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Hum Mol Genet. 2012 Dec 1;21(23):5185-92. doi: 10.1093/hmg/dds344. Epub 2012 Aug 21.

Conditional analysis identifies three novel major histocompatibility complex loci associated with psoriasis.

Collaborators (152)

Donnelly P, Barroso I, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Deloukas P, Duncanson A, Jankowski J, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood NW, Spencer CC, Band G, Bellenguez C, Freeman C, Hellenthal G, Giannoulatou E, Pirinen M, Pearson R, Strange A, Su Z, Vukcevic D, Donnelly P, Langford C, Hunt SE, Edkins S, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Gray E, Hammond N, Jayakumar A, McCann OT, Liddle J, Potter SC, Ravindrarajah R, Ricketts M, Waller M, Weston P, Widaa S, Whittaker P, Barroso I, Deloukas P, Mathew CG, Blackwell JM, Brown MA, Corvin A, Spencer CC, Lepre T, Novelli G, Perricone C, Trembath RC, Barker JN, Burden AD, Cork MJ, Estivill X, Griffiths CE, Kere J, McManus R, Novelli G, Reis A, Samuelsson L, Schalkwijk J, Ståhle M, Tazi-Ahnini R, Weger W, Worthington J, Allen MH, Barker JN, Capon F, Hayday A, Knight J, Nestle FO, Smith CH, Trembath RC, Weale ME, Hofer A, Salmhofer W, Weger W, Wolf P, Kainu K, Kere J, Saarialho-Kere U, Suomela S, Badorf P, Hüffmeier U, Kurrat W, Küster W, Lascorz J, Mössner R, Reis A, Schürmeier-Horst F, Ständer M, Traupe H, Bergboer JG, den Heijer M, Schalkwijk J, van de Kerkhof PC, Zeeuwen PL, Barnes L, Campbell LE, Coleman C, Conroy J, Cusack C, Ennis S, Fitzgerald O, Gallagher P, Kirby B, Irvine AD, Markham T, McLean WH, McManus R, McPartlin J, Rogers SF, Ryan AW, Zawirska A, Giardina E, Estivill X, Martín-Ezquerra G, Pujol RM, Riveira-Munoz E, Inerot A, Naluai ÅT, Samuelsson L, Mallbris L, Ståhle M, Wolk K, Burden AD, Leman J, Barton A, Griffiths CE, Warren RB, Worthington J, Young HS, Cork MJ, Tazi-Ahnini R, Franke A, Ellinghaus E, Wijmenga C, Schreiber S, Trynka G, Gutierrez-Achury J.

Author information

1
National Institute for Health Research, Biomedical Research Centre, Guy’s and St Thomas’ NHS Foundation Trust, Toronto, ON, Canada M5T 1R8.

Abstract

Psoriasis is a common, chronic, inflammatory skin disorder. A number of genetic loci have been shown to confer risk for psoriasis. Collectively, these offer an integrated model for the inherited basis for susceptibility to psoriasis that combines altered skin barrier function together with the dysregulation of innate immune pathogen sensing and adap-tive immunity. The major histocompatibility complex (MHC) harbours the psoriasis susceptibility region which exhibits the largest effect size, driven in part by variation contained on the HLA-Cw*0602 allele. However, the resolution of the number and genomic location of potential independent risk loci are hampered by extensive linkage disequilibrium across the region. We leveraged the power of large psoriasis case and control data sets and the statistical approach of conditional analysis to identify potential further association signals distributed across the MHC. In addition to the major loci at HLA-C (P = 2.20 × 10(-236)), we observed and replicated four additional independent signals for disease association, three of which are novel. We detected evidence for association at SNPs rs2507971 (P = 6.73 × 10(-14)), rs9260313 (P = 7.93 × 10(-09)), rs66609536 (P = 3.54 × 10(-07)) and rs380924 (P = 6.24 × 10(-06)), located within the class I region of the MHC, with each observation replicated in an independent sample (P ≤ 0.01). The previously identified locus is close to MICA, the other three lie near MICB, HLA-A and HCG9 (a non-coding RNA gene). The identification of disease associations with both MICA and MICB is particularly intriguing, since each encodes an MHC class I-related protein with potent immunological function.

PMID:
22914738
PMCID:
PMC3490509
DOI:
10.1093/hmg/dds344
[Indexed for MEDLINE]
Free PMC Article

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