title: The PDGF-C regulatory region SNP rs28999109 decreases promoter transcriptional activity and is associated with CL/P.
abstract: 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.
authors.affiliation: Human Craniofacial Genetic Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892-1423, USA.
authors.forename: Sun J
authors.initials: SJ
authors.lastname: Choi
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
authors.forename: P Suzanne
authors.initials: PS
authors.lastname: Hart
authors.forename: Pawel P
authors.initials: PP
authors.lastname: Sulima
authors.forename: L Leigh
authors.initials: LL
authors.lastname: Field
authors.forename: Toby Goldstein
authors.initials: TG
authors.lastname: McHenry
authors.forename: Manika
authors.initials: M
authors.lastname: Govil
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Ariadne
authors.initials: A
authors.lastname: Letra
authors.forename: Renato
authors.initials: R
authors.lastname: Menezes
authors.forename: Somnya
authors.initials: S
authors.lastname: Narayanan
authors.forename: Maria Adela
authors.initials: MA
authors.lastname: Mansilla
authors.forename: José M
authors.initials: JM
authors.lastname: Granjeiro
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Vieira
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Lidral
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Hart
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008222:Lymphokines / Q000235:genetics*; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C