Abstract 17706: A Common Variant in the PTPN11 Gene Contributes to the Risk of Tetralogy of Fallot

Abstract

Background: Tetralogy of Fallot (TOF) is the commonest form of cyanotic congenital heart disease. In 80% of cases, TOF behaves as a complex disease exhibiting significant heritability. We investigated whether common genetic variation in 23 candidate genes, selected either because of their expression in the second heart field or their involvement in syndromic congenital heart disease, predisposes to risk of “sporadic”, non-syndromic TOF. Methods and Results: 207 haplotype-tagging single nucleotide polymorphisms (SNPs) in the candidate genes with minor allele frequencies ≥0.05 were genotyped in a test cohort comprising 362 non-syndromic British Caucasian cases of TOF, and 900 controls (717 unaffected parents of cases, and 183 unrelated healthy people). Six SNPs with suggestive evidence of association (p<0.01) were taken forward for genotyping in a replication cohort comprising 392 cases of TOF, 218 unaffected parents of cases, and 1319 controls. Significant association at p<0.01 was confirmed for one SNP, rs11066320 in the PTPN11 gene, in the replication cohort. Genotype at rs11066320 was associated with a per-allele odds ratio of 1.35 (95% CI 1.20-1.52; p=2.94x10-6) in the total cohort of TOF cases and controls. Genotype at rs11066320 was responsible for a population attributable risk of TOF of approximately 5%. Association between rs11066320 genotype and TOF remained significant after Bonferroni correction for 207 analyses (corrected p=0.00061) Conclusions: Common variation in the PTPN11 gene contributes to the risk of non-syndromic TOF.