Interaction between interferon regulatory factor 6 and glycine receptor beta shows a protective effect on developing nonsyndromic cleft lip with or without cleft palate in the Han Chinese population

Single‐nucleotide polymorphisms ( SNP s) in protein‐coding regions of genes which were previously reported to be associated with nonsyndromic cleft lip, with or without palate involvement ( NSCL /P), were investigated. Twelve candidate loci [platelet‐derived growth factor C ( PDGFC ) , platelet‐derived growth factor subunit A ( PDGFA ) , platelet‐derived growth factor receptor alpha ( PDGFRA ) , glycine receptor alpha 2 ( GLRA 2 ), glycine receptor beta ( GLRB ) , ATP binding cassette subfamily A member 4 ( ABCA 4 ), MAF bZIP transcription factor B ( MAFB ) , interferon regulatory factor 6 ( IRF 6 ), CCDC 26 long non‐coding RNA ( CCDC 26 ), paired box 7 ( PAX 7 ), ventral anterior homeobox 1 ( VAX 1 ), and netrin 1 ( NTN 1 )] covering 1.5 Mbp were sequenced in 136 NSCL /P patients and 54 healthy controls. Twenty‐five genomic variants identified were further validated in another 400 NSCL /P and 200 controls. Two SNP s in IRF 6 showed a protective effect against the development of NSCL /P (rs12405750, OR  = 0.54, 95% CI : 0.41–0.69; and rs2235371, OR  = 0.55, 95% CI : 0.43–0.71). The missense variant, rs2235371, alters the conserved amino acid valine to isoleucine at codon 274 (V274I). We observed that SNP s at IRF 6 (rs2235371 and rs12405750) and GLRB (rs73856838 and rs72685584) show consistent interaction effects. The association between the missense SNP rs2235371 in gene IRF 6 and NSCL /P suggests that this SNP may play an important role as a risk factor for NSCL /P in the Han Chinese populations. The marginal signal near 4q31 detected in previous genome‐wide association studies might be caused by an interaction between the IRF 6 and GLRB genes. This interaction needs to be further validated by experimentation in follow‐up studies.