Haplotype and Haplotype-Environment Interaction Analysis Revealed Roles of SPRY2 for NSCL/P among Chinese Populations.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of common birth defects in China, with genetic and environmental components contributing to the etiology. Genome wide association studies (GWASs) have identified and to be associated with NSCL/P among Chinese populations. This study aimed to further explore potential genetic effect and gene-environment interaction among genes based on haplotype analysis, using 806 Chinese case-parent NSCL/P trios drawn from an international consortium which conducted a genome-wide association study. After the process of quality control, 190 single nucleotide polymorphisms (SNPs) of genes were included for analyses. Haplotype and haplotype-environment interaction analyses were conducted in Population-Based Association Test (PBAT) software. A 2-SNP haplotype and three 3-SNP haplotypes showed a significant association with the risk of NSCL/P after Bonferroni correction (corrected significance level = 2.6 × 10). Moreover, haplotype-environment interaction analysis identified these haplotypes respectively showing statistically significant interactions with maternal multivitamin supplementation or maternal environmental tobacco smoke. This study showed SPRY2 to be associated with NSCL/P among the Chinese population through not only gene effects, but also a gene-environment interaction, highlighting the importance of considering environmental exposures in the genetic etiological study of NSCL/P.