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: 10.99). 02/2005; 76(1):180-3. DOI: 10.1086/427344
Source: PubMed

ABSTRACT 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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    ABSTRACT: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) are common birth defects with a complex etiology. Multiple interacting loci and possible environmental factors influence the risk of NSCL/P. 12 single nucleotide polymorphisms (SNPs) in 7 candidate genes were tested using an allele-specific primer extension for case-control and case-parent analyses in northeast China in 236 unrelated patients, 185 mothers and 154 fathers, including 128 complete trios, and 400 control individuals. TGFA and IRF6 genes showed a significant association with NSCL/P. In IRF6, statistical evidence of an association between rs2235371 (p = 0.003), rs2013162 (p<0.0001) and NSCL/P was observed in case-control analyses. Family based association tests (FBATs) showed over-transmission of the C allele at the rs2235371 polymorphism (p = 0.007). In TGFA, associations between rs3771494, rs3771523 (G3822A), rs11466285 (T3851C) and NSCL/P were observed in case-control and FBAT analyses. Associations between other genes (BCL3, TGFB3, MTHFR, PVRL1 and SUMO1) and NSCL/P were not detected.
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    ABSTRACT: Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common birth defect results from the genetic factors alone or interactions with environmental changes. Single nucleotide polymorphisms (SNPs) of CRISPLD2 gene have been found to be an etiologic factor in the development of nsCL/P. However, few studies to date focused on the association of genetic variation of CRISPLD2 gene with nsCL/P, and the results are conflicting based on the different study population. The main purpose of the present study was to investigate the association between the CRISPLD2 gene and nsCL/P in Xinjiang Uyghur population. Eighteen SNPs were screened in a group of 200 patients with nsCL/P and in a control group consisting of 180 unaffected individuals by next generation sequencing using MiSeq Benchtop Sequencer (Illumina). Our case-control association analysis showed that the SNP marker rs1546124 showed statistically significant differences in genotype (CC vs. CG vs. GG P=0.004) and allele frequencies (49% vs. 37.8% OR=1.58; 95% CI=1.19-2.1, P=0.002) between nsCL/P and controls. Under the recessive model of inheritance, the GG homozygotes had an OR of 2.4 (95% CI=1.37-4.18; P=0.002), and the result of significance was maintained even after multiple testing correction. Haplotype combinations of CACC were significantly more frequent in the nsCL/P patients than in controls (P=0.037). Finally, the MDR analysis identified the two-SNP model including rs1546124 and rs4782675 as best combination of possibly interactive polymorphisms (P<0.001). Our results demonstrate that genetic polymorphism of CRISPLD2 gene is associated with an increased risk of nsCL/P in a Xinjiang Uyghur population. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    International Journal of Pediatric Otorhinolaryngology 11/2014; 79(2). DOI:10.1016/j.ijporl.2014.10.043 · 1.32 Impact Factor
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    ABSTRACT: Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects; it is a multifactorial disease affecting > 1/1,000 live births in Europe, and its etiology is largely unknown, although it is very likely genetic and environmental factors contribute to this malformation. Orofacial development is a complex process involving many genes and signaling pathways. Mutations in the gene for the interferon regulatory factor 6 (IRF6) cause a hereditary dominant malformation syndrome including CL/P, and polymorphisms are associated with non-syndromic CL/P (MIM 119530). Five SNPs at the locus with high heterozygosity in Caucasian populations were chosen for the present research due to their very strong association with CL/P. A case–parent trio study was performed using 292 samples from Mexico. Association with the rs1319435-C/C genotype (P = 0.02) was found in patients (73) as compared to pseudocontrols (219), while the genotype rs1319435-T/C was related with protection (P = 0.041) in the triad design. Significant over-transmission of the G allele for marker rs2235375 (P = 0.049) was found. Only the TACGT haplotype was diminished in the affected child, either in single (P = 0.0208) or double (P = 0.0208) dose. The pairwise analysis showed rs2235543 and rs2235371 were in strong linkage disequilibrium. These results point to a substantial contribution of IRF6 in the etiology of non-syndromic CL/P in a sample of the Mexican population.
    06/2015; 4. DOI:10.1016/j.mgene.2015.02.002

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