Contribution of variants in and near the IRF6 gene to the risk of nonsyndromic cleft lip with or without cleft palate in a Malay population

Abstract

Several studies have shown evidence for the contribution of interferon regulatory factor 6 (IRF6) variants to the risk of nonsyndromic oral clefts in Asians; however, this has not included the Malay population. The current study attempts to address this research gap using allele and haplotype transmission disequilibrium analyses. The results showed a strong transmission distortion for multiple haplotypes to patients with nonsyndromic cleft lip with or without cleft palate. Haplotypes carrying the 243 bp allele of D1S2136 and common alleles at the rs861019 and rs2235371 were over-transmitted to patients. By contrast, haplotypes consisting of the 251 bp allele of D1S2136 and the rare allele at rs2235371 were more under-transmitted. Furthermore, several variants and haplotypes showed excess maternal transmission, but none of them attained statistical significance in maternal relative risk analyses. In contrast, a significant child genotype effect was observed for several haplotypes, indicating fetal genotype could be the major genetic contribution rather than maternal genotype. The present study therefore further supports a role for IRF6 variants in clefting in this Southeast Asian population. Overall, Asian genetic backgrounds are most likely more susceptible to the haploinsufficiency of IRF6 variants. These variants may contribute to the condition either themselves, or they may be in linkage disequilibrium with other casual variants.

Potential genetic markers for nonsyndromic oral clefts in the Brazilian population: A systematic review and meta‐analysis

“…Later, this same group revealed that the association of rs2235371 with the disease is dependent of rs642961, a polymorphism that disrupts the binding site of the transcription factor AP‐2a in the IRF6 promoter, which is in strong linkage disequilibrium with rs2235371 (Rahimov et al, ). The association of IRF6 variants with NOC has been replicated in various populations (Birnbaum et al, a; Huang et al, ; Krasone et al, ; Mijiti, Ling, Guli, & Moming, ; Moreno Uribe et al, ; Park et al, ; Salahshourifar, Sulaiman, Zilfalil, & Halim, ; Tang et al, ; Tomita et al, ) and supported by animal studies (Ingraham et al, ; Iwata et al, ). Nevertheless, this association has not been identified in studies of African cohorts (Butali et al, ; Figueiredo, Ly, & Raimondi, ; Weatherley‐White et al, ).…”

A Novel Heterozygous Mutation (F252Y) in Exon 7 of the IRF6 Gene is Associated with Oral Squamous Cell Carcinomas

“…The exon 7 of IRF6 gene encodes for major region of the C-terminal IAD region and hence mutations within this region may be expected cause functional impairment. Indeed, a single point mutation that causes conversion of GTC to ATC creating valine to isoleucine substitution at position 274 in IRF6 protein has been found to be significantly associated with cleft in several populations (Mangold et al, 2011;Salahshourifar et al, 2011;Stuppia et al, 2011). The identification of loss of IRF6 expression due to promoter hypermethylation of IRF6 in cutaneous squamous cell carcinomas and function impairing mutations in exon 7 of IRF6 in CL/CP/CLP prompted us to investigate, whether such mutations occurred in well differentiated OSCC lesions.…”

Investigation of the SNPs of IRF6 gene in non-syndromic cleft lip and/or palate (NSCLP) in a Turkish population

“…an association between IRF6 and NSCLP (10-13;[16][17][18][19][20][21][22][23] suggests that this is an important gene and clearly warrants further study. Though this study does not indicate that…”