THE C677T MUTATION OF THE 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE GENE IS A MODERATE RISK FACTOR FOR SPINA-BIFIDA IN ITALY

Objective-To estimate the risk for spina bifida associated with the co mmon mutation C677T of the MTHFR gene in a country with a relatively l ow prevalence of NTDs. Design-Case-control study. Subjects-Cases: 203 living patients affected with spina bifida (173 myelomeningocele and 3 0 lipomeningocele); controls: 583 subjects (306 young adults and 277 u nselected newborns) from northern and central-southern Italy. Setting- Cases: three spina bifida centres; young adult controls: DNA banks; ne wborn controls: regional neonatal screening centres. Main outcome meas ures-Prevalence of the C677T genotypes in cases and controls by place of birth; odds ratios for spina bifida and estimated attributable frac tion. Results-The prevalence of T/T, T/C, and C/C genotype was 16.6%, 53.7%, and 29.7% in controls and 25.6%, 43.8%, and 30.6% in cases, res pectively. We found no differences between type of defect or place of birth. The odds ratio for spina bifida associated with the T/T genotyp e v C/C plus T/C was 1.73 (95% CI 1.15, 2.59) and the corresponding at tributable fraction was 10.8%. No increased risk was found for heteroz ygous patients (OR=0.79, 95% CI 0.53-1.18). Conclusion-This study, as well as the meta-analysis we updated, shows that homozygosity for the MTHFR C677T mutation is a moderate risk factor in Europe, and even in Italy where there is a relatively low prevalence of spina bifida. The estimated attributable fraction associated with this risk factor expla ins only a small proportion of cases preventable by periconceptional f olic acid supplementation. Thus, other genes involved in folate-homocy steine metabolism, their interaction, and the interaction between gene tic and environmental factors should be investigated further.