Large-Scale Imputation of KIR Copy Number and HLA Alleles in North American and European Psoriasis Case-Control Cohorts Reveals Association of Inhibitory KIR2DL2 With Psoriasis

Frontiers in Immunology

Jorge Oksenberg¹  Rajan P. Nair²  James T. Elder²  Lam C. Tsoi⁴  Wolfgang Lieb⁵  Stephan Weidinger⁶  Andre Franke⁷  Eric Jorgenson⁸  Wilson Liao^1,10  Damjan Vukcevic^1,11  Joanne Nititham^1,12  Jill A. Hollenbach^1,14  John Foerster^1,14  Paul J. Norman^1,15  Richard Ahn^1,16  Eva Ellinghaus^1,17  Allan Motyer^1,19  David McG. Squire^1,19  Stephen Leslie^1,19 

[1] Bioinformatics, University of Michigan, Ann Arbor, MI, United States;0Department of Dermatology, University of Michigan, Ann Arbor, MI, United States;1Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States;;2Department of Computational Medicine &3College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, United Kingdom;4Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany;5Department of Dermatology, University Hospital Schleswig Holstein, Kiel, Germany;6Ann Arbor Veterans Affairs Hospital, Dermatology, Ann Arbor, MI, United States;7Division of Research, Kaiser Permanente, Oakland, CA, United States;8School of Biosciences, The University of Melbourne, Parkville, VIC, Australia;Clinical Epidemiology and Biostatistics Unit, Murdoch Children’s Research Institute, Parkville, VIC, Australia;Department of Dermatology, University of California, San Francisco, San Francisco, CA, United States;Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States;Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States;Division of Personalized Medicine, Department of Immunology and Microbiology, University of Colorado, San Francisco, CA, United States;Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, United States;Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany;Melbourne Integrative Genomics, The University of Melbourne, Parkville, VIC, Australia;School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, Australia;

关键词: psoriasis;    KIR;    HLA;    imputation;    genetics;    autoimmunity;   

DOI  :  10.3389/fimmu.2021.684326

来源: DOAJ

【 摘 要 】

Killer cell immunoglobulin-like receptors (KIR) regulate immune responses in NK and CD8+ T cells via interaction with HLA ligands. KIR genes, including KIR2DS1, KIR3DL1, and KIR3DS1 have previously been implicated in psoriasis susceptibility. However, these previous studies were constrained to small sample sizes, in part due to the time and expense required for direct genotyping of KIR genes. Here, we implemented KIR*IMP to impute KIR copy number from single-nucleotide polymorphisms (SNPs) on chromosome 19 in the discovery cohort (n=11,912) from the PAGE consortium, University of California San Francisco, and the University of Dundee, and in a replication cohort (n=66,357) from Kaiser Permanente Northern California. Stratified multivariate logistic regression that accounted for patient ancestry and high-risk HLA alleles revealed that KIR2DL2 copy number was significantly associated with psoriasis in the discovery cohort (p ≤ 0.05). The KIR2DL2 copy number association was replicated in the Kaiser Permanente replication cohort. This is the first reported association of KIR2DL2 copy number with psoriasis and highlights the importance of KIR genetics in the pathogenesis of psoriasis.

【 授权许可】

Unknown