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

Abstract

Objective Takayasu’s arteritis is a rare large vessel vasculitis with incompletely understood etiology. We performed the first unbiased genome-wide association study (GWAS) in Takayasu’s arteritis. Methods Two independent Takayasu’s arteritis cohorts 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 European-derived patients and 1,047 controls. 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’s arteritis. Results We identified genetic susceptibility loci for Takayasu’s arteritis with a genome-wide level of significance in IL6 (rs2069837, OR= 2.07, P= 6.70×10−9), RPS9/LILRB3 (rs11666543, OR= 1.65, P= 2.34×10−8), and an intergenic locus on chromosome 21q22 (rs2836878, OR= 1.79, P= 3.62×10−10). The genetic susceptibility locus in RPS9/LILRB3 is located within the leukocyte receptor complex (LRC) 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= 2.29×10−8). In addition, we identified candidate susceptibility genes with suggestive levels of association (P <1×10−5) including PCSK5, LILRA3, PPM1G/NRBP1, and PTK2B in Takayasu’s arteritis. Conclusion This study identified novel genetic susceptibility loci for Takayasu’s arteritis and uncovered potentially important aspects in the pathophysiology of this form of vasculitis.

A case of primarily facial pyoderma gangrenosum associated with Takayasu arteritis

“…Although the pathogenesis of TA remains unknown, upregulated proinflammatory cytokines, such as interleukin (IL)-6, IL-8, IL-18, IL-23, and tumor necrosis factor-α in patients with TA has been shown 6 . A very recent genomewide association study also found some susceptible genes associated with immunoregulatory pathways, including IL6 7 . On the other hand, significant upregulation of IL-6 and IL-8 has been reported in PG 8 .…”

The genetics of Takayasu arteritis

“…We recently identified a genome-wide significant association in the RPS9/LILRB3 locus (rs11666543) [40]. The associated SNP co-localized with a putative active enhancer marked by H3K27ac histone modifications in multiple cell types.…”

“…A genetic effect in an intron of the IL6 pro-inflammatory gene was recently associated with TAK susceptibility at a genome-wide significance level [40]. This effect co-localized with a putative enhancer element that was marked by H3K27ac histone modification in multiple cell types.…”

Update on Takayasu's arteritis

“…Three important new papers have been published since the review was written, please refer to [98][99][100].…”