The PDGF-C regulatory region SNP rs28999109 decreases promoter transcriptional activity and is associated with CL/P.
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.
Choi
Sun J
SJ
Human Craniofacial Genetic Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892-1423, USA.
Marazita
Mary L
ML
Hart
P Suzanne
PS
Sulima
Pawel P
PP
Field
L Leigh
LL
McHenry
Toby Goldstein
TG
Govil
Manika
M
Cooper
Margaret E
ME
Letra
Ariadne
A
Menezes
Renato
R
Narayanan
Somnya
S
Mansilla
Maria Adela
MA
Granjeiro
José M
JM
Vieira
Alexandre R
AR
Lidral
Andrew C
AC
Murray
Jeffrey C
JC
Hart
Thomas C
TC
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*
D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C