The "thermolabile" variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother

被引:186
作者
Shields, DC
Kirke, PN
Mills, JL
Ramsbottom, D
Molloy, AM
Burke, H
Weir, DG
Scott, JM
Whitehead, AS
机构
[1] Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Ctr Expt Therapeut, Philadelphia, PA 19104 USA
[3] NICHHD, Bethesda, MD 20892 USA
[4] Univ Dublin Trinity Coll, Dept Genet, Dublin 2, Ireland
[5] Univ Dublin Trinity Coll, Dept Clin Med, Dublin 2, Ireland
[6] Univ Dublin Trinity Coll, Dept Biochem, Dublin 2, Ireland
[7] Univ Dublin Trinity Coll, Hlth Res Board, Dublin 2, Ireland
[8] Royal Coll Surg Ireland, Dept Clin Pharmacol, Dublin 2, Ireland
关键词
D O I
10.1086/302310
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Recent reports have implicated the "thermolabile" (T) variant of methylenetetrahydrofolate reductase (MTHFR) in the causation of folate-dependent neural tube defects (NTDs). We report herein the largest genetic study of NTD cases (n = 271) and families (n = 218) to date, establishing that, in Ireland, the "TT" genotype is found in 18.8% of cases versus 8.3% of controls (odds ratio 2.57; confidence interval [CI] 1.48-4.45; P=.0005). The maternal and paternal TT genotypes have intermediate frequencies of 13.8% and 11.9%, respectively, indicating that the predominant MTHFR-related genetic effect acts via the TT genotype of the developing embryo. Analysis of the 218 family triads of mother, father, and affected child with log-linear models supports this interpretation, providing significant evidence that the case TT genotype is associated with NTDs (P =.02) but no evidence of a maternal TT genotypic effect (P =.83). The log-linear model predicted that the risk of NTDs conferred by the case TT genotype is 1.61 (CI 1.06-2.46), consistent with the paramount importance of the case TT genotype in determining risk. There is no compelling evidence for more than a modest additional risk conferred by a maternal TT genotype. These results favor a biological model of MTHFR-related NTD pathogenesis in which suboptimal maternal folate status imposes biochemical stress on the developing embryo, a stress it is ill-equipped to tolerate if it has a TT genotype.
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页码:1045 / 1055
页数:11
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