rs2235371

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 case-control study examined IRF6 rs2235371 as a risk factor for non-syndromic cleft palate (CP) phenotypes in 158 Indonesian Deutero-Malay patients and 106 controls. The A mutant allele and GA genotype showed significant association with cleft palate only (CP) phenotype (OR=2.492, p=0.017 for allele; OR=2.114, p=0.048 for genotype), with the GA genotype showing elevated IRF6 mRNA expression levels compared to GG (p=0.031). The variant was not a significant risk factor for other cleft phenotypes (unilateral cleft lip-palate, bilateral cleft lip-palate, or cleft lip only).

This transmission disequilibrium analysis study of 98 case-parent trios from a Malay population found that IRF6 gene variants contribute to nonsyndromic cleft lip with or without cleft palate (NSCL/P). Key findings include preferential over-transmission of haplotypes carrying the 243 bp D1S2136 allele with T allele of rs861019 (OR=2.05) and V allele of rs2235371 to affected offspring, while protective haplotypes carried the 251 bp allele with the I allele of rs2235371. Child genotype effects were significant (relative risk 2.44-3.96 for risk alleles), supporting a fetal rather than maternal genetic contribution.

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.

This case-control and family-based study evaluated 64 SNPs in 34 genes for associations with spina bifida in 558 Irish case-families and 994 controls. Spina bifida was significantly associated with LEPR rs1805134 (GRR: 1.5, P = 0.0264) and COMT rs737865 (GRR: 1.4, P = 0.0206), with additional confirmations of previous findings in MTHFR 677C>T and other genes, suggesting roles for leptin signaling and methylation pathways in neural tube defect pathogenesis.

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).

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.

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.

Case-control study of 246 Indonesian subjects (158 non-syndromic cleft lip/palate cases, 106 controls) examining IRF6 rs2235371 polymorphism. The A allele was a significant risk factor for cleft palate only (CP) phenotype with OR=2.492 (p=0.017), and the GA genotype had OR=2.114 (p=0.048), but showed no association with other cleft phenotypes. RT-qPCR analysis confirmed GA genotype showed elevated IRF6 mRNA expression compared to GG genotype (p=0.031).

This family-based linkage and association study investigated the role of IRF6 gene variants in nonsyndromic cleft lip with or without cleft palate (NSCLP) in a Honduran population (276 individuals from 59 families). Three SNPs (rs1856161, rs2235371, rs2235377) in IRF6 showed significant association with NSCLP with p-values ≤0.05, with the strongest support for the haplotype TTC (p=0.006 when cleft palate-only cases excluded). This is the first genetic study of cleft etiology in Honduras and confirms IRF6's role in cleft susceptibility across diverse populations.

Population-based case-control study in Norway examining six SNPs in the IRF6 gene and facial cleft risk. Strong associations found with cleft lip/palate (CL/P) but not cleft palate only (CPO). Maternal rs4844880 double-dose showed increased CL/P risk (RR=1.85, p=0.036). The p.V274I polymorphism (rs2235371) showed protective effect with single-dose (RR=0.38, p=0.031) but increased risk with double-dose (RR=7.25, p=0.026).