Genetic susceptibility and validation of angiographic patterns in Takayasu arteritis

BACKGROUND: Prior studies identified subsets of patients with Takayasu arteritis (TAK) based on angiographic patterns of disease in cohorts from India and North America. This study aimed to validate these patterns in a TAK cohort from Turkey and determine the role of genetics in arterial patterns. METHODS: 421 Turkish patients with TAK underwent angiography of the aorta and branch vessels, with disease involvement characterized in 13 arterial territories. K-means cluster analysis identified angiographically-based subgroups. 282 patients with TAK from Turkey and 115 European-American patients from North America were genotyped. Approximately 6.5 million SNPs were evaluated in a meta-analysis of both cohorts. Logistic regressions identified genetic associations with angiographic clusters (threshold for association: p-value<1x10^-5). Associated variants were functionally annotated. RESULTS: Three clusters were identified in Turkish patients, validating the previously-identified cluster pattern. Genome-wide meta-analyses revealed a locus in the solute carrier family gene SLC24A2 in Cluster One as the most significant association (rs2891138, OR = 3.34, p-value = 2.32x10^-7). Several genetic loci were associated with Cluster Two, including in LGALSL (rs883021, OR = 0.43, p-value = 1.00X10^-5), AK4P3 (rs1072778, OR = 0.39, p-value = 4.07X10^-6), and TMEM132B (rs4765045, OR = 3.05, p-value = 6.18X10^-6). The most significant locus associated with Cluster Three was in FRMD6 (rs55692665, OR = 2.79, p-value = 1.11X10^-7). Genetic effects were consistent between the cohorts. Several loci were associated with levels of mRNA expression in arterial tissues. A Cluster Two-associated variant in APBB2 (rs2465578, OR = 0.35, p-value = 6.69x10^-6) showed evidence for chromatin interaction with the NSUN7 promoter and increased aortic NSUN7 expression. CONCLUSIONS: Genetic factors are associated with distinct subsets of TAK defined by angiographic pattern of disease.