Identification of Susceptibility Loci in IL6, RPS9/LILRB3, and an Intergenic Locus on Chromosome 21q22 in Takayasu Arteritis in a Genome-Wide Association Study

WOS: 000353775900027
PubMed ID: 25604533
Objective. Takayasu arteritis is a rare large vessel vasculitis with incompletely understood etiology. This study was undertaken to perform the first unbiased genome-wide association analysis of Takayasu arteritis. Methods. Two independent cohorts of patients with Takayasu arteritis from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 patients and 1,047 controls of European ancestry. Genotyping was performed using the Omni1-Quad and Omni2.5 genotyping arrays. Genotyping data were subjected to rigorous quality control measures and subsequently analyzed to discover genetic susceptibility loci for Takayasu arteritis. Results. We identified genetic susceptibility loci for Takayasu arteritis with a genome-wide level of significance in IL6 (rs2069837) (odds ratio [OR] 2.07, P = 6.70 x 10(-9)), RPS9/LILRB3 (rs11666543) (OR 1.65, P = 2.34 x 10(-8)), and an intergenic locus on chromosome 21q22 (rs2836878) (OR 1.79, P = 3.62 x 10(-10)). The genetic susceptibility locus in RPS9/LILRB3 lies within the leukocyte receptor complex gene cluster on chromosome 19q13.4, and the disease risk variant in this locus correlates with reduced expression of multiple genes including the inhibitory leukocyte immunoglobulin-like receptor gene LILRB3 (P = 2.29 x 10(-8)). In addition, we identified candidate susceptibility genes with suggestive levels of association (P < 1 x 10(-5)) with Takayasu arteritis, including PCSK5, LILRA3, PPM1G/NRBP1, and PTK2B. Conclusion. Our findings indicate novel genetic susceptibility loci for Takayasu arteritis and uncover potentially important aspects of the pathophysiology of this form of vasculitis.
University of MichiganUniversity of Michigan System; Vasculitis Foundation; NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [U54-AR-7319, U01-AR5-1874-04]; NIH (National Center for Research Resources)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [U54-RR-9497]; NIH (National Center for Advancing Translational Sciences, Office of Rare Diseases Research); NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [3-P50-CA-093459, 5-P50-CA-097007, 5-R01-ES-011740, 5-R01-CA-133996]; AbbVieAbbott Laboratories; MSD; PfizerPfizer; Hoffmann-La RocheHoffmann-La Roche; GlaxoSmithKlineGlaxoSmithKline; Arthritis Research UKVersus Arthritis [19289]
Supported by the University of Michigan and the Vasculitis Foundation. The Vasculitis Clinical Research Consortium has received support from the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grants U54-AR-7319 and U01-AR5-1874-04, National Center for Research Resources grant U54-RR-9497, and the National Center for Advancing Translational Sciences, Office of Rare Diseases Research). Genotyping data from European American controls were obtained from the High Density SNP Association Analysis of Melanoma: Case-Control and Outcomes Investigation data set (dbGaP study accession: phs000187.v1.p1). Research support for this data set was provided by the NIH (grants 3-P50-CA-093459, 5-P50-CA-097007, 5-R01-ES-011740, and 5-R01-CA-133996).; Dr. Aydin has received consulting fees, speaking fees, and/or honoraria from AbbVie, MSD, and Pfizer (less than $10,000 each). Dr. Pagnoux has received consulting fees, speaking fees, and/or honoraria from Hoffmann-La Roche and GlaxoSmithKline (less than $10,000 each).