Human Genetics Research Unit, School of Biotechnology and Biological Sciences, West Bengal University of Technology, Kolkata, West Bengal, India.
Am J Med Genet A. 2012 Nov;158A(11):2843-8. doi: 10.1002/ajmg.a.35626. Epub 2012 Sep 14.
To explore the role of CRELD1 variants on congenital heart defects, we sequenced the entire reading frame of CRELD1 in the samples from Kolkata and adjoining areas. Nearly, 400 participants were included in the genetic association study and they were stratified as Down syndrome (DS) with atrioventricular septal defect (AVSD), DS without AVSD, euploid with AVSD, and euploid without AVSD. A significant association was found between AVSD and three polymorphisms, namely rs9878047 (c.1049-129T > C), rs3774207 (c.1119C > T), and rs73118372 (c.1136T > C) among the Down syndrome and euploid individuals. The polymorphism rs73118372, involves a transition (c.1136T > C) that leads to change in amino acid methionine to threonine which alters protein secondary structure as confirmed by the bioinformatics software SOPMA. In addition, two haplotypes, C-T-C and C-T-T, in the order of loci rs9878047-rs3774207-rs73118372 were associated with incidence of AVSD among euploid and Down syndrome, with a slightly higher odds ratio in the later group. We hypothesize that these haplotypes increase the risk of AVSD, and the susceptibility is exacerbated in DS, possibly due to the trisomy 21 genetic background. Moreover, we report for the first time on an interaction between the mutant alleles of rs3774207 and rs73118372 which could disrupt the delicate balance between different CRELD1 isoforms.
为了探索 CRELD1 变异在先天性心脏病中的作用，我们对来自加尔各答及其周边地区的样本进行了 CRELD1 全长外显子测序。将近 400 名参与者参与了遗传关联研究，并根据唐氏综合征（DS）伴房室间隔缺损（AVSD）、DS 不伴 AVSD、整倍体伴 AVSD 和整倍体不伴 AVSD 进行了分层。在唐氏综合征和整倍体个体中，发现三个多态性与 AVSD 显著相关，即 rs9878047（c.1049-129T > C）、rs3774207（c.1119C > T）和 rs73118372（c.1136T > C）。多态性 rs73118372 涉及一个转换（c.1136T > C），导致甲硫氨酸到苏氨酸的氨基酸变化，这改变了蛋白质二级结构，这一点通过 SOPMA 生物信息学软件得到了证实。此外，在 rs9878047-rs3774207-rs73118372 位点的顺序中，两个单倍型 C-T-C 和 C-T-T 与整倍体和唐氏综合征患者 AVSD 的发生率相关，后者的比值比略高。我们假设这些单倍型增加了 AVSD 的风险，并且在 DS 中风险加剧，可能是由于 21 三体的遗传背景。此外，我们首次报道了 rs3774207 和 rs73118372 的突变等位基因之间的相互作用，这种相互作用可能破坏不同 CRELD1 异构体之间的微妙平衡。
