Browse by author
Lookup NU author(s): Professor Judith Goodship, Dr Darroch Hall, Dr Ana TopfORCiD, Valentina Mamasoula, Dr Helen GriffinORCiD, Dr Thahira Rahman, Dr Elise Glen, Angeline Tan, Addison Palomino Doza, Professor Caroline Relton, Professor Heather Cordell, Professor Bernard Keavney
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
Background-Tetralogy of Fallot (TOF) is the commonest cyanotic form of congenital heart disease. In 80% of cases, TOF behaves as a complex genetic condition exhibiting significant heritability. As yet, no common genetic variants influencing TOF risk have been robustly identified. Methods and Results-Two hundred and seven haplotype-tagging single nucleotide polymorphisms in 22 candidate genes were genotyped in a test cohort comprising 362 nonsyndromic British white patients with TOF together with 717 unaffected parents of patients and 183 unrelated healthy controls. Single nucleotide polymorphisms with suggestive evidence of association in the test cohort (P < 0.01) were taken forward for genotyping in an independent replication cohort comprising 392 cases of TOF, 218 unaffected parents of patients, and 1319 controls. Significant association was observed for 1 single nucleotide polymorphism, rs11066320 in the PTPN11 gene, in both the test and the replication cohort. Genotype at rs11066320 was associated with a per-allele odds ratio of 1.34 (95% confidence interval [CI], 1.19 to 1.52; x 10(-6)) in the total cohort of TOF cases and controls; this remained highly significant after Bonferroni correction for 207 analyses (corrected P=0.00061). Genotype at rs11066320 was responsible for a population-attributable risk of TOF of approximately 10%. Conclusions-Common variation in the linkage disequilibrium block including the PTPN11 gene contributes to the risk of nonsyndromic TOF. Rare mutations in PTPN11 are known to cause the autosomal dominant condition Noonan syndrome, which includes congenital heart disease, by upregulating Ras/mitogen-activated protein kinase (MAPK) signaling. Our results suggest a role for milder perturbations in PTPN11 function in sporadic, nonsyndromic congenital heart disease. (Circ Cardiovasc Genet. 2012;5:287-292.)
Author(s): Goodship JA, Hall D, Topf A, Mamasoula C, Griffin H, Rahman TJ, Glen E, Tan H, Doza JP, Relton CL, Bentham J, Bhattacharya S, Cosgrove C, Brook D, Granados-Riveron J, Bu'Lock FA, O'Sullivan J, Stuart AG, Parsons J, Cordell HJ, Keavney B
Publication type: Article
Publication status: Published
Journal: Circulation: Cardiovascular Genetics
Year: 2012
Volume: 5
Issue: 3
Pages: 287-292
Print publication date: 13/04/2012
ISSN (print): 1942-325X
ISSN (electronic): 1942-3268
Publisher: Lippincott Williams & Wilkins
URL: http://dx.doi.org/10.1161/CIRCGENETICS.111.962035
DOI: 10.1161/CIRCGENETICS.111.962035
Altmetrics provided by Altmetric
