Three polymorphisms in IRF6 and 8q24 are associated with nonsyndromic cleft lip with or without cleft palate: Evidence from 20 studies

Abstract

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common craniofacial malformation in humans. Three polymorphisms, rs2235371 and rs642961 in interferon regulatory factor 6 (IRF6), rs987525 on 8q24, have been shown to be associated with NSCL/P risk in several studies. However, the magnitudes of the association varied between studies. We therefore performed a meta-analysis to investigate this relationship. Two authors independently extracted information on the characteristics of the eligible studies. Either a fixed- or a random-effects model was used to calculate the overall combined risk estimates. Overall, 20 published case-control studies were included in the meta-analysis. We found that rs2235371 A allele had a significantly decreased risk (OR: 0.73, 95% CI: 0.61-0.88), whereas rs642961 A allele had a significantly increased risk of NSCL/P (OR: 1.44, 95% CI: 1.30-1.59), compared with the G allele. For 8q24 rs987525, the A allele was associated with a significantly increased risk of NSCL/P, compared with the C allele (OR: 1.71, 95% CI: 1.40-2.09). Furthermore, in the stratified analysis by ethnicity and types of NSCL/P, significant associations were still observed in the subgroups of ethnicity and types. Taken together, the results suggest that the IRF6 rs2235371, rs642961, and 8q24 rs987525 polymorphisms are associated with NSCL/P risk.

Association between IRF6 and 8q24 polymorphisms and nonsyndromic cleft lip with or without cleft palate: Systematic review and meta‐analysis

“…Our findings are consistent with previous human GWAS studies (Birnbaum et al, 2009b;Grant et al, 2009;Beaty et al, 2010;Ludwig et al, 2012). In addition, our findings are also consistent with the previous meta-analysis of genetic association studies by Wang et al (2012), that included 10, 6, and 8 studies in the pooling of rs2235371 and rs642961 for IRF6, and rs987525 for 8q24, respectively. We confirmed the previous findings by expanding to a larger number of included genetic association studies (i.e., 15, 11, and 12 studies for these corresponding polymorphisms) and applying Bonferroni correction for multiple tests.…”

2p24.2 (rs7552) is a susceptibility locus for nonsyndromic cleft lip with or without cleft palate in the Brazilian population

“…4 Indeed, interferon regulatory factor 6 (IRF6) gene and the 8q24 region are the most reliable genetic risk factors for NSCLAEP and have been validated in different populations. 5,6 In previous studies, we have investigated the association of several GWAS-susceptibility signals in the Brazilian population, confirming some associations, including 8q24 region, and failing to confirm others, such as IRF6, most probably due to differential frequencies of the risk alleles which are dependent upon ethnicity. [7][8][9][10][11][12][13] Two recent well-designed GWAS on NSCLAEP have been conducted.…”

“…Previous studies based on genome‐wide screening (mainly genome‐wide association studies‐GWAS) have identified several NSCL±P risk genes and chromosomal regions, but few have shown consistent replication across different populations . Indeed, interferon regulatory factor 6 ( IRF6 ) gene and the 8q24 region are the most reliable genetic risk factors for NSCL±P and have been validated in different populations . In previous studies, we have investigated the association of several GWAS‐susceptibility signals in the Brazilian population, confirming some associations, including 8q24 region, and failing to confirm others, such as IRF6 , most probably due to differential frequencies of the risk alleles which are dependent upon ethnicity .…”

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

“…This is clearly exemplified in interferon regulatory factor 6 ( IRF6 ) and 8q24 locus, the most reliable genetic factors for NOC (Beaty, Marazita, & Leslie, ; Dixon et al, ). Differences in the prevalence of IRF6 rs2235371 and 8q24 rs987525 alleles among Caucasians and Asians are observed, resulting in distinct effects on NOC susceptibility (Wang, Pan, Zhang, & Wang, ). While IRF6 rs2235371 showed a protective effect among Asians, with no effects in Caucasians, 8q24 rs987525 increased the risk for NOC among Caucasians but not among Asians (Wang et al, ).…”

“…Differences in the prevalence of IRF6 rs2235371 and 8q24 rs987525 alleles among Caucasians and Asians are observed, resulting in distinct effects on NOC susceptibility (Wang, Pan, Zhang, & Wang, ). While IRF6 rs2235371 showed a protective effect among Asians, with no effects in Caucasians, 8q24 rs987525 increased the risk for NOC among Caucasians but not among Asians (Wang et al, ). The effects of bone morphogenetic protein 4 ( BMP4 ) gene are also influenced by ethnicity, since the C allele of BMP4 rs17563 is a risk factor for NOC in Asians and Caucasians, but demonstrates a protective effect in the Brazilian population (Li et al, ).…”