Reduced folate carrier polymorphism (80A → G) and neural tube defects
Reduced folate carrier polymorphism (80A → G) and neural tube defects
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DOI：
10.1038/sj.ejhg.5200946
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发表时间：
2003-03-01
影响因子：
5.2
通讯作者：
Capra, V
中科院分区：
文献类型：
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作者：
De Marco, P;Calevo, MG;Capra, V
哺乳动物细胞中叶酸的转运是通过载体介导的机制实现的。人类叶酸携带者(RFC-1)基因已被分离和鉴定。在该基因中，最近发现了一种常见的多态性，80A->；G，将外显子2(H27R)上的组氨酸改变为精氨酸。叶酸代谢缺陷，如载体分子缺陷，可能与神经管缺陷(NTDS)的病因学有关。在目前的病例对照研究中，我们招募了174名患有非综合征NTD的意大利先证者、43名母亲、53名父亲和156名对照个体，并评估了RFC-1变异对NTD风险的影响。NTD患者(OR=2.35；95%可信区间1.21~4.58)和母亲(OR=2.74，95%可信区间0.92~8.38)的80GG基因携带者的发病风险具有统计学意义。相反，母亲的杂合子和父亲的杂合子和纯合子似乎都不是NTD的显著危险因素。此外，根据NTDS的多因素遗传，我们发现病例的MTHFR 1298A-->；C和RFC-1 80A-->；G多态的联合基因导致NTD的风险大于RFC-1 80A-->；G变异体的杂合子或纯合子。相反，我们的数据没有提供证据表明NTD表型与MTHFR C677T/RFC-1 A80G联合基因型之间存在关联。此外，我们还描述了两个MTHFR多态位点(677CT和1298AC)与RFC-1基因的组合。我们发现，患者和对照组最多都可能有四重突变组合。有趣的是，27%(7/26)的母亲和18.75%(30/160)的病例有四个突变等位基因，而对照组的这一比例为8.5%(11/129)。NTD患者和母亲携带两个MTHFR多态和RFC-1 80GG纯合子(677CT/1298AC/80GG)(病例=11.3%；母亲11.5%)的频率高于对照组(1.6%)。总之，我们的发现支持这样的假设，即RFC-1A80G变异可能与意大利人群中NTD的易感性有关。
Transport of folates in mammalian cells occurs by a carrier-mediated mechanism. The human folate carrier (RFC-1) gene has been isolated and characterized. Within this gene, a common polymorphism, 80A-->G, changing a histidine to an arginine in exon 2 (H27R), was recently identified. Defects in folate metabolism, such as defective carrier molecules, could be implicated in the etiology of neural tube defects (NTDs). In the present case-control study, we recruited 174 Italian probands with nonsyndromic NTD, 43 mothers, 53 fathers and 156 control individuals and evaluated the impact of RFC-1 variant on NTD risk. A statistically significant risk was calculated for the 80GG genotype of the NTD cases (OR = 2.35; 95% Cl 1.21-4.58) and mothers (OR = 2.74, 95% Cl 0.92-8.38). On the contrary, the heterozygous genotype of the mothers and both heterozygous and homozygous genotypes of the fathers did not seem to be significant NTD risk factors. Furthemore, according to the multifactorial inheritance of NTDs, we demonstrated that the combined genotypes for MTHFR 1298A --> C and RFC-1 80A --> G polymorphisms of cases resulted in greater NTD risk than heterozygosity or homozygosity for RFC-1 80A --> G variant alone. Conversely, our data provide no evidence for an association between NTD phenotype and combined MTHFR C677T/RFC-1 A80G genotypes. Moreover, here we describe the combinations of the two MTHFR polymorphic sites (677CT and 1298AC) with RFC-1 genotypes. We found that both patients and controls could have at most quadruple-mutation combinations. Interestingly, 27% (7/26) of the mothers and 18.75% (30/160) of the cases genotyped presented four mutant alleles in comparison with 8.5% (11/129) of the controls. Finally, the frequency of NTD cases and mothers carrying combined heterozygosity for the two MTHFR polymorphisms and RFC-1 80GG homozygosity (677CT/1298AC/80GG) (cases = 11.3%; mothers 11.5%) was increased compared with controls (1.6%). Altogether, our findings support the hypothesis that RFC-1 A80G variant may contribute to NTD susceptibility in the Italian population.