Brazilian Multiethnic Association Study of Genetic Variant Interactions among FOS, CASP8 , MMP2 and CRISPLD2 in the Risk of Nonsyndromic Cleft Lip with or without Cleft Palate.

Associations of (cysteine-rich secretory protein LCCL domain containing 2) and genes belonging to its activation pathway, including (Fos proto-oncogene), (caspase 8) and with nonsyndromic orofacial cleft risk, have been reported, but the results are yet unclear. The aim of this study was to evaluate single nucleotide polymorphisms (SNPs) in , and and to determine their SNP-SNP interactions with variants in the risk of nonsyndromic cleft lip with or without cleft palate (NSCL±P) in the Brazilian population. The SNPs rs1046117 (), rs3769825 () and rs243836 () were genotyped using TaqMan allelic discrimination assays in a case-control sample containing 801 NSCL±P patients (233 nonsyndromic cleft lip only (NSCLO) and 568 nonsyndromic cleft lip and palate (NSCLP)) and 881 healthy controls via logistic regression analysis adjusted for the effects of sex and genomic ancestry proportions with a multiple comparison value set at ≤0.01. SNP-SNP interactions with rs1546124, rs8061351, rs2326398 and rs4783099 in were performed with the model-based multifactor dimensionality reduction test complemented with a 1000 permutation-based strategy. Although the association between rs1046117 and risk of NSCL±P reached only nominal values, NSCLO risk was significantly higher in carriers of the rs1046117 C allele (OR: 1.28, 95% CI: 1.10-1.64, = 0.004), TC heterozygous genotype (OR: 1.59, 95% CI: 1.16-2.18, = 0.003), and in the dominant model (OR: 1.50, 95% CI: 1.10-2.02, = 0.007). Individually, no significant associations between cleft risk and the SNPs in and were observed. SNP-SNP interactions involving variants and rs1046117 (), rs3769825 () and rs243836 () yielded several significant values, mostly driven by rs1046117 and rs3769825 in NSCL±P, rs1046117 in NSCLO and rs8061351 in NSCLP. Our study is the first in the Brazilian population to reveal the association of rs1046117 with NSCLO risk, and to support that , , and interactions may be related to the pathogenesis of this common craniofacial malformation.