Fine Mapping Major Histocompatibility Complex Associations in Psoriasis and Its Clinical Subtypes

Yukinori Okada,Remy Pollock,Fawnda Pellett,Soumya Raychaudhuri,Proton Rahman,Trilokraj Tejasvi,Michael Weichenthal,Eva Ellinghaus,Buhm Han,Vinod Chandran,Gerald G Krueger ,André Franke ,Goncalo R Abeçasis ,John J Voorhees ,Lam C Tsoi ,James T Elder ,Rajan P Nair ,Dafna D Gladman ,Peter K Gregersen ,Philip E Stuart ,Paul I W De Bakker ,Anne M Bowcock

doi:10.1016/j.ajhg.2014.07.002

Abstract

Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C∗06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10−364). Stepwise analysis revealed multiple HLA-C∗06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C∗12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10−8), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (pomnibus = 2.2 × 10−11), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.

Highlights

Psoriasis vulgaris (PsV [MIM 177900]) is a common immune-mediated skin disease characterized by epidermal hyperplasia, inflammatory cell infiltration, and vascular remodeling.[1,2] Approximately one-third of PsV-affected individuals develop a related inflammatory musculoskeletal condition called psoriatic arthritis (PsA), which is considered more severe than the other more common PsV subtype, cutaneous psoriasis (PsC).[3]
human leukocyte antigen (HLA)-C*06:02 Has the Strongest Association with PsV Risk Unsurprisingly, when we tested the imputed variants in the major histocompatibility complex (MHC) region for overall PsV risk (PsV-affected versus control individuals), the top association signal mapped to HLA-C (Figures 1A and 2A; Table S2)
The most strongly associated variant was the classical HLA-C*06:02 allele (p 1⁄4 1.7 3 10À364), highly consistent with previous reports that HLA-C*06:02 has the strongest association with PsV risk.[7,8,9,10,11,12,17,18]

Summary

Introduction

Psoriasis vulgaris (PsV [MIM 177900]) is a common immune-mediated skin disease characterized by epidermal hyperplasia, inflammatory cell infiltration, and vascular remodeling.[1,2] Approximately one-third of PsV-affected individuals develop a related inflammatory musculoskeletal condition called psoriatic arthritis (PsA), which is considered more severe than the other more common PsV subtype, cutaneous psoriasis (PsC).[3].

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Methods

Results

Conclusion