MAT1A variants modulate the effect of dietary fatty acids on plasma homocysteine concentrations

Abstract

Background and Aim

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.

Methods and Results

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.

Result

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.

Conclusions

Our results suggest that MAT1A genotypes appear to modulate effects of dietary fat on plasma Hcy.

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.