Abstract
PURPOSE: To conduct the first whole exome sequencing (WES) on Takayasu arteritis (TAK) to identify common and rare variants responsible for disease susceptibility. PATIENTS AND METHODS: A total of 200 patients and 1675 healthy controls from China were recruited for this study. Site-based association analysis for common variants and gene-based burden analysis for rare variants were conducted. A weighted genetic risk score (wGRS) was calculated for each patient with TAK based on the independent risk alleles identified in the association analyses. The ability of the patient wGRS to discriminate between different phenotypes was evaluated. RESULTS: In the site-based analysis, the top association signal was CCHCR1 (rs1265067, p = 8.27 × 10(-12), OR = 2.41), a proxy for HLA-B*52:01. HLA-DQB1 (rs9273902), HLA-DQB2 (rs34109750), and a haplotype block in the human leukocyte antigen (HLA) class III region (represented by rs3130618) also exhibited significant associations independently. In addition, four novel non-HLA susceptibility loci were identified: PRRT4, TLL2, LRP1B, and DLGAP2. Twelve independently associated single nucleotide polymorphisms were used to calculate the wGRS. TAK patients with a higher wGRS were found to have an increased risk of pulmonary artery involvement compared with those with a lower wGRS (p = 5.76 × 10(-7), OR = 13.92). The wGRS algorithm showed good predictive capability for pulmonary artery involvement in TAK (sensitivity, 92.1%; specificity, 59.9%). In the gene-based analysis, risk genes that reached exome-wide significance were not identified. CONCLUSION: This WES study on TAK supports a previously reported association within the HLA region. Moreover, novel susceptibility loci were identified outside the HLA region. These risk alleles showed potential associations with pulmonary artery involvement in TAK. However, additional studies are warranted to verify our findings.