MAT1A variants modulate the effect of dietary fatty acids on plasma homocysteine concentrations
Introduction
Elevated plasma homocysteine (Hcy), a thiol-containing amino acid byproduct of methionine metabolism [1], has been demonstrated to be an independent risk factor for cardiovascular disease (CVD) [1]. In addition to pathophysiological conditions, including menopause, renal disease, and hypothyroidism [2], the etiology of hyperhomocysteinemia (HHcy) is known to be multifactorial, including genetic and environmental factors, such as diet and lifestyle [2], [3]. The genetic causes of elevated plasma Hcy include rare inborn errors of Hcy metabolism, such as cystathionine beta-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) [4]. Recently, studies of polymorphisms from the critical genes involved in Hcy metabolic pathways demonstrated that MTHFR 677C > T [5], MTHFR 1298A > C [6], 5-methyltetrahydrofolate-homocysteine methyltransferase (MTRR) 66A > G [7] and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTR) 2756A > G [8] were associated with elevated plasma Hcy concentration. For environmental factors, lifestyle and diet play an important role in Hcy metabolism. Two-thirds of HHcy subjects in an elderly US population were associated with low plasma/serum concentrations of one or more of B group vitamins [9]. Smoking, drinking alcohol and physical activity have also been associated with elevated plasma Hcy [10].
Importantly, n-3 polyunsaturated fatty acids (n-3 PUFA), which have a protective effect on the cardiovascular system [11], were shown to improve Hcy metabolism [12]. Previously, we reported that plasma Hcy was significantly negatively correlated with the plasma/platelet phospholipids (PL) n-3 PUFA and n-3:n-6 PUFA ratio [12], [13]. Subsequent intervention studies have demonstrated that n-3 PUFA supplementation decreases plasma Hcy [14]. However, the results from studies evaluating the relationship between fatty acids and plasma Hcy are inconclusive [15]. Whether genetic variation may account for such inconsistent results is unknown. The relationship between n-3 PUFA and plasma Hcy is not yet fully understood. Methionine adenosyltransferase (MAT), an essential enzyme in methionine metabolism, catalyzes the conversion of methionine to S-adenosylmethionine (SAM). SAM is subsequently converted to S-adenosyl homocysteine and then Hcy in separate reactions [16]. We previously demonstrated that MAT1A variants were associated with stroke and hypertension [16]. Therefore, we hypothesize that MAT1A variants, single nucleotide polymorphisms (SNPs), modulate the effect of dietary fatty acids on plasma Hcy.
In the present study, we conducted a population-based evaluation to investigate the combined contributions of MAT1A genotype and dietary fatty acids to HHcy in the Boston Puerto Rican population. This population has experienced severe health disparity, including high rates of hypertension, diabetes, obesity, and CVD (16, 17). We examined the effects of MAT1A variants and dietary fatty acids on plasma Hcy concentration and assessed their potential interactions in modifying plasma Hcy.
Section snippets
Study design and subjects
This study was conducted within the ongoing Boston Puerto Rican Health Study (BPRHS) as described previously [17]. The analysis included 994 subjects who participated in the BPRHS study and had complete data on dietary intake, anthropometry, biochemical parameters, and MAT1A genotype. Interviews were conducted in volunteers’ homes to collect demographic and anthropometric data, and detailed data were collected on dietary intake using a questionnaire previously adapted from the NCI/Block food
Results
Information about demographic, biochemical, and dietary intake data are provided in Table 1. Men and women had similar mean ages. No significant differences were observed across sex for vitamins B6, and B12. However, BMI was significantly higher in women than in men, whereas smoking and alcohol consumption were more prevalent in men than in women. Plasma Hcy concentration for all subjects ranged from 3.90 to 30.4 μmol/L. Men had significantly higher mean Hcy. Genotype frequencies of eight MAT1A
Discussion
In the present study we report that dietary n-6 PUFA and n-3:n-6 PUFA ratio were significantly associated with plasma Hcy concentration, although no difference in plasma Hcy based on MAT1A genotype was detected. We also identified interactions of dietary n-3:n-6 ratio and MUFA with MAT1A variants (SNP or haplotypes) in relation to plasma Hcy concentration. While these interactions have not been reported previously, several other studies provide evidence to support our findings (below).
Based on
Author’s contributions to manuscript
TH, YL, and JS carried out the studies, analyzed data and drafted the manuscript; CL, LP, YL, CS and JC participated in manuscript preparation; and CL, KT, DL and JO participated in the project design. All authors read and approved the final manuscript.
Conflicts of interest
No potential conflicts of interest.
Acknowledgement
This work is supported by the China Scholarship Council, the National Institutes of Health, National Institute on Aging, Grant Number 5P01AG023394-02, NIH/NHLBI grant number HL54776 and HL078885 and contracts 53-K06–5-10 and 58–1950-9–001 from the U.S. Department of Agriculture Research Service.
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Cited by (13)
N-3 polyunsaturated fatty acid and homocysteine metabolism
2022, Advances in Dietary Lipids and Human HealthGene-diet interactions and cardiovascular diseases: Saturated and monounsaturated fat
2019, Principles of Nutrigenetics and Nutrigenomics: Fundamentals of Individualized NutritionDeterminants of hyperhomocysteinemia in healthy and hypertensive subjects: A population-based study and systematic review
2017, Clinical NutritionCitation Excerpt :The main characteristics of the included studies are shown in Tables 3 and 4. Subjects were ethnically diverse, and the studies were conducted in North America [23–28], Europe [8,29–62], Asia [9,63–87], Africa [88,89], and Australia [90]. The correlates of Hcy were shown in Table 4.
Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular and all-cause mortality
2012, Clinical NutritionCitation Excerpt :In 2002, an updated meta-analysis focusing on prospective observational studies confirmed this association, with an estimated 25% reduction in Hcy levels associated with 11% lower risk of CHD and 19% lower risk of stroke.40 Even though dietary fatty acids have been demonstrated recently to be associated with plasma Hcy concentration,41,42 B vitamins appear to be the more effective Hcy-lowering nutrients.15 The large-scale clinical trials of sufficient dose and duration were conducted to determine whether lowering Hcy levels by folic acid, vitamin B6 and vitamin B12 reduces the risk of vascular disease.