Variation in Folate Pathway Genes Contributes to Risk of Congenital Heart Defects Among Individuals With Down Syndrome

被引:53
作者
Locke, Adam E. [1 ]
Dooley, Kenneth J. [2 ]
Tinker, Stuart W. [1 ]
Cheong, Soo Yeon [3 ]
Feingold, Eleanor [3 ,4 ]
Allen, Emily G. [1 ]
Freeman, Sallie B. [1 ]
Torfs, Claudine P. [5 ]
Cua, Clifford L. [6 ]
Epstein, Michael P. [1 ]
Wu, Michael C. [7 ]
Lin, Xihong [7 ]
Capone, George [8 ]
Sherman, Stephanie L. [1 ]
Bean, Lora J. H. [1 ]
机构
[1] Emory Univ, Dept Human Genet, Sch Med, Atlanta, GA 30322 USA
[2] Childrens Hosp Atlanta, Sibley Heart Ctr Cardiol, Atlanta, GA USA
[3] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA
[4] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA
[5] Inst Publ Hlth, Emeryville, CA USA
[6] Natl Childrens Hosp, Ctr Heart, Columbus, OH USA
[7] Harvard Univ, Dept Biostat, Cambridge, MA 02138 USA
[8] Kennedy Krieger Inst, Div Neurol & Dev Med, Baltimore, MD USA
关键词
Down syndrome; atrioventricular septal defect; folate; trisomy; congenital heart defects; CARRIER A80G; LINKAGE DISEQUILIBRIUM; ASSOCIATION TEST; UNIFIED APPROACH; HOMOCYSTEINE; METABOLISM; MTHFR; POLYMORPHISM; GENOTYPE; VARIANTS;
D O I
10.1002/gepi.20518
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Cardiac abnormalities are one of the most common congenital defects observed in individuals with Down syndrome. Considerable research has implicated both folate deficiency and genetic variation in folate pathway genes with birth defects, including both congenital heart defects (CHD) and Down syndrome (DS). Here, we test variation in folate pathway genes for a role in the major DS-associated CHD atrioventricular septal defect (AVSD). In a group of 121 case families (mother, father, and proband with DS and AVSD) and 122 control families (mother, father, and proband with DS and no CHD), tag SNPs were genotyped in and around five folate pathway genes: 5,10-methylenetetrahyrdofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine beta-synthase (CBS), and the reduced folate carrier (SLC19A1, RFC1). SLC19A1 was found to be associated with AVSD using a multilocus allele-sharing test. Individual SNP tests also showed nominally significant associations with odds ratios of between 1.34 and 3.78, depending on the SNP and genetic model. Interestingly, all marginally significant SNPs in SLC19A1 are in strong linkage disequilibrium (r(2) >= 0.8) with the nonsynonymous coding SNP rs1051266 (c. 80A>G), which has previously been associated with nonsyndromic cases of CHD. In addition to SLC19A1, the known functional polymorphism MTHFR c. 1298A was over-transmitted to cases with AVSD (P=0.05) and under-transmitted to controls (P=0.02). We conclude, therefore, that disruption of the folate pathway contributes to the incidence of AVSD among individuals with DS. Genet. Epidemiol. 34 : 613-623, 2010. (C) 2010 Wiley-Liss, Inc.
引用
收藏
页码:613 / 623
页数:11
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