Identification of multiple genetic susceptibility loci in Takayasu arteritis

Abstract

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 (r(2) < 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)).

Figure 1

Manhattan Plot Showing the Results of a Meta-analysis between the Two Cohorts of Cases with Takayasu Arteritis and Controls Included in This Study The −log₁₀ p values for each genetic variant evaluated are plotted against its chromosomal location.

Figure 2

Results of the Meta-analysis Showing Genotyped and Imputed Variants in the HLA Region Two independent genetic effects are detected (r² < 0.2). (A) The entire HLA region evaluated in this study. (B and C) Regional plots for the meta-analysis results in the HLA-B/MICA locus (B) and the HLA-DQB1/HLA-DRB1 locus (C). The red line represents the genome-wide level of significance (p = 5 × 10⁻⁸). Genotyped and imputed variants are shown in diamonds and circles, respectively.

Figure 3

Genetic Association Results in the FCGR2A/FCGR3A Region in Takayasu Arteritis (A) Association results from the meta-analysis. (B and C) Association results in the Turkish (B) and the European-American (C) cohorts. The red line represents the genome-wide level of significance (p = 5 × 10⁻⁸). Genotyped and imputed variants are shown in diamonds and circles, respectively. The colors represent r² values with the index SNP in each locus (white, r² < 0.2; yellow, r² ≥ 0.2–0.5; orange, r² ≥ 0.5–0.8; red, r² ≥ 0.8).