Methionine Synthase A2756G Polymorphism Research Articles

Effects of Methionine Synthase (MS) A2756G and Methionine Synthase Reductase (MSR) A66G Polymorphisms on Methionine Metabolism in Brazilian Pregnant Women and Their Neonates.

Methionine synthase (MS) is a cobalamin dependent enzyme that catalyses the remethylation of homocysteine to methionine. The methionine synthase reductase (MSR) maintains adequate levels of methylcob(III)alamin, the activated cofactor for MS. The aim of this study was to investigate the effect of MS A2756G and MSR A66G polymorphisms on total homocysteine (tHcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) levels in 390 pregnant women and their 292 newborns, from Sorocaba city, Brazil. Genotypes of two polymorphisms were determined by PCR-RFLP. Pregnant women with MS 2756AA genotype have higher tHcy and lower Cbl levels than those with 2756G alleles. The MMA values were increased in neonates with MS 2756AA genotypes (Table 1). There are no difference between the maternal values of Cbl, serum folate, tHcy, MMA and SAM according to MSR A66G genotypes.The values of SAM were lower in neonates with MSR 66G alleles than those with AA genotypes (Table 2). We conclude that MS 2756AA genotypes are associated with higher tHcy levels in pregnant women and higher MMA levels in neonates. The MSR 66GG genotypes is associated with lower SAM levels in neonates.Table 1- Distribution of geometric means and confidence intervals 95% (CI 95%) and numbers of subjects for maternal and neonatal values of cobalamin (Cbl), serum folate, total homocysteine (tHcy), methymalonic acid (MMA) and S- adenosylmethionine (SAM) according to genotypes for the polymorphism MS A2756G.VariablesGenotypes for MS A2756GStudent t TestAAAG + GGPregnant WomenCbl (pmol/L)139 (133 – 144) 235156 (146 – 166) 129P= 0.001SF (nmol/L)14.3 (13.6 – 15.0) 23414.5 (13.6 – 15.5) 129P= 0.667tHcy( μmol/L)6.8 (6.5 – 7.1) 2356.2 (5.9 – 6.6) 128P= 0.036MMA(nmol/L)234 (219 – 245) 194241 (219 – 265) 106P= 0.610SAM(nmol/L)81.8 (77.9 – 86,0) 22983.1 (79.1 – 87.4) 124P= 0.663NeonatesCbl (pmol/L)227 (212 – 244) 188234 (213 – 257) 101P= 0.646SF (nmol/L)32.0 (31.0 – 33.0) 18632.0 (30.8 – 33.2) 99P= 0.967tHcy μmol/L)5.8 (5.5 – 6.1) 1855.5 (5.1 – 5.9) 100P= 0.229MMA(nmol/L)383 (364 – 402) 183342 (317 – 369) 100P= 0.011SAM(nmol/L)188 (181 – 196) 178182 (168 – 197) 98P= 0.491Table 2 - Distribution of geometric means and confidence intervals 95% (CI (%%) and number of subjects for neonatal values of cobalamin (Cbl), serum folate, total homocysteine (tHcy), methylmalonic acid (MMA) and S- adenosylmethionine (SAM) according to genotypes for the polymorphism MSR A66G.VariablesGenotypes MSR A66GStudent t TestAAAGGGNeonatesCbl (pmol/L)225 (202 – 249) 86229 (214 – 246) 166247 (205 – 298) 35P= 0.602SF (nmol/L)33.0 (31.6 – 34.4) 8431.7 (30.7 – 32.7) 16631.8 (29.7 – 34.2) 33P= 0.352tHcy μmol/L) (5.7 (5.3 – 6.2) 845.6 (5.3 – 5.9) 1655.9 (5.3 – 6.6) 34P= 0.618MMA (nmol/L)360 (334 – 389) 84378 (357 – 400) 163339 (299 – 384) 34P= 0.230SAM (nmol/L)200 (186 – 215)a 82184 (176 – 192)a 159170 (149 – 195)b 33P= 0.032Groups not sharing a common superscript letter are significantly different at P<0.05 based on Tukey's test

Methionine synthase polymorphism is a risk factor for Alzheimer disease

Alzheimer disease (AD) patients show increased plasma levels of homocysteine, whose conversion to methionine is catalyzed by methionine synthase (MS). Although altered MS activity may result from the MS A2756G polymorphism, the latter's possible association with AD remains unexplored. To assess whether the MS A2756G polymorphism holds any influence on AD risk, we have analyzed 172 AD patients and 166 controls. We have also investigated whether the MS-A or MS-G allele interacts with the APOE4 allele. Our results indicate that association with the MS-AA genotype is an APOE4 allele-independent risk factor for AD. These findings provide novel evidence implicating genetic enzymatic alterations of homocysteine metabolic pathways in the pathogenesis of AD.