> c.66A>G, OR?=?1.62, 95% CI?=?1.20-2.19, <i>p</i>?=?0.002). <b><i>Conclusion:</i></b> <i>MTHFR</i> c.677C>T and c.1298A>C and <i>MTRR</i> c.66A>G were associated with RPL in Southeast Chinese women.
Project description:Homocysteine (Hcy) is a potential risk factor for age-related cataract (ARC). Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme for Hcy metabolism, and variants of MTHFR may affect MTHFR enzyme activity. This study mainly evaluated the associations between variants in MTHFR gene, plasma MTHFR enzyme activity, total Hcy (tHcy) levels and ARC risk in Chinese population. Four single nucleotide polymorphisms (SNPs) in MTHFR gene were genotyped using the high-resolution melting (HRM) method in 502 ARC patients (mean age, 70.2 [SD, 9.0], 46.0% male) and 890 healthy controls (mean age, 67.1 [SD, 11.1], 47.6% male). The plasma MTHFR activity, folic acid (FA), vitamins B12 and B6 levels were detected by enzyme-linked immunosorbent assays (ELISA). The plasma tHcy levels were measured by an automated enzymatic assay. After the Bonferroni correction, the minor allele T of SNP rs1801133 showed a significant association with an increased risk of overall ARC (OR = 1.26, P = 0.003). Consistent association was also found between SNP rs1801133 and cortical ARC risk (OR = 1.44, P = 0.003). Haplotype analyses revealed an adverse effect of the haplotype "C-A-T-C" (alleles in order of SNPs rs3737967, rs1801131, rs1801133 and rs9651118) on ARC risk (OR = 1.55, P = 0.003). Moreover, in a joint analysis of SNPs rs9651118 and rs1801133, subjects with two unfavorable genotypes had a 1.76-fold increased risk of ARC compared with the reference group, and a statistically significant dose-response trend (Ptrend = 0.001) was also observed. Further, in healthy controls and patients with cortical ARC, the allele T of SNP rs1801133 and the increasing number of unfavorable genotypes were significantly correlated with decreased MTHFR activity as well as increased tHcy levels. However, there was no significant association between FA, vitamins B12, B6 levels and MTHFR variants. Our data indicated that variants in MTHFR gene might individually and jointly influence susceptibility to ARC by affecting MTHFR enzyme activity and tHcy levels.
Project description:Background:Genetic polymorphisms can explain some of the population- and individual-based variations in nutritional status biomarkers. Objective:We sought to screen the entire human genome for common genetic polymorphisms that influence folate-status biomarkers in healthy individuals. Design:We carried out candidate gene analyses and genome-wide association scans in 2232 young, healthy Irish subjects to evaluate which common genetic polymorphisms influence red blood cell folate, serum folate, and plasma total homocysteine. Results:The 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C?T (rs1801133) variant was the major genetic modifier of all 3 folate-related biomarkers in this Irish population and reached genome-wide significance for red blood cell folate (P = 1.37 × 10-17), serum folate (P = 2.82 × 10-11), and plasma total homocysteine (P = 1.26 × 10-19) concentrations. A second polymorphism in the MTHFR gene (rs3753584, P = 1.09 × 10-11) was the only additional MTHFR variant to exhibit any significant independent effect on red blood cell folate. Other MTHFR variants, including the 1298A?C variant (rs1801131), appeared to reach genome-wide significance, but these variants shared linkage disequilibrium with MTHFR 677C?T and were not significant when analyzed in MTHFR 677CC homozygotes. No additional non-MTHFR modifiers of red blood cell or plasma folate were detected. Two additional genome-wide significant modifiers of plasma homocysteine were found in the region of the dipeptidase 1 (DPEP1) gene on chromosome 16 and the Twist neighbor B (TWISTNB) gene on chromosome 7. Conclusions:The MTHFR 677C?T variant is the predominant genetic modifier of folate status biomarkers in this healthy Irish population. It is not necessary to determine MTHFR 677C?T genotype to evaluate folate status because its effect is reflected in concentrations of standard folate biomarkers. The MTHFR 1298A?C variant had no independent effect on folate status biomarkers. To our knowledge, this is the first genome-wide association study report on red blood cell folate and the first report of an association between homocysteine and TWISTNB.
Project description:AIM:Observational studies have reported that elevated homocysteine (Hcy) levels are associated with the risk of cardiovascular disease (CVD). However, interventions that lower Hcy do not provide a corresponding risk reduction. Therefore, the causal role of Hcy in CVD remains unclear. This 5-year prospective study investigated the associations of Hcy levels, folate intake, and host factors with arterial stiffness among the general Japanese population. METHODS:We prospectively recruited 658 participants (40-69 years old) from the general population during regular health checkup examinations. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) at baseline and the 5-year follow-up. Folate intake was estimated using a structured questionnaire. Genotyping was used to evaluate the MTHFR C677T and MS A2756G gene polymorphisms. Ultrafast liquid chromatography was used to measure total plasma Hcy levels. Association between these variables and CAVI values was evaluated using general linear regression and logistic regression models that were adjusted for atherosclerosis-related factors. RESULTS:Men had higher Hcy levels and CAVI values and lower folate intake than women (all, p?0.001). At baseline, Hcy, folate intake, and the two genotypes were not associated with CAVI values for both sexes. Among men, Hcy levels were positively associated with CAVI values at the 5-year follow-up (p=0.033). Folate intake and the two genotypes were not associated with the 5-year CAVI values. CONCLUSION:Plasma Hcy may be involved in arterial stiffness progression, as monitored using CAVI, among men.
Project description:Aim: Variants of the MTHFR gene have been associated with a wide range of diseases. Materials & methods: The present study analyzed data from clinical genotyping of MTHFR 677C>T and 1298A>C in 1405 patients in urban primary care settings. Results: Striking differences in ethnogeographic frequencies of MTHFR polymorphisms were observed. African-Americans appear to be protected from MTHFR deficiency. Hispanics and Caucasians may be at elevated risk due to increased frequencies of 677C>T and 1298A>C, respectively. Conclusion: Individuals carrying mutations for both genes were rare and doubly homozygous mutants were absent, suggesting the TTcc is extremely rare in the greater population. The results suggest multilocus MTHFR genotyping may yield deeper insight into the ethnogeographic association between MTHFR variants and disease.
Project description:Background:Elevated homocysteine (Hcy) is associated with several pathologies. Gene-diet interactions related to Hcy might be used to customize dietary advice to reduce disease incidence. To explore this possibility, we investigated interactions between anthropometry, biochemical markers and diet and single-nucleotide polymorphisms (SNPs) in relation to Hcy concentrations. Five SNPs of Hcy-metabolizing enzymes were analyzed in 2010 black South Africans. Results:Hcy was higher with each additional methylenetetrahydrofolate reductase (MTHFR) C677T minor allele copy, but was lower in methionine synthase (MTR) 2756AA homozygotes than heterozygotes. Individuals harboring cystathionine ? synthase (CBS) 833 T/844ins68 had lower Hcy concentrations than others. No interactive effects were observed with any of the anthropometrical markers. MTHFR C677T and CBS T833C/844ins68 homozygote minor allele carriers presented with lower Hcy as high density lipoprotein cholesterol (HDL-c) increased. Hcy concentrations were negatively associated with dietary protein and animal protein intake in the TT and TC genotypes, but positively in the CC genotype of CBS T833C/844ins68. Hcy was markedly higher in TT homozygotes of MTHFR C677T as added sugar intake increased. In CBS T833C/844ins68 major allele carriers, biotin intake was negatively associated with Hcy; but positively in those harboring the homozygous minor allele. Conclusions:The Hcy-SNP associations are modulated by diet and open up the possibility of invoking dietary interventions to treat hyperhomocysteinemia. Future intervention trials should further explore the observed gene-diet and gene-blood lipid interactions.
Project description:Background:Methylenetetrahydrofolate reductase (MTHFR) is indispensable for the conversion of homocysteine (Hcy) to methionine. The single nucleotide polymorphism (SNP) of MTHFR gene (rs1801133, C667T) is correlated with decreased enzyme activity that eventually results in elevated plasma Hcy levels. Hyperhomocysteinemia has been confirmed to be involved in the pathogenesis of stroke, cerebral small vessel disease (CSVD), various metabolic disorders and so on. However, the relationship between the MTHFR gene polymorphisms, Hcy, and CSVD has not been investigated. In this study, the relationship between SNPs of MTHFR gene and CSVD was determined after adjusting for cardiovascular risk factors, and the potential mechanism based on Hcy levels was explored. Methods:A total of 163 consecutive CSVD patients were collected as the case group. In the corresponding period, 326 healthy people were selected as the control group, who were matched to these cases according to age (±2 years) and gender at a ratio of 2:1. SNPs of MTHFR rs1801133, rs1801131, rs2274976, rs4846048, rs4846049, rs13306561 and rs3737964, were genotyped with TaqMan Pre-Designed SNP Genotyping Assays. Plasma Hcy levels were detected using Hcy reagent through enzymatic cycling assay. Multivariate analysis was used to identify the SNPs associated with CSVD susceptibility. Plasma Hcy levels were compared between different genotypes. Results:The MTHFR rs1801133 TT and CT genotype had increased risk for CSVD, and the OR was higher in the TT genotype than in the CT genotype (2.307 vs 1.473). The plasma Hcy levels of different genotypes showed the tendency of the TT genotype > CT genotype > CC genotype (19.91 ± 8.73 pg/ml vs 17.04 ± 5.68 pg/ml vs 14.96 ± 4.85 pg/ml). Conclusions:The SNP of MTHFR rs1801133 was correlated with CSVD, and the TT and CT genotypes had increased risk for CSVD compared to the CC genotype. The potential mechanism was associated with elevated Hcy levels.