Gene-gene interaction between MSX1 and TP63 in Asian case-parent trios with nonsyndromic cleft lip with or without cleft palate

BackgroundSmall ubiquitin-like modification, also known as sumoylation, is a crucial post-translational regulatory mechanisms involved in development of the lip and palate. Recent studies reported two sumoylation target genes, MSX1 and TP63, to have achieved genome-wide level significance in tests of association with nonsyndromic clefts. Here, we performed a candidate gene analysis considering gene-gene and gene-environment interaction for SUMO1, MSX1, and TP63 to further explore the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P). MethodsA total of 130 single-nucleotide polymorphisms (SNPs) in or near SUMO1, MSX1, and TP63 was analyzed among 1,038 Asian NSCL/P trios ascertained through an international consortium. Conditional logistic regression models were used to explore gene-gene (G x G) and gene-environment (G x E) interaction involving maternal environmental tobacco smoke and multivitamin supplementation. Bonferroni correction was used for G x E analysis and permutation tests were used for G x G analysis. ResultsWhile transmission disequilibrium tests and gene-environment interaction analysis showed no significant results, we did find signals of gene-gene interaction between SNPs near MSX1 and TP63. Three pairwise interactions yielded significant p values in permutation tests (rs884690 and rs9290890 with p=9.34 x 10(-5) and empirical p=1.00 x 10(-4), rs1022136 and rs4687098 with p=2.41 x 10(-4) and empirical p=2.95 x 10(-4), rs6819546 and rs9681004 with p=5.15 x 10(-4) and empirical p=3.02 x 10(-4)). ConclusionGene-gene interaction between MSX1 and TP63 may influence the risk of NSCL/P in Asian populations. Our study provided additional understanding of the genetic etiology of NSCL/P and underlined the importance of considering gene-gene interaction in the etiology of this common craniofacial malformation.