endothelin-1 and Cleft-Palate

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.

Topics: Adenine; B-Cell Lymphoma 3 Protein; Case-Control Studies; Cell Adhesion Molecules; Chromosome Mapping; Cleft Lip; Cleft Palate; Cytosine; Endothelin-1; Epistasis, Genetic; Estonia; Gene Frequency; Guanine; Haplotypes; Humans; Immunoglobulins; Intercellular Signaling Peptides and Proteins; Interferon Regulatory Factors; Jagged-2 Protein; Membrane Proteins; Methylenetetrahydrofolate Reductase (NADPH2); MSX1 Transcription Factor; Nectins; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins; Risk Factors; Thymine; Transcription Factors

There is good evidence from linkage analysis and mouse model knockouts that the endothelin-1 gene (EDN1) is a good candidate for non-syndromic orofacial cleft (OFC) disease. EDN1 maps to the chromosomal region of the OFC1 locus in 6p23. Therefore we have examined three other candidate genes in the endothelin pathway (ECE1, EDNRA and EDNRB, which map to chromosomes 1, 4 and 13 respectively) in a linkage study of 9 families with OFC, where the disorder is not linked to chromosome 6p23. The total lod score for these 9 multiplex families never exceeded -2.00 and thus our data suggest that EDN1 and related genes are not involved in non-syndromic familial OFC.

Topics: Animals; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 4; Chromosomes, Human, Pair 6; Cleft Lip; Cleft Palate; DNA; Endothelin-1; Female; Genetic Linkage; Humans; Lod Score; Male; Mice; Mutation; Receptors, Endothelin