De Marco Patrizia, Merello Elisa, Calevo Maria Grazia, Mascelli Samantha, Raso Alessandro, Cama Armando, Capra Valeria
Unità Operativa di Neurochirurgia, Istituto G. Gaslini, Largo G. Gaslini 5, 16148, Genoa, Italy.
Servizio di Epidemiologia e Biostatistica, Istituto G. Gaslini, Genoa, Italy.
J Hum Genet. 2006;51(2):98-103. doi: 10.1007/s10038-005-0329-6. Epub 2005 Nov 29.
Genetic variants of enzymes involved in the folate pathway might be expected to have an impact on neural tube defect (NTD) risk. Given its key role in folate metabolism, the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene could represent an attractive candidate in NTD aetiology. In this study, the impact of the MTHFD1 1958G > A polymorphism on NTD risk in the Italian population was examined both by hospital-based case-control and family-based studies. The MTHFD1 1958G > A polymorphism was genotyped in 142 NTD cases, 125 mothers, 108 fathers and 523 controls. An increased risk was found for the heterozygous 1958G/A (OR = 1.69; P = 0.04) and homozygous 1958A/A (OR = 1.91; P = 0.02) genotypes in the children. Significant association was also found when combined 1958G/A and 1958A/A genotypes of cases were compared with the 1958G/G genotype (OR = 1.76; P = 0.02). The risk of an NTD-affected pregnancy of the mothers was increased 1.67-fold (P = 0.04) only when a dominant effect (1958G/A or 1958A/A vs 1958G/G) of the 1958A allele was analysed. The combined TDT/1-TDT (Z = 2.11; P = 0.03) and FBAT (Z = 2.4; P = 0.01) demonstrated a significant excess of transmission of the 1958A allele to affected individuals. In summary, our results indicate that heterozygosity and homozygosity for the MTHFD1 1958G > A polymorphism are genetic determinants of NTD risk in the cases examined.
参与叶酸代谢途径的酶的基因变异可能会影响神经管缺陷（NTD）风险。鉴于亚甲基四氢叶酸脱氢酶1（MTHFD1）基因在叶酸代谢中的关键作用，它可能是神经管缺陷病因学中一个有吸引力的候选基因。在本研究中，通过基于医院的病例对照研究和基于家系的研究，检测了MTHFD1基因1958G>A多态性对意大利人群神经管缺陷风险的影响。对142例神经管缺陷病例、125名母亲、108名父亲和523名对照进行了MTHFD1基因1958G>A多态性基因分型。在儿童中，发现杂合子1958G/A（比值比=1.69；P=0.04）和纯合子1958A/A（比值比=1.91；P=0.02）基因型的风险增加。当将病例的1958G/A和1958A/A基因型组合与1958G/G基因型进行比较时，也发现了显著关联（比值比=1.76；P=0.02）。仅在分析1958A等位基因的显性效应（1958G/A或1958A/A与1958G/G）时，母亲怀有神经管缺陷胎儿的风险增加了1.67倍（P=0.04）。联合传递不平衡检验/1-传递不平衡检验（Z=2.11；P=0.03）和家系传递不平衡检验（Z=2.4；P=0.01）表明，1958A等位基因向患病个体的传递显著过量。总之，我们的结果表明，在所检测的病例中，MTHFD1基因1958G>A多态性的杂合性和纯合性是神经管缺陷风险的遗传决定因素。
