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

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          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 (p omnibus = 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.

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          Most cited references 27

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          A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC.

          The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.
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            Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.

            Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an approximately 300-kb region containing HLA-C and at least 10 other genes. In an effort to identify the PSORS1 gene, we cloned and completely sequenced this region from both chromosomes of five individuals. Two of the sequenced haplotypes were associated with psoriasis (risk), and the other eight were clearly unassociated (nonrisk). Comparison of sequence of the two risk haplotypes identified a 298-kb region of homology, extending from just telomeric of HLA-B to the HCG22 gene, which was flanked by clearly nonhomologous regions. Similar haplotypes cloned from unrelated individuals had nearly identical sequence. Combinatorial analysis of exonic variations in the known genes of the candidate interval revealed that HCG27, PSORS1C3, OTF3, TCF19, HCR, STG, and HCG22 bore no alleles unique to risk haplotypes among the 10 sequenced haplotypes. SPR1 and SEEK1 both had messenger RNA alleles specific to risk haplotypes, but only HLA-C and CDSN yielded protein alleles unique to risk. The risk alleles of HLA-C and CDSN (HLA-Cw6 and CDSN*TTC) were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated, despite good statistical power. By grouping recombinants with similar breakpoints, the most telomeric quarter of the 298-kb candidate interval could be excluded with high confidence. These results strongly suggest that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.
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              The IMGT/HLA database

              It is 14 years since the IMGT/HLA database was first released, providing the HLA community with a searchable repository of highly curated HLA sequences. The HLA complex is located within the 6p21.3 region of human chromosome 6 and contains more than 220 genes of diverse function. Of these, 21 genes encode proteins of the immune system that are highly polymorphic. The naming of these HLA genes and alleles and their quality control is the responsibility of the World Health Organization Nomenclature Committee for Factors of the HLA System. Through the work of the HLA Informatics Group and in collaboration with the European Bioinformatics Institute, we are able to provide public access to these data through the website http://www.ebi.ac.uk/imgt/hla/. Regular updates to the website ensure that new and confirmatory sequences are dispersed to the HLA community and the wider research and clinical communities. This article describes the latest updates and additional tools added to the IMGT/HLA project.
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                Author and article information

                Contributors
                Journal
                Am J Hum Genet
                Am. J. Hum. Genet
                American Journal of Human Genetics
                Elsevier
                0002-9297
                1537-6605
                07 August 2014
                : 95
                : 2
                : 162-172
                Affiliations
                [1 ]Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-0085, Japan
                [2 ]Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
                [3 ]Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
                [4 ]Division of Genetics, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
                [5 ]Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA
                [6 ]Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA
                [7 ]Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
                [8 ]Institute of Clinical Molecular Biology, Kiel University, Kiel 24105, Germany
                [9 ]Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON M5T 2S8, Canada
                [10 ]Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada
                [11 ]National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK
                [12 ]Department of Dermatology, University of Utah, Salt Lake City, UT 84112, USA
                [13 ]Department of Dermatology, Christian-Albrechts-Universität zu Kiel, Kiel 24105, Germany
                [14 ]Memorial University of Newfoundland, St. John’s, NL A1C5S7, Canada
                [15 ]The Feinstein Institute for Medical Research, North Shore – Long Island Jewish Health System, Manhasset, NY 11030, USA
                [16 ]Toronto Western Research Institute, University of Toronto, Toronto, ON M5G 2M9, Canada
                [17 ]Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA
                [18 ]Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands
                [19 ]Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands
                [20 ]Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester M13 9PT, UK
                Author notes
                []Corresponding author pdebakker@ 123456umcutrecht.nl
                [∗∗ ]Corresponding author soumya@ 123456broadinstitute.org
                [21]

                These authors contributed equally to this work

                Article
                S0002-9297(14)00311-5
                10.1016/j.ajhg.2014.07.002
                4129407
                25087609
                © 2014 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

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                Genetics

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