IRF6 polymorphisms are associated with nonsyndromic orofacial clefts in a Chinese Han population

Abstract

IRF6 plays an important role in orofacial development. In the present study, we genotyped two polymorphisms (rs642961 and rs2235371) within the IRF6 locus and estimated their associations with risk of nonsyndromic orofacial clefts (NSOC), including the subgroups, in a hospital-based case-control study in a Chinese Han population. In the single locus analyses, we found rs642961 AG and AG/AA genotypes were associated with increased risk of NSOC, especially cleft lip with or without cleft palate (CL/P) and cleft lip with cleft palate (CLP), while significantly decreased risks were associated with rs2235371 CT and CT/TT genotypes. When examining the combined effects of these two polymorphisms and using the rs642961 A and rs2235371 C alleles as the risk alleles, we found genotypes containing 2-4 risk alleles conferred high risk to NSOC, CL/P, and CLP. Furthermore, to test whether rs642961 could modulate IRF6 expression in vivo, we surgically collected lip skin tissues within the adjacent region of lip cleft site and found rs642961 genotypes were associated with differential levels of IRF6 mRNA and protein expression in an allele-dosage manner, providing the first evidence that rs642961 affected IRF6 expression in vivo. Taken together, these findings confirm the contribution of IRF6 genetic variants in the etiology of NSOC in a Chinese Han population.

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

“…The most significant results, persisting after Bonferroni correction, were observed when the additive model was used, confirming dosage risk effect of minor allele A. Positive association between the IRF6 rs642961 variant and nsCL/P has been confirmed by multiple studies involving various ethnicities [21][22][23][24] . Also, our results are in accordance with the findings from two case-control studies on Central European populations which showed similar magnitudes of odds ratios 10,19 .…”

Different roles of two novel susceptibility loci for nonsyndromic orofacial clefts in a Chinese Han population.

“…As previously mentioned [Pan et al, 2010a;Pan et al, 2010b], this ongoing hospital-based case-control study, consisted of 396 NSOC cases (i.e., no other major anomalies and no syndrome causation for the cleft) and 384 healthy controls, was approved by the Institutional Review Board of Nanjing Medical University. The cases were consequently recruited from three participating sites in The Smile Train Project: The Stomatological Hospital of JiangSu Province (from August 2008 to February 2010), Nanjing Children's Hospital, and Xuzhou First People's Hospital (from January 2010 to October 2010), where the majority of orofacial cleft patients in JiangSu Province and surrounding areas attended for well-child visits.…”

“…The former two, believed to be etiologically distinct from CPO, are frequently collapsed into a single entity, referred as cleft lip with or without cleft palate (CL/P). Nevertheless, recent research suggested these two kinds of NSOC might have distinct genetic origins and should also be analyzed separately [Rahimov et al, 2008;Pan et al, 2010a].…”

IRF6 is a risk factor for nonsyndromic cleft lip in the Brazilian population

“…. Only one in vivo study, conducted in a small sample, suggested that rs642961 genotypes modulate IRF6 expression in an allele-dosage manner in skin lip from affected patients [Pan et al, 2010]. The SNP rs590223 (A>G) also is predicted to modulate in vivo the transcriptional levels of IRF6 in liver cells [Schadt et al, 2008], and its association with NSCL/P is controversial [Jagom€ agi et al, 2010;Mostowska et al, 2010].…”