The PDGF-C regulatory region SNP rs28999109 decreases promoter transcriptional activity and is associated with CL/P

• Published in: European journal of human genetics : EJHG 2009-06, Vol.17 (6), p.774-784
• Main Authors: Choi, Sun J, Marazita, Mary L, Hart, P Suzanne, Sulima, Pawel P, Field, L Leigh, McHenry, Toby Goldstein, Govil, Manika, Cooper, Margaret E, Letra, Ariadne, Menezes, Renato, Narayanan, Somnya, Mansilla, Maria Adela, Granjeiro, José M, Vieira, Alexandre R, Lidral, Andrew C, Murray, Jeffrey C, Hart, Thomas C
• Format: Article
• Language: English
• Subjects: Alleles; Binding sites; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; C gene; Case-Control Studies; Chromosome 4; Cleft Lip - genetics; Cleft lip/palate; Cleft Palate - genetics; Cytogenetics; Etiology; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene polymorphism; General aspects. Genetic counseling; Genetic Predisposition to Disease; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genotyping; Growth factors; Human Genetics; Humans; Lymphokines - genetics; Medical genetics; Medical sciences; Molecular and cellular biology; Mutation; Platelet-derived growth factor; Platelet-Derived Growth Factor - genetics; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic - genetics; Single-nucleotide polymorphism; Transcription; Transcription, Genetic - genetics; Transfection
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2008.245

Human linkage and association studies suggest a gene(s) for nonsyndromic cleft lip with or without cleft palate (CL/P) on chromosome 4q31–q32 at or near the platelet-derived growth factor-C ( PDGF-C) locus. The mouse Pdgfc −/− knockout shows that PDGF-C is essential for palatogenesis. To evaluate the role of PDGF-C in human clefting, we performed sequence analysis and SNP genotyping using 1048 multiplex CL/P families and 1000 case–control samples from multiple geographic origins. No coding region mutations were identified, but a novel −986 C>T SNP (rs28999109) was significantly associated with CL/P ( P =0.01) in cases from Chinese families yielding evidence of linkage to 4q31–q32. Significant or near-significant association was also seen for this and several other PDGF-C SNPs in families from the United States, Spain, India, Turkey, China, and Colombia, whereas no association was seen in families from the Philippines, and Guatemala, and case–controls from Brazil. The −986T allele abolished six overlapping potential transcription regulatory motifs. Transfection assays of PDGF-C promoter reporter constructs show that the −986T allele is associated with a significant decrease (up to 80%) of PDGF-C gene promoter activity. This functional polymorphism acting on a susceptible genetic background may represent a component of human CL/P etiology.