Maternal polymorphisms for methyltetrahydrofolate reductase (MTHFR) and methioninesynthetasi-reductase (MTRR) and risk of children with down syndrome: A geographic effect?

Abstract

(MTHFR) AND METHIONINESYNTHETASI-REDUCTASE (MTRR) AND RISK OF CHILDREN WITH DOWN SYNDROME: A GEOGRAPHIC EFFECT? ELISA POZZI, PATRIZIA VERGANI, LEDA DALPRA, ROMINA COMBI, FRANCESCA CROSTI, MARIA GRAZIA DELL’ORTO, MARTA GOZZI, University of Milano-Bicocca, Obstetrics and Gynecology, Monza, Milan, Italy, University of MilanoBicocca, Neuroscienze e Biotecnologie Mediche, Monza, Milan, Italy, University of Milano-Bicocca, Laboratorio di Genetica Medica, Monza, Milan, Italy, University of Milano-Bicocca, Pediatric Clinic, Monza, Milan, Italy OBJECTIVE: The role of genetic factors responsible for centromeric hypometilation, i.e. variants of the enzymes involved in homocysteine metabolism such as MTHFR and MTRR, in the etiology of DS is controversial and seems to vary with the geographic distribution of the population studied. STUDY DESIGN: We have evaluated the association between maternal MTHFR C677T and MTRR A66G polymorphisms and children with DS only due to errors in maternal meiosis. A population of women from Northern Italy with children affected by DS were compared with matched mothers of unaffected controls with negative obstetric history for miscarriages or fetal malformations. Matching was conducted on a 1:2 basis whenever possible based on race, geographic area of origin, and maternal age at conception. Statistical analysis included Fisher’s exact test and Chi-square with P!0.05 considered significant. RESULTS: 74 cases of DS due to an error either in maternal meiosis I or II were compared with 141 matched controls. The frequencies of the MTHFR C677T polymorphism and of individual genotype were similar between the two groups. On the contrary the wild type AA of the MTRR A66G polymorphism was significantly more frequent among mothers of euploid than those of DS children (42% vs 23%, P=0.009) whereas the frequency of the mutated gene alleles (AG or GG) was more common in women with DS children than in controls (77% vs 58%, P=0.01).The compound genotypes of the MTHFR C677T and the MTRR A66G polymorphisms failed to show significant differences in the frequency distributions between cases and controls. CONCLUSION: The reported association between maternal MTHFR mutations and DS is not confirmed in geographic areas like Northern Italy where a high prevalence of the mutated T allele was observed in the control sample. On the other hand, analysis of polymorphisms of MTRR A66G, shows significantly higher rates of the gene mutations in women with DS children than in controls.