| Summary: | 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 <i>SPRY1</i> and <i>SPRY2</i> to be associated with NSCL/P among Chinese populations. This study aimed to further explore potential genetic effect and gene—environment interaction among <i>SPRY</i> 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 <i>SPRY</i> 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<sup>−4</sup>). 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.
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