Institute of Genetic Medicine, Newcastle University, Newcastle, UK.
BMC Genet. 2013 Jun 19;14:57. doi: 10.1186/1471-2156-14-57.
Epidemiological studies indicate a substantial excess familial recurrence of non-syndromic Tetralogy of Fallot (TOF), implicating genetic factors that remain largely unknown. The Rho induced kinase 1 gene (ROCK1) is a key component of the planar cell polarity signalling pathway, which plays an important role in normal cardiac development. The aim of this study was to investigate the role of genetic variation in ROCK1 on the risk of TOF.
ROCK1 was sequenced in a discovery cohort of 93 non-syndromic TOF probands to identify rare variants. TagSNPs were selected to capture commoner variation in ROCK1. Novel variants and TagSNPs were genotyped in a discovery cohort of 458 TOF cases and 1331 healthy controls, and positive findings were replicated in a further 209 TOF cases and 1290 healthy controls. Association between genotypes and TOF was assessed using LAMP.A rare SNP (c.807C > T; rs56085230) discovered by sequencing was associated with TOF risk (p = 0.006) in the discovery cohort. The variant was also significantly associated with the risk of TOF in the replication cohort (p = 0.018). In the combined cohorts the odds ratio for TOF was 2.61 (95% CI 1.58-4.30); p < 0.0001. The minor allele frequency of rs56085230 in the cases was 0.02, and in the controls it was 0.007. The variant accounted for 1% of the population attributable risk (PAR) of TOF. We also found significant association with TOF for an uncommon TagSNP in ROCK1, rs288979 (OR 1.64 [95% CI 1.15-2.30]; p = 1.5x10⁻⁵). The minor allele frequency of rs288979 in the controls was 0.043, and the variant accounted for 11% of the PAR of TOF. These association signals were independent of each other, providing additional internal validation of our result.
Low frequency intermediate penetrance (LFIP) variants in the ROCK1 gene predispose to the risk of TOF.
流行病学研究表明，非综合征性法洛四联症（TOF）存在明显的家族性复发过剩，这暗示了遗传因素的存在，但这些遗传因素在很大程度上仍不清楚。Rho 诱导激酶 1 基因（ROCK1）是平面细胞极性信号通路的关键组成部分，在心脏正常发育中发挥着重要作用。本研究旨在探讨 ROCK1 基因遗传变异与 TOF 发病风险的关系。
在一个 93 例非综合征性 TOF 先证者的发现队列中对 ROCK1 进行测序，以鉴定罕见变异。选择标签单核苷酸多态性（TagSNP）以捕获 ROCK1 中的常见变异。在一个包含 458 例 TOF 病例和 1331 例健康对照的发现队列中对新变异和 TagSNP 进行基因分型，阳性结果在另一个包含 209 例 TOF 病例和 1290 例健康对照的复制队列中得到验证。使用 LAMP 评估基因型与 TOF 之间的关联。通过测序发现的一个罕见 SNP（c.807C > T; rs56085230）与发现队列中的 TOF 风险相关（p = 0.006）。该变异在复制队列中也与 TOF 风险显著相关（p = 0.018）。在合并队列中，TOF 的优势比为 2.61（95%CI 1.58-4.30）；p < 0.0001。rs56085230 变异在病例中的次要等位基因频率为 0.02，在对照组中的频率为 0.007。该变异解释了 TOF 人群归因风险（PAR）的 1%。我们还发现 ROCK1 中的一个罕见 TagSNP（rs288979）与 TOF 显著相关（OR 1.64 [95%CI 1.15-2.30]；p = 1.5x10⁻⁵）。rs288979 变异在对照组中的次要等位基因频率为 0.043，该变异解释了 TOF 人群归因风险的 11%。这些关联信号相互独立，为我们的结果提供了额外的内部验证。
ROCK1 基因中的低频中度外显率（LFIP）变异使 TOF 发病风险增加。
