ALBERT

Description: 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. Variables Genotypes for MS A2756G Student t Test AA AG + GG Pregnant Women Cbl (pmol/L) 139 (133 – 144) 235 156 (146 – 166) 129 P= 0.001 SF (nmol/L) 14.3 (13.6 – 15.0) 234 14.5 (13.6 – 15.5) 129 P= 0.667 tHcy( μmol/L) 6.8 (6.5 – 7.1) 235 6.2 (5.9 – 6.6) 128 P= 0.036 MMA(nmol/L) 234 (219 – 245) 194 241 (219 – 265) 106 P= 0.610 SAM(nmol/L) 81.8 (77.9 – 86,0) 229 83.1 (79.1 – 87.4) 124 P= 0.663 Neonates Cbl (pmol/L) 227 (212 – 244) 188 234 (213 – 257) 101 P= 0.646 SF (nmol/L) 32.0 (31.0 – 33.0) 186 32.0 (30.8 – 33.2) 99 P= 0.967 tHcy μmol/L) 5.8 (5.5 – 6.1) 185 5.5 (5.1 – 5.9) 100 P= 0.229 MMA(nmol/L) 383 (364 – 402) 183 342 (317 – 369) 100 P= 0.011 SAM(nmol/L) 188 (181 – 196) 178 182 (168 – 197) 98 P= 0.491 Table 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. Variables Genotypes MSR A66G Student t Test AA AG GG Groups not sharing a common superscript letter are significantly different at P

Description: In the homocysteine metabolic pathway, several key enzymes, including methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), have been implicated in abnormal homocysteine accumulation in the presence of rare alleles. In previous study, we showed that lower maternal Cbl levels were associated with higher tHcy and lower S-adenosylmethionine/S-adenosylhomocysteine ratio in pregnant women and their neonates.The aim of this study is to investigate whether MTHFR and MTRR polymorphisms are involved in the risk for elevated total homocysteine (tHcy) and its interaction with low cobalamin (Cbl) or serum folate (SF) levels. Genotypes for polymorphisms MTHFR C677T and MTRR A66G were determined by PCR-FLRP. The serum levels of Cbl, SF and tHcy were determined in 377 pregnant women (37–42 weeks of gestational age), and cutoff values for Cbl and SF were considered the first quartile (low values). Four models of univariate logistic regression analyses were used (Table 1). Pregnant women with MTHFR 677T allele have high risk for elevated tHcy that is increased when 677T allele is associated with low Cbl. Increased risk for elevated tHcy is also met when MTRR 66G allele and low Cbl levels were associated. Women with low SF and common MTHFR and MTRR alleles have high risk for elevated tHcy, that is increased when in association with 677T allele or with 66G allele. Interaction between MTHFR C677T and MTRR A66G polymorphisms and vitamins levels in pregnant women Dependent variables Comparation levels (N) P value Odd Ratios 95% CI P for trend: (a) P115.8 pmol/L (145) 0.015 2.09 1.16 – 3.77 MTHFR 677CT and 677TT genotypes and≤Cbl 115.8 pmol/L (48) 0.001 4.63 2.22 – 9.65 tHcy〉8.3μmol/L MTHFR 677CC genotype and SF 〉 10.9 nmol/L (ref) (148) b 1.00 MTHFR 677CC genotype and≤SF 10.9 nmol/L (33) 0.008 3.20 1.35 – 7.59 MTHFR 677CT and 677TT genotypes and SF 〉 10.9 nmol/L (133) 0.035 1.95 1.05 – 3.61 MTHFR 677CT and 677TT genotypes and≤SF 10.9 nmol/L (59) 0.001 6.62 3.31 – 13.26 tHcy〉8.3μmol/L MTRR 66AA genotype and Cbl〉 115.8 pmol/L (ref) (96) c 1.00 MTRR 66AA genotype and ≤Cbl 115.8 pmol/L (23) 0.222 1.90 0.68 – 5.29 MTRR 66AG and 66GG genotypes and Cbl〉115.8 pmol/L (183) 0.418 1.29 0.70 – 2.39 MTRR 66AG and 66GG genotypes and ≤Cbl 115.8 pmol/L (69) 0.013 2.46 1.21 – 5.01 tHcy〉8.3μmol/L MTRR 66AA genotype and SF 〉 10.9 nmol/L (ref) (92) d 1.00 MTRR 66AA genotype and ≤SF 10.9 nmol/L (27) 0.006 3.83 1.47 – 9.96 MTRR 66AG and 66GG genotypes and SF 〉 10.9 nmol/L (186) 0.399 1.34 0.68 – 2.63 MTRR 66AG and 66GG genotypes and≤SF 10.9 nmol/L (65) 0.001 4.78 2.26 – 10.10 In conclusion, the interaction between MTHFR and MTRR polymorphisms and low folate and cobalamin serum levels may explain the increased risk for elevated tHcy found in pregnant women.