ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 625

Fine-Mapping Major Histocompatibility Complex Associations Identified Contribution of Multiple Class I and II HLA Genes on Risk of Psoriasis and Its Clinical Subtypes

Yukinori Okada1, Buhm Han2, Lam C. Tsoi3, Philip E. Stuart4, Eva Ellinghaus5, Trilokraj Tejasvi6, Vinod Chandran7, Fawnda Pellett8, Remy Pollock9, Anne M. Bowcock10, Gerald G. Krueger11, Michael Weichenthal5, John J. Voorhees6, Proton Rahman12, Peter K. Gregersen13, Andre Franke14, Rajan P. Nair6, Gonçalo R. Abecasis15, Dafna D. Gladman7, James T. Elder6, Paul IW. de Bakker16 and Soumya Raychaudhuri17, 1Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan, 2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 3Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 4Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, 5Christian-Albrechts-University of Kiel, Kiel, Germany, 6University of Michigan Medical School, Ann Arbor, MI, 7University of Toronto, Toronto Western Hospital, Toronto, ON, Canada, 8University of Toronto, Toronto, ON, Canada, 9Rheumatology, University of Toronto, Toronto, ON, Canada, 10Imperial College, London, United Kingdom, 11Dermatology, University of Utah, Salt Lake City, UT, 12Faculty of Medicine, Memorial University of Newfoundland, St. John's, NF, Canada, 13The Feinstein Institute for Medical Research, Manhasset, NY, 14Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany, 15University of Michigan, Ann Arbor, MI, 16University Medical Center, Utrecht, Netherlands, 17Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Title: Spondyloarthropathies and Psoriatic Arthritis - Pathogenesis, Etiology

Session Type: Abstract Submissions (ACR)

Background/Purpose: Psoriasis vulgaris (PsV) risk is strongly associated with genetic variation within the major histocompatibility complex (MHC) region, although its fine genetic architecture has not been elucidated.

Methods: To fully characterize and fine-map the MHC associations of PsV, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV cases and 13,589 controls of European descent. We also evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and purely cutaneous psoriasis (PsC, defined as 10 years of psoriasis without developing PsA; n = 3,098). We imputed class I and II HLA gene variants by applying SNP2HLA software to the SNP genotype data. In addition, we newly constructed an imputation reference panel of sequence variants for MICA, an HLA-like gene within the MHC region that has been implicated for PsA risk. We applied MICA variant imputation to the SNP genotype data and evaluated their risk as well.

Results: As previously described, we observed that HLA-C*06:02 demonstrated the most significant impact on overall PsV risk (odds ratio [OR] = 3.38, 95% confidence interval [95%CI]: 3.18-3.60, P = 1.7×10-364). Stepwise conditional analysis revealed multiple independent risk variants of both class I and class II HLA genes for PsV susceptibility independent of HLA-C*06:02 (HLA-C*12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQa1 amino acid position 53; P < 5.0x10-8), but no apparent independent risk conferred by MICA. Strikingly, we found that risk heterogeneity between PsA and PsC may be driven by one amino acid position at HLA-B (Glu at HLA-B amino acid position 45; OR = 1.46, 95%CI: 1.31-1.62, P = 2.9×10-12), which demonstrated much more significant association signals compared to classical HLA-B alleles including HLA-B*27 and HLA-B*39:01 (P > 1.0×10-4).

Conclusion: These results indicate that multiple class I and II HLA genes (HLA-C, HLA-B, HLA-A, and HLA-DQA1) contribute to development of PsV, and suggest that different genetic factors, most evident at HLA-B, underlie for the differential risk of specific PsV sub-phenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine-mapping causal variants in the MHC.

Disclosure:

Y. Okada,
None;

B. Han,
None;

L. C. Tsoi,
None;

P. E. Stuart,
None;

E. Ellinghaus,
None;

T. Tejasvi,
None;

V. Chandran,
None;

F. Pellett,
None;

R. Pollock,
None;

A. M. Bowcock,
None;

G. G. Krueger,
None;

M. Weichenthal,
None;

J. J. Voorhees,
None;

P. Rahman,
None;

P. K. Gregersen,
None;

A. Franke,
None;

R. P. Nair,
None;

G. R. Abecasis,
None;

D. D. Gladman,

Abbvie, Amgen, Celgene, Janssen, Pfizer, UCB,

2,

Abbvie, Amgen, BMS, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB,

5;

J. T. Elder,
None;

P. I. de Bakker,
None;

S. Raychaudhuri,
None.

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/fine-mapping-major-histocompatibility-complex-associations-identified-contribution-of-multiple-class-i-and-ii-hla-genes-on-risk-of-psoriasis-and-its-clinical-subtypes/