title: A common variant in the PTPN11 gene contributes to the risk of tetralogy of Fallot.
abstract: 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.
  
  
  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.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.forename: Darroch
authors.initials: D
authors.lastname: Hall
authors.forename: Ana
authors.initials: A
authors.lastname: Topf
authors.forename: Chrysovalanto
authors.initials: C
authors.lastname: Mamasoula
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.forename: Thahira J
authors.initials: TJ
authors.lastname: Rahman
authors.forename: Elise
authors.initials: E
authors.lastname: Glen
authors.forename: Huay
authors.initials: H
authors.lastname: Tan
authors.forename: Julian
authors.initials: J
authors.lastname: Palomino Doza
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Relton
authors.forename: Jamie
authors.initials: J
authors.lastname: Bentham
authors.forename: Shoumo
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Catherine
authors.initials: C
authors.lastname: Cosgrove
authors.forename: David
authors.initials: D
authors.lastname: Brook
authors.forename: Javier
authors.initials: J
authors.lastname: Granados-Riveron
authors.forename: Frances A
authors.initials: FA
authors.lastname: Bu'Lock
authors.forename: John
authors.initials: J
authors.lastname: O'Sullivan
authors.forename: A Graham
authors.initials: AG
authors.lastname: Stuart
authors.forename: Jonathan
authors.initials: J
authors.lastname: Parsons
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.forename: Bernard
authors.initials: B
authors.lastname: Keavney
mesh_terms: D000483:Alleles; D015331:Cohort Studies; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D013771:Tetralogy of Fallot / Q000235:genetics*
chemical_list: D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11