Strong Evidence of Linkage Disequilibrium between Polymorphisms at the IRF6 Locus and Nonsyndromic Cleft Lip With or Without Cleft Palate, in an Italian Population

Department of Morphology and Embryology, Section of Histology and Embryology, University of Ferrara, Via Fossato di Mortara 64/B, 44100 Ferrara, Italy.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2005; 76(1):180-3. DOI: 10.1086/427344
Source: PubMed


Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects, but its etiology is largely unknown. It is very likely that both genetic and environmental factors contribute to this malformation. Mutations in the gene for interferon regulatory factor 6 (IRF6) have been shown to be the cause of Van der Woude syndrome, a dominant disorder that has CL/P as a common feature. Recently, it has been reported that genetic polymorphisms at the IRF6 locus are associated with nonsyndromic CL/P, with stronger association in Asian and South American populations. We investigated four markers spanning the IRF6 locus, using the transmission/disequilibrium test. A sample of 219 Italian triads of patients and their parents were enrolled in the study. Strong evidence of linkage disequilibrium was found between markers and disease in both single-allele (P=.002 at marker rs2235375) and haplotype (P=.0005) analyses. These findings confirm the contribution of IRF6 in the etiology of nonsyndromic CL/P and strongly support its involvement in populations of European ancestry.

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Available from: Francesco Carinci
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    • "expressed in the medial edges of the paired palatal shelves immediately before and during their fusion (Knight et al., 2006). Several studies have demonstrated that NSCL/P may be associated with variations in the IRF6 gene (Ghassibe et al., 2005; Scapoli et al., 2005; Jugessur et al., 2008; Pegelow et al., 2008). In addition, Rahimov et al. (2008) showed an association between NS cleft lip with or without cleft palate (NSCL6P) and rs642961 (G . "
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    ABSTRACT: Objectives : (1) To detect interferon regulatory factor 6 gene (IRF6) mutations in newly recruited Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) families. (2) To test for association, in nonsyndromic cleft lip and/or cleft palate (NSCL/P) and in VWS/PPS families, the single nucleotide polymorphism (SNP) rs642961, from the IRF6 enhancer AP-2α region, alone or as haplotype with rs2235371, a coding SNP (Val274Ile). Design : IRF6 mutation screening was performed by direct sequencing and genotyping of rs642961 and rs2235371 by TaqMan technology. Patients : Seventy-one Swedish NSCL/P families, 24 Finnish cleft palate (CP) families, and 24 VWS/PPS families (seven newly recruited) were studied. Results : Allelic and genotypic frequencies in each phenotype were compared to those of the controls, and no significant difference could be observed. IRF6 gene mutation was detected in six of the seven new VWS/PPS families. Association analysis of the entire VWS/PPS sample set revealed the A allele from rs642961 to be a risk allele. Significant association was detected in the Swedish CP subset of our NSCL/P collection where the G-C haplotype for rs642961-rs2235371 were at risk (P = .013). Conclusions : Our results do not support the previously reported association between the A allele of rs642961 and the NSCL phenotype. However, in the VWS/PPS families, the A allele was a risk allele and was, in a large majority (>80%), transmitted on the same chromosome as the IRF6 mutation.
    Full-text · Article · Feb 2013 · The Cleft Palate-Craniofacial Journal
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    • "However, previous articles discussed not only the rs235371 variant, but also the more general genetic background of IRF6, including an extensive haplotype analysis of an additional 2–35 SNPs in the IRF6 gene. Most importantly, this haplotype-based analysis has recently been confirmed in Italian, European-American, and Belgian CL/P families (Blanton et al., 2005; Ghassibé et al., 2005; Scapoli et al., 2005) and in Asian populations (Park et al., 2007). Isolated forms of CL/P have a complex etiology, with multiple genetic and environmental factors contributing (Beaty et al., 1997). "
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    ABSTRACT: Analyses of previous data have confirmed the contribution of the IRF6 gene to susceptibility to non- syndromic oral clefts (NSOC) in some populations. We tested for associations between the rs2013162, rs2235375, and rs2235371 polymorphisms in IRF6 and the risk of NSOC, using both case-parent trio and case-control designs on samples from western China. Our study group consisted of 332 persons with NSOC, their parents (289 mothers and 243 fathers for 206 complete trios for these three SNPs), and 174 control individuals. We found strong evidence of over- and under-transmission of the C allele (the Val allele) at rs2235371, and the C allele at rs2235375 in cleft case-parent trios (P = 0.013 and P = 0.000, respectively). There were significant differences in the frequency distributions of both genotypes and alleles when cases were compared with control infants at rs2235371 and rs2235375. Five specific haplotypes showed significant over- and under-transmission. These results further support a role for IRF6 variants in western Chinese populations.
    Full-text · Article · Sep 2009 · Journal of dental research
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    • "Less than 3% of our study population had the I allele of the V274I variant, resulting in too few informative subjects. IRF6 S153S (rs2013162) has also been associated with nonsyndromic CLP in previous reports (Scapoli et al., 2005). In our study, case-control and TDT association tests for IRF6 S153S produced uncorrected P-values <0.05 for isolated CLP; however, the results were not statistically significant after adjustment for multiple comparisons. "
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    ABSTRACT: Suggestive, but not conclusive, studies implicate many genetic variants in oral cleft etiology. We used a large, ethnically homogenous study population to test whether reported associations between nonsyndromic oral clefts and 12 genes (CLPTM1, CRISPLD2, FGFR2, GABRB3, GLI2, IRF6, PTCH1, RARA, RYK, SATB2, SUMO1, TGFA) could be confirmed. Thirty-one single nucleotide polymorphisms (SNPs) in exons, splice sites, and conserved non-coding regions were studied in 509 patients with cleft lip with or without cleft palate (CLP), 383 with cleft palate only (CP), 838 mothers and 719 fathers of patients with oral clefts, and 902 controls from Ireland. Case-control and family-based statistical tests were performed using isolated oral clefts for the main analyses. In case-control comparisons, the minor allele of PTCH1 A562A (rs2066836) was associated with reduced odds of CLP (odds ratios [OR], 0.29; 95% confidence interval [CI], 0.13-0.64 for homozygotes), whereas the minor allele of PTCH1 L1315P (rs357564) was associated with increased odds of CLP (OR, 1.36; 95% CI, 1.07-1.74 for heterozygotes; and OR, 1.56; 95% CI, 1.09-2.24 for homozygotes). The minor allele of one SUMO1 SNP, rs3769817 located in intron 2, was associated with increased odds of CP (OR, 1.45; 95% CI, 1.06-1.99 for heterozygotes). Transmission disequilibrium was observed for the minor allele of TGFA V159V (rs2166975) which was over-transmitted to CP cases (p = 0.041). For 10 of the 12 genes, this is the largest candidate gene study of nonsyndromic oral clefts to date. The findings provide further evidence that PTCH1, SUMO1, and TGFA contribute to nonsyndromic oral clefts.
    Full-text · Article · Jan 2009 · Birth Defects Research Part A Clinical and Molecular Teratology
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