Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome.
Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome.
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DOI：
10.1002/gepi.20518
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发表时间：
2010-09
影响因子：
2.1
通讯作者：
Bean, Lora J. H.
中科院分区：
文献类型：
--
作者：
Locke, Adam E.;Dooley, Kenneth J.;Tinker, Stuart W.;Cheong, Soo Yeon;Feingold, Eleanor;Allen, Emily G.;Freeman, Sallie B.;Torfs, Claudine P.;Cua, Clifford L.;Epstein, Michael P.;Wu, Michael C.;Lin, Xihong;Capone, George;Sherman, Stephanie L.;Bean, Lora J. H.
心脏异常是唐氏综合症患者最常见的先天性缺陷之一。大量研究表明叶酸缺乏和叶酸通路基因的遗传变异与出生缺陷有关，包括先天性心脏缺陷（CHD）和唐氏综合征（DS）。在这里，我们测试了叶酸途径基因变异在主要ds相关冠心病房室间隔缺损（AVSD）中的作用。在121个病例家庭（患有DS和AVSD的母亲、父亲和先证）和122个对照家庭（患有DS和AVSD的母亲、父亲和先证）中，标记snp在5个叶酸通路基因中及其周围进行了基因分型：5,10-亚甲基四氢叶酸还原酶（MTHFR）、蛋氨酸合成酶（MTR）、蛋氨酸合成酶还原酶（MTRR）、半胱甘氨酸β合成酶（CBS）和还原性叶酸载体（SLC19A1, RFC1）。通过多位点等位基因共享检测发现SLC19A1与AVSD相关。根据SNP和遗传模型的不同，个体SNP测试也显示出名义上显著的关联，比值比在1.34到3.78之间。有趣的是，SLC19A1的所有边际显著SNP都与非同义编码SNP rs1051266 （c.80A>G）存在强烈的连锁不平衡（r2≥0.8），该SNP先前与非综合征性冠心病病例相关。除SLC19A1外，已知功能多态性MTHFR c.1298A在AVSD患者中呈过传递（P = 0.05），在对照组中呈低传递（P = 0.02）。因此，我们得出结论，叶酸通路的破坏有助于DS患者发生AVSD。
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 β-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 (r2≥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.
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影响因子：
5.2
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Horvath, S;Xu, X;Laird, NM
通讯作者：
Laird, NM
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Sherman, SL
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Almasy, L
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Cleves, MA
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通讯作者：
Lie, Rolv T.