ARS | Publication request: MAT1A variants are associated with hypertension, stroke, and DNA damage and are modulated by vlasma vitamin B6 and folate concentration

Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 20, 2010
Publication Date: May 20, 2010
Citation: Lai, C., Tucker, K., Parnell, L.D., Shen, J., Caouette, H., Warodomwichit, D., Lee, Y., Crott, J., Ordovas, J.M. 2010. MAT1A variants are associated with hypertension, stroke, and DNA damage and are modulated by plasma vitamin B6 and folate concentration. American Journal of Clinical Nutrition. 91(5):1377-1386.

Interpretive Summary: Elevated plasma homocysteine is a cardiovascular disease (CVD) risk factor, but how homocysteine affects CVD risk is not well defined. S-adenosylmethionine synthetase isoform type-1 (MAT1A) is a key enzyme in the metabolism of homocysteine, converting dietary methionine into S-adenosyl methionine. We examined the relationship between eight genetic variants, called SNPs, at the MAT1A gene and hypertension, stroke, homocysteine, and DNA damage in 299 men and 707 women of the Boston Puerto Rican Health Study. There was a strong relationship between MAT1A variants and hypertension and stroke, independent of common variations in another gene important in the same biochemical pathway (MTHFR). Subjects carrying two copies of the less common variant d18777A had significantly greater likelihood of stroke (OR=4.30, P=0.006), while subjects with two copies of the less common version of another SNP 3U1510A had a lower likelihood of hypertension (OR=0.67, P=0.022) and stroke (OR=0.35, P=0.015). Furthermore, we noted that individuals carrying the stroke-associated allele d18777A who also had low folate levels in the blood showed significantly higher homocysteine levels, compared to the rest of the population. In contrast, those persons with adequate plasma folate concentration showed no significant difference in homocysteine regardless of MAT1A genotype. Additionally, those individuals carrying the non-risk version of MAT1A of 3U1510A showed lower urinary levels of 8-OHdG, a measure of damage to DNA, only when vitamin B6 levels were high, whereas individuals harboring two copies of the risk variant 3U1510G had elevated 8-OHdG levels regardless of vitamin B6 levels. In summary, MAT1A variants were strongly associated with hypertension and stroke. Improving folate status of general populations or vitamin B6 status of those persons who carry 3U1510A reduces their plasma homocysteine concentrations and DNA damage, respectively, hence likely decreases their risk of CVD.

Technical Abstract: Elevated plasma homocysteine is a cardiovascular disease (CVD) risk factor. However, the mechanism underlying this relationship is not understood. S-adenosylmethionine synthetase isoform type-1 (MAT1A) is a key enzyme in the metabolism of homocysteine, converting dietary methionine into S-adenosyl methionine. We examined associations between eight SNPs at MAT1A and hypertension, stroke, homocysteine, and DNA damage in 299 men and 707 women of the Boston Puerto Rican Health Study. MAT1A variants and haplotypes were strongly associated with hypertension and stroke, independent of methylenetetrahydrofolate reductase (MTHFR). Homozygotes of the minor allele d18777A had significantly greater likelihood of stroke (OR=4.30, P=0.006), whereas homozygotes of the minor allele 3U1510A had lower likelihood of hypertension (OR=0.67, P=0.022) and stroke (OR=0.35, P=0.015). Furthermore, we observed strong interactions between MAT1A genotypes and plasma folate and vitamin B6 status on plasma homocysteine and urine measures of 8-hydroxydeoxyguanosine (8-OHdG), a bio-marker of oxidative DNA damage. Homozygotes with stroke-associated allele d18777A and low plasma folate concentration had significantly higher homocysteine concentrations, compared to the rest of the population (12.2 vs 10.5 µmol/L, P=0.004). In contrast, subjects with adequate plasma folate concentration showed no significant difference in homocysteine across genotypes. Additionally, carriers of the non-risk-allele 3U1510A displayed lower 8-OHdG in those with higher vitamin B6, whereas homozygotes for the risk-allele 3U1510G had high 8-OHdG concentrations, regardless of B6 status. In summary, MAT1A variants were strongly associated with hypertension and stroke. Improving folate and vitamin B6 status appears likely to improve CVD risk factors only for a subset of the population, depending on genotype.