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Fine Mapping Major Histocompatibility Complex Associations in Psoriasis and Its Clinical Subtypes
Cited 154 time in
Web of Science
Cited 177 time in Scopus
- Authors
- Issue Date
- 2014-08
- Publisher
- University of Chicago Press
- Citation
- American Journal of Human Genetics, Vol.95 No.2, pp.162-172
- 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 x 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-DQ alpha 1 amino acid position 53; p < 5.0 x 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 (P-omnibus = 2.2 x 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.
- ISSN
- 0002-9297
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