Functional polymorphisms of the neuropilin 1 gene are associated with the risk of tetralogy of Fallot in a Chinese Han population.

Tetralogy of Fallot (TOF) is one of the most severe forms of cyanotic congenital heart disease (CHD) and is also the most common. Previous genome-wide association study (GWAS) and replication studies have suggested that a polymorphism in the neuropilin 1 (NRP1) gene is significantly associated with the risk of TOF. To further confirm the association between the NRP1 polymorphism and the risk of TOF and to identify additional positive functional single-nucleotide polymorphisms (SNPs) for TOF risk, we systematically screened for functional polymorphisms throughout the regulatory and coding regions of the NRP1 gene. A total of 11 functional SNPs in 747 Chinese Han individuals, including 314 TOF patients and 433 healthy controls, were genotyped using the MassARRAY system and GeneScan. The results revealed that the allelic and genotypic frequencies of the NRP1 polymorphism rs2228638 were strongly associated with the risk of TOF (p = 0.002 and 0.001, respectively). To increase the robustness of rs2228638 as a TOF risk SNP, we conducted a meta-analysis that combined published studies and our current case-control study. The meta-analysis showed that the T allele of the NRP1 polymorphism rs2228638 was significantly associated with an increased risk of TOF in the combined population, which included European and Chinese Han individuals [combined p < 0.00001, odds ratio (OR) = 1.53, 95% confidence interval (95% CI) = 1.35-1.73]. In addition, the association analysis suggested for the first time that there is a strong association between the allele distribution of rs10080 and susceptibility to TOF (p = 0.001). Our data provide further evidence of the association between NRP1 polymorphisms and TOF risk, and suggest that rs2228638 may be an excellent marker for TOF risk in European and Chinese Han populations.