Identification of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map.
Psoriasis is a chronic inflammatory disease of the skin with both genetic and environmental risk factors. Here we describe the creation of a single-nucleotide polymorphism (SNP) map spanning 900-1200 kb of chromosome 3q21, which had been previously recognized as containing a psoriasis susceptibility locus, PSORS5. We genotyped 644 individuals, from 195 Swedish psoriatic families, for 19 polymorphisms. Linkage disequilibrium (LD) between marker and disease was assessed using the transmission/disequilibrium test (TDT). In the TDT analysis, alleles of three of these SNPs showed significant association with disease (P<0.05). A 160-kb interval encompassing these three SNPs was sequenced, and a coding sequence consisting of 13 exons was identified. The predicted protein shares 30-40% homology with the family of cation/chloride cotransporters. A five-marker haplotype spanning the 3' half of this gene is associated with psoriasis to a P value of 3.8<10(-5). We have called this gene SLC12A8, coding for a member of the solute carrier family 12 proteins. It belongs to a class of genes that were previously unrecognized as playing a role in psoriasis pathogenesis.
Hewett
Duncan
D
UK Discovery Genetics, GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
Samuelsson
Lena
L
Polding
Joanne
J
Enlund
Fredrik
F
Smart
Devi
D
Cantone
Kathryn
K
See
Chee Gee
CG
Chadha
Sapna
S
Inerot
Annica
A
Enerback
Charlotta
C
Montgomery
Doug
D
Christodolou
Chris
C
Robinson
Phil
P
Matthews
Paul
P
Plumpton
Mary
M
Wahlstrom
Jan
J
Swanbeck
Gunnar
G
Martinsson
Tommy
T
Roses
Allen
A
Riley
John
J
Purvis
Ian
I
D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000209:etiology / Q000235:genetics*; D028021:Sodium-Potassium-Chloride Symporters
D026901:Membrane Transport Proteins; C455505:SLC12A8 protein, human; D028021:Sodium-Potassium-Chloride Symporters