Genetic risk factors for nonsyndromic cleft lip with or without cleft palate in a Brazilian population with high African ancestry.

Nonsyndromic cleft lip with or without cleft palate (NSCL +/- P) is the most common orofacial birth defect, exhibiting variable prevalence around the world, often attributed to ethnic and environmental differences. Linkage analyses and genome-wide association studies have identified several genomic susceptibility regions for NSCL +/- P, mostly in European-derived or Asian populations. Genetic predisposition to NSCL +/- P is ethnicity-dependent, and the genetic basis of susceptibility to NSCL +/- P likely varies among populations. The population of Brazil is highly admixed, with highly variable ancestry; thus, the genetic determinants of NSCL +/- P susceptibility may be quite different. This study tested association of 8 single-nucleotide polymorphisms (SNPs), previously identified by genome-wide studies in other populations, with NSCL +/- P in a Brazilian population with high African ancestry. SNPs rs560426, rs642961, rs1530300, rs987525, rs3758249, rs7078160, rs17085106, and rs13041247 were genotyped in 293 Brazilian patients with NSCL +/- P and 352 unaffected Brazilian controls. Each sample was also genotyped for 40 biallelic short insertion/deletion polymorphic markers to characterize genetic ancestry. The average African ancestry background was 31.1% for the NSCL +/- P group and 36.7% for the control group. After adjustment for ancestry and multiple testing, the minor alleles of rs3758249 (OR: 1.58, 95% CI: 1.25-2.01, P = 0.0001) and rs7078160 (OR: 1.59, 95% CI: 1.21-2.07, P = 0.0002) were significantly associated with risk of NSCL +/- P. Polymorphisms located in IRF6 (rs642961) and 8q24 (rs1530300 and rs987525) showed marginal associations in this Brazilian population with high African ancestry. These results indicate that rs3758249 at 9q22 and rs7078160 at 10q25.3 represent risk loci for NSCL +/- P in the Brazilian population with high African ancestry.