Identification of Multiple Genetic Susceptibility Loci in Takayasu Arteritis

• Published in: American journal of human genetics 2013-08, Vol.93 (2), p.298-305
• Main Authors: Saruhan-Direskeneli, Güher, Hughes, Travis, Aksu, Kenan, Keser, Gokhan, Coit, Patrick, Aydin, Sibel Z., Alibaz-Oner, Fatma, Kamalı, Sevil, Inanc, Murat, Carette, Simon, Hoffman, Gary S., Akar, Servet, Onen, Fatos, Akkoc, Nurullah, Khalidi, Nader A., Koening, Curry, Karadag, Omer, Kiraz, Sedat, Langford, Carol A., McAlear, Carol A., Ozbalkan, Zeynep, Ates, Askin, Karaaslan, Yasar, Maksimowicz-McKinnon, Kathleen, Monach, Paul A., Ozer, Hüseyin T., Seyahi, Emire, Fresko, Izzet, Cefle, Ayse, Seo, Philip, Warrington, Kenneth J., Ozturk, Mehmet A., Ytterberg, Steven R., Cobankara, Veli, Onat, A. Mesut, Guthridge, Joel M., James, Judith A., Tunc, Ercan, Duzgun, Nurşen, Bıcakcıgil, Muge, Yentür, Sibel P., Merkel, Peter A., Direskeneli, Haner, Sawalha, Amr H.
• Format: Article
• Language: English
• Subjects: Custom design; Female; Gene loci; Genetic Loci; Genetic Predisposition to Disease; Genotype & phenotype; Genotyping Techniques; Histocompatibility Antigens Class I - genetics; HLA-B Antigens - genetics; HLA-DQ beta-Chains - genetics; HLA-DRB1 Chains - genetics; Humans; Inflammatory diseases; Interleukin-12 Subunit p40 - genetics; Male; Mutation; North America - epidemiology; Pathogenesis; Receptors, IgG - genetics; Risk; Takayasu Arteritis - ethnology; Takayasu Arteritis - genetics; Turkey - epidemiology; Veins & arteries
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2013.05.026

Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B∗52. We genotyped ∼200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r2 < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10−16) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10−9; and rs189754752, OR = 2.47, p = 4.22 × 10−9). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10−12). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10−8).