Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus.
PSORS1, near HLA-C, is the major genetic determinant of psoriasis. We present genetic and structural evidence suggesting a major role for the HCR gene at the PSORS1 locus. Genotyping of 419 families from six populations revealed that coding single-nucleotide polymorphisms of HCR formed a conserved allele HCR*WWCC that associated highly significantly with psoriasis and with the HLA-Cw6 allele in all populations. Because of strong linkage disequilibrium between HLA-Cw6 and HCR*WWCC, the two genes could not be genetically distinguished by this sample size. However, the variant HCR allele was predicted to differ in secondary structure from the wild-type protein. HCR protein expression in lesional psoriatic skin differed considerably from that observed in normal skin. These results provide strong evidence for the HCR*WWCC allele as a major genetic determinant for psoriasis, probably by a mechanism impacting on keratinocyte proliferation.
Asumalahti
Kati
K
Department of Medical Genetics and Finnish Genome Center, University of Helsinki, 00014 Helsinki, Finland.
Veal
Colin
C
Laitinen
Tarja
T
Suomela
Sari
S
Allen
Michael
M
Elomaa
Outi
O
Moser
Michael
M
de Cid
Rafael
R
Ripatti
Samuli
S
Vorechovsky
Igor
I
Marcusson
Jan A
JA
Nakagawa
Hidemi
H
Lazaro
Conxi
C
Estivill
Xavier
X
Capon
Francesca
F
Novelli
Giuseppe
G
Saarialho-Kere
Ulpu
U
Barker
Jonathan
J
Trembath
Richard
R
Kere
Juha
J
D017668:Age of Onset; D000483:Alleles; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002874:Chromosome Mapping; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium; D008297:Male; D010375:Pedigree; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D011565:Psoriasis / Q000235:genetics* / Q000276:immunology / Q000473:pathology
C412616:CCHCR1 protein, human; D006023:Glycoproteins; D015236:HLA-C Antigens; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins