Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot

BMC Genetics

Bernard Keavney²  Deborah J Henderson²  Judith Goodship²  Caroline Relton²  Jonathan Parsons⁶  A Graham Stuart⁷  John O’Sullivan⁴  Frances A Bu’Lock³  Javier Granados-Riveron¹  J David Brook¹  Catherine Cosgrove¹  Shoumo Bhattacharya⁵  Jamie Bentham⁵  Ana Topf²  Julian Palomino Doza² 

[1] Institute of Genetics, Nottingham University, Nottingham, UK;Institute of Genetic Medicine, Newcastle University, Newcastle, UK;University Hospitals of Leicester NHS Trust, Leicester, UK;Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK;Department of Cardiovascular Medicine, Oxford University, Oxford, UK;Leeds Teaching Hospitals NHS Trust, Leeds, UK;Bristol Royal Hospital for Children, Bristol, UK

关键词: Planar cell polarity pathway;    Genetics;    Tetralogy of fallot;    Congenital heart disease;   

Others  :  1086915
DOI  :  10.1186/1471-2156-14-57

 received in 2012-06-13, accepted in 2013-06-05,  发布年份 2013

【 摘 要 】

Background

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.

Results

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.

Conclusions

Low frequency intermediate penetrance (LFIP) variants in the ROCK1 gene predispose to the risk of TOF.

【 授权许可】

   
2013 Palomino Doza et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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