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A common variant in the PTPN11 gene contributes to the risk of tetralogy of Fallot.

Authors: Goodship, Judith A  Hall, Darroch  Topf, Ana  Mamasoula, Chrysovalanto  Griffin, Helen  Rahman, Thahira J  Glen, Elise  Tan, Huay  Palomino Doza, Julian  Relton, Caroline L  Bentham, Jamie  Bhattacharya, Shoumo  Cosgrove, Catherine  Brook, David  Granados-Riveron, Javier  Bu'Lock, Frances A  O'Sullivan, John  Stuart, A Graham  Parsons, Jonathan  Cordell, Heather J  Keavney, Bernard 
Citation: Goodship JA, etal., Circ Cardiovasc Genet. 2012 Jun;5(3):287-92. doi: 10.1161/CIRCGENETICS.111.962035. Epub 2012 Apr 13.
Pubmed: (View Article at PubMed) PMID:22503907
DOI: Full-text: DOI:10.1161/CIRCGENETICS.111.962035


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; P=2.9 × 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.

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CRRD Object Information
CRRD ID: 12743641
Created: 2017-02-13
Species: All species
Last Modified: 2017-02-13
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.