Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot.
<p><strong>Background</strong>: 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...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
BioMed Central
2013
|
| _version_ | 1826271082664951808 |
|---|---|
| author | Palomino Doza, J Topf, A Bentham, J Bhattacharya, S Cosgrove, C Brook, J Granados-Riveron, J Bu'Lock, F O'Sullivan, J Stuart, A Parsons, J Relton, C Goodship, J Henderson, D Keavney, B |
| author_facet | Palomino Doza, J Topf, A Bentham, J Bhattacharya, S Cosgrove, C Brook, J Granados-Riveron, J Bu'Lock, F O'Sullivan, J Stuart, A Parsons, J Relton, C Goodship, J Henderson, D Keavney, B |
| author_sort | Palomino Doza, J |
| collection | OXFORD |
| description | <p><strong>Background</strong>: 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.</p> <p><strong>Results</strong>: 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.</p> 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<sup>−5</sup>). 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. <p><strong>Conclusions</strong>: Low frequency intermediate penetrance (LFIP) variants in the ROCK1 gene predispose to the risk of TOF.</p> |
| first_indexed | 2024-03-06T21:51:02Z |
| format | Journal article |
| id | oxford-uuid:4b452399-7e28-4968-9a8e-0207d3c6aff4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:51:02Z |
| publishDate | 2013 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:4b452399-7e28-4968-9a8e-0207d3c6aff42022-03-26T15:42:33ZLow-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4b452399-7e28-4968-9a8e-0207d3c6aff4EnglishSymplectic Elements at OxfordBioMed Central2013Palomino Doza, JTopf, ABentham, JBhattacharya, SCosgrove, CBrook, JGranados-Riveron, JBu'Lock, FO'Sullivan, JStuart, AParsons, JRelton, CGoodship, JHenderson, DKeavney, B<p><strong>Background</strong>: 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.</p> <p><strong>Results</strong>: 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.</p> 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<sup>−5</sup>). 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. <p><strong>Conclusions</strong>: Low frequency intermediate penetrance (LFIP) variants in the ROCK1 gene predispose to the risk of TOF.</p> |
| spellingShingle | Palomino Doza, J Topf, A Bentham, J Bhattacharya, S Cosgrove, C Brook, J Granados-Riveron, J Bu'Lock, F O'Sullivan, J Stuart, A Parsons, J Relton, C Goodship, J Henderson, D Keavney, B Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot. |
| title | Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot. |
| title_full | Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot. |
| title_fullStr | Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot. |
| title_full_unstemmed | Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot. |
| title_short | Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot. |
| title_sort | low frequency intermediate penetrance variants in the rock1 gene predispose to tetralogy of fallot |
| work_keys_str_mv | AT palominodozaj lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT topfa lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT benthamj lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT bhattacharyas lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT cosgrovec lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT brookj lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT granadosriveronj lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT bulockf lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT osullivanj lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT stuarta lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT parsonsj lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT reltonc lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT goodshipj lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT hendersond lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot AT keavneyb lowfrequencyintermediatepenetrancevariantsintherock1genepredisposetotetralogyoffallot |