rs642961

A targeted genome-wide study examining SNPs in three understudied populations (260 children with orofacial clefts from the DRC, Vietnam, and Philippines) confirmed four cleft susceptibility regions: 1q32.2 (IRF6), 10q25.3 (VAX1), 17q22 (NOG), and 15q13.3. Notable findings include rs10787738 near VAX1 (P=4.98E-03) and rs7987165 on chromosome 13 (P=2.2E-05) in meta-analysis, with risk alleles varying by population and no significant associations found in African populations.

Association study of MMP3 and TIMP2 promoter polymorphisms with nonsyndromic oral clefts in Brazilian case-control (494 cases, 413 controls) and US family-based (881 families) cohorts. MMP3 rs522616 showed strong association with all clefts (P=0.00002), cleft lip/palate (P=0.0009), and cleft palate (P=0.006). TIMP2 rs8179096 associated with all clefts (P=0.004), cleft lip/palate (P=0.01), and cleft palate (P=0.02). Significant gene-gene interaction between MMP3-TIMP2 detected (P=0.000001).

This Brazilian population study examines IRF6 gene variants rs642961 and rs590223 for association with nonsyndromic cleft lip/palate (NSCL/P) in 471 patients and 391 controls. A significant association was found between rs642961 and cleft lip only (CLO, P=0.009; OR 1.72-1.83), with a dominant genetic model, particularly in the high-heritability Barbalha subpopulation. No association was detected for rs590223, and expression analysis in mesenchymal stem cells showed no correlation between SNP genotypes and IRF6 expression levels.

This family-based association study examined the correlation between IRF6 rs642961 polymorphism and nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 352 Iranian individuals from 102 nuclear families. Using FBAT statistical analysis, the study found no significant association between the rs642961 variant and NSCL/P risk under additive (p=0.76), dominant (p=0.66), or recessive (p=0.9) genetic models, contrasting with previous findings in other populations and suggesting population-specific genetic effects.

Family-based study of 120 multiplex families and 325 simplex trios confirming association between six SNPs on chromosome 8q24.21 and nonsyndromic cleft lip and palate (NSCLP) in non-Hispanic whites, with relative risks ranging from 1.01-1.55 for heterozygotes and homozygotes. The study demonstrates ethnic heterogeneity, finding no association in Hispanic families and no linkage in African-American families, suggesting the 8q24 locus affects primarily individuals of Western European descent.

A large candidate gene study testing associations between nonsyndromic oral clefts and 12 genes (CLPTM1, CRISPLD2, FGFR2, GABRB3, GLI2, IRF6, PTCH1, RARA, RYK, SATB2, SUMO1, TGFA) in an Irish population of 509 cleft lip with or without palate (CLP) cases, 383 cleft palate only cases, and 902 controls. The study confirmed associations with PTCH1, SUMO1, and TGFA as contributing to nonsyndromic oral clefts, with PTCH1 P1315L showing significant association with CLP.

Gene-environment interaction study of 326 Chinese case-parent trios examining IRF6 gene variants and non-syndromic cleft lip with/without cleft palate (CL/P). After Bonferroni correction, 14 SNPs showed significant association with CL/P. Evidence of G×E interaction was found for maternal multivitamin supplementation (rs2076153 nominal P=0.019, rs17015218 nominal P=0.012) and environmental tobacco smoke (rs1044516 P=0.041, OR=1.96).