title: Multiple Loci within the major histocompatibility complex confer risk of psoriasis.
abstract: Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; then, we followed up our findings in an independent Han Chinese 1,139 psoriasis cases and 1,132 controls. Using the phased CEPH dataset as a reference, we imputed the HLA-Cw*0602 in all samples with high accuracy. The association of the imputed HLA-Cw*0602 dosage with disease was much stronger than that of the most significantly associated SNP, rs12191877. Adjusting for HLA-Cw*0602, there were two remaining association signals: one demonstrated by rs2073048 (p = 2 x 10(-6), OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9 x 10(-6), OR = 1.3), located 30 kb centromeric of HLA-B and 16 kb telomeric of MICA. When HLA-Cw*0602, rs2073048, and rs13437088 were all included in a logistic regression model, each of them was significantly associated with disease (p = 3 x 10(-47), 6 x 10(-8), and 3 x 10(-7), respectively). Both putative loci were also significantly associated in the Han Chinese samples after controlling for the imputed HLA-Cw*0602. A detailed analysis of HLA-B in both populations demonstrated that HLA-B*57 was associated with an increased risk of psoriasis and HLA-B*40 a decreased risk, independently of HLA-Cw*0602 and the C6orf10 locus, suggesting the potential pathogenic involvement of HLA-B. These results demonstrate that there are at least two additional loci within the MHC conferring risk of psoriasis.
authors.affiliation: Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Bing-Jian
authors.initials: BJ
authors.lastname: Feng
authors.forename: Liang-Dan
authors.initials: LD
authors.lastname: Sun
authors.forename: Razieh
authors.initials: R
authors.lastname: Soltani-Arabshahi
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bowcock
authors.forename: Rajan P
authors.initials: RP
authors.lastname: Nair
authors.forename: Philip
authors.initials: P
authors.lastname: Stuart
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Schrodi
authors.forename: Ann B
authors.initials: AB
authors.lastname: Begovich
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Zhang
authors.forename: Kristina P
authors.initials: KP
authors.lastname: Callis-Duffin
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Krueger
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
mesh_terms: D000328:Adult; D044466:Asian People / Q000208:ethnology / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D055106:Genome-Wide Association Study; D015235:HLA-B Antigens / Q000235:genetics*; D059947:HLA-B40 Antigen; D015236:HLA-C Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D011565:Psoriasis / Q000208:ethnology / Q000235:genetics*; D055815:Young Adult
chemical_list: D015235:HLA-B Antigens; D059947:HLA-B40 Antigen; C103707:HLA-B57 antigen; D015236:HLA-C Antigens; C491620:HLA-C*06:02 antigen
references.citation: Am J Hum Genet. 2000 Jun;66(6):1833-44
references.pmid: 10801386
references.citation: Am J Hum Genet. 2005 Mar;76(3):449-62
references.pmid: 15700229
references.citation: Exp Dermatol. 2003 Aug;12(4):435-44
references.pmid: 12930300
references.citation: Am J Hum Genet. 2006 May;78(5):827-851
references.pmid: 16642438
references.citation: Chin Med Sci J. 1999 Jun;14(2):70
references.pmid: 12901611
references.citation: Am J Hum Genet. 2005 Jan;76(1):164-71
references.pmid: 15529278
references.citation: Br J Dermatol. 1978 Mar;98(3):287-92
references.pmid: 147699
references.citation: N Engl J Med. 2005 May 5;352(18):1899-912
references.pmid: 15872205
references.citation: J Invest Dermatol. 2000 Nov;115(5):824-8
references.pmid: 11069619
references.citation: J Rheumatol. 2008 May;35(5):891-5
references.pmid: 18381784
references.citation: Swiss Med Wkly. 2003 Oct 11;133(39-40):541-3
references.pmid: 14655055
references.citation: Ann Rheum Dis. 2005 Mar;64 Suppl 2:ii37-9; discussion ii40-1
references.pmid: 15708933
references.citation: J Biol Chem. 2005 May 13;280(19):18973-80
references.pmid: 15722350
references.citation: Nat Genet. 2009 Feb;41(2):199-204
references.pmid: 19169254
references.citation: Lancet. 2007 Jul 21;370(9583):263-271
references.pmid: 17658397
references.citation: Eur J Dermatol. 2006 Sep-Oct;16(5):523-9
references.pmid: 17101473
references.citation: Nat Genet. 2009 Feb;41(2):205-10
references.pmid: 19169255
references.citation: Am J Hum Genet. 2001 Apr;68(4):978-89
references.pmid: 11254454
references.citation: J Invest Dermatol. 2005 Mar;124(3):545-52
references.pmid: 15737195
references.citation: Hum Mol Genet. 1999 Nov;8(12):2165-70
references.pmid: 10545595
references.citation: Arch Dermatol Res. 2002 May;294(3):127-30
references.pmid: 12029499
references.citation: J Invest Dermatol. 1996 Apr;106(4):711-4
references.pmid: 8618009
references.citation: Genes Immun. 2006 Sep;7(6):450-67
references.pmid: 16791278
references.citation: Tissue Antigens. 1999 Feb;53(2):135-46
references.pmid: 10090613
references.citation: Am J Hum Genet. 2005 Apr;76(4):634-46
references.pmid: 15747258
references.citation: Nature. 2007 Feb 22;445(7130):866-73
references.pmid: 17314973
references.citation: Am J Hum Genet. 2007 Feb;80(2):273-90
references.pmid: 17236132
references.citation: J Invest Dermatol. 2005 Nov;125(5):928-32
references.pmid: 16297191
references.citation: Genet Epidemiol. 2007 May;31(4):348-57
references.pmid: 17323369
references.citation: Clin Exp Immunol. 2004 Oct;138(1):83-93
references.pmid: 15373909
references.citation: Hum Genet. 2005 Dec;118(3-4):466-76
references.pmid: 16235096
references.citation: Int J Dermatol. 2004 Mar;43(3):181-7
references.pmid: 15009387
references.citation: Int J Immunogenet. 2008 Jun;35(3):179-92
references.pmid: 18397301
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: Br J Dermatol. 2007 Jul;157(1):165-7
references.pmid: 17553030
references.citation: Biometrics. 1999 Dec;55(4):997-1004
references.pmid: 11315092
references.citation: Nature. 2007 Oct 18;449(7164):851-61
references.pmid: 17943122
references.citation: PLoS One. 2008 May 28;3(5):e2270
references.pmid: 18509540
references.citation: Br J Dermatol. 1998 Dec;139(6):978-83
references.pmid: 9990359
references.citation: Br J Dermatol. 2003 Feb;148(2):233-5
references.pmid: 12588373
references.citation: J Invest Dermatol. 1999 Sep;113(3):322-8
references.pmid: 10469328
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Nat Genet. 2006 Oct;38(10):1166-72
references.pmid: 16998491
references.citation: Dermatol Clin. 2004 Oct;22(4):339-47, vii
references.pmid: 15450331
references.citation: J Invest Dermatol. 2007 Aug;127(8):1886-92
references.pmid: 17446901
references.citation: J Invest Dermatol. 2007 Jan;127(1):163-9
references.pmid: 16858420
references.citation: PLoS Genet. 2008 Mar 21;4(3):e1000038
references.pmid: 18369457
references.citation: Tissue Antigens. 1998 Jun;51(6):618-22
references.pmid: 9694354