Abstract
Recent studies suggest that multiple interacting loci, with possible additional environmental factors, influence the risk for nonsyndromic oral clefts, one of the most common birth defects in humans. Advances in high-throughput genotyping technology allow the testing of multiple markers, simultaneously, in many candidate genes. We tested for associations between 176 haplotype-tagging single nucleotide polymorphisms (SNPs) in 18 candidate genes/loci and nonsyndromic clefts in a case-control study in an Estonian sample (153 patients, 205 controls). The most significant associations with nonsyndromic cleft lip with or without cleft palate (CL/P) were found for SNPs in MSX1, MTHFR, and PVRL2, including several common haplotypes in the MTHFR and MSX1 genes. The strongest association was observed for rs6446693 in the MSX1 region, which remained statistically significant after Bonferroni correction. The strongest association with nonsyndromic cleft palate (CP) was found for the SNP rs11624283 in the JAG2 gene. Epistatic interactions were observed for SNPs within PVRL2, between BCL3 and EDN1, and between IRF6 and MSX1 genes. This study provides further evidence implicating MSX1 and MTHFR in the etiology of nonsyndromic CL/P across different populations.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine
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B-Cell Lymphoma 3 Protein
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Case-Control Studies
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Cell Adhesion Molecules / genetics
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Chromosome Mapping
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Cleft Lip / etiology*
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Cleft Lip / genetics
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Cleft Palate / etiology*
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Cleft Palate / genetics
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Cytosine
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Endothelin-1 / genetics
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Epistasis, Genetic / genetics
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Estonia
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Gene Frequency / genetics
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Guanine
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Haplotypes / genetics
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Humans
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Immunoglobulins / genetics
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Intercellular Signaling Peptides and Proteins / genetics
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Interferon Regulatory Factors / genetics
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Jagged-2 Protein
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MSX1 Transcription Factor / genetics*
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Membrane Proteins / genetics
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Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
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Nectins
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Polymorphism, Single Nucleotide / genetics
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Proto-Oncogene Proteins / genetics
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Risk Factors
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Thymine
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Transcription Factors / genetics
Substances
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B-Cell Lymphoma 3 Protein
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BCL3 protein, human
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Cell Adhesion Molecules
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Endothelin-1
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IRF6 protein, human
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Immunoglobulins
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Intercellular Signaling Peptides and Proteins
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Interferon Regulatory Factors
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JAG2 protein, human
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Jagged-2 Protein
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MSX1 Transcription Factor
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MSX1 protein, human
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Membrane Proteins
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Nectins
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Proto-Oncogene Proteins
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Transcription Factors
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Guanine
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Cytosine
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Methylenetetrahydrofolate Reductase (NADPH2)
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Adenine
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Thymine