Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study

Abstract

Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 3 10 À5 ) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.

New-Onset Ulcerative Colitis in a Young Caucasian Woman with Unclassified Arteritis

“…Unfortunately, the previous studies were still small and did not involve a comprehensive variety of individuals. This knowledge changed in the past year with promising results from a large genome-wide study [7]. Most recently, the largest study to date involving over 6670 individuals including over 1200 with Takayasu arteritis within different global populations determined critical insight about patient susceptibility to contracting Takayasu arteritis [7].…”

“…This knowledge changed in the past year with promising results from a large genome-wide study [7]. Most recently, the largest study to date involving over 6670 individuals including over 1200 with Takayasu arteritis within different global populations determined critical insight about patient susceptibility to contracting Takayasu arteritis [7]. Of hundreds of traits compared, whole-genome analysis, and genetic marker analysis, the researchers found the closest genetic similarity between Takayasu arteritis and inflammatory bowel disease [7].…”

“…The etiology of the disease is still unclear, but it is commonly found in patients assigned female at birth of Asian descent [6]. Of recent interest, there appears to be a genetic similarity between this disease and another, much more common autoimmune disease, inflammatory bowel disease [7]. Previous case studies have shown similar human leukocyte antigen (HLA) B52, HLA-DR2, and HLA-B39 haplotypes in patients with coexisting Takayasu arteritis and ulcerative colitis [8][9][10][11].…”

“…Previous case studies have shown similar human leukocyte antigen (HLA) B52, HLA-DR2, and HLA-B39 haplotypes in patients with coexisting Takayasu arteritis and ulcerative colitis [8][9][10][11]. Within the past year, analyses of whole genomes, diseases, and traits, including thorough analyses comparing hundreds of thousands of genetic markers with Takayasu arteritis patients, are showing the closest similarity in genetic signatures with inflammatory bowel disease [7].…”

Childhood-onset Takayasu arteritis

“…The most well recognized genetic susceptibility locus for the disease is the classical human leukocyte antigen (HLA) allele, HLA-BÃ52, which has been confirmed in several ethnicities [12]. However, several other independent signals within the HLA region and limited non-HLA loci that confer genetic susceptibility have also been documented [2,12]. Large-scale genetic studies have been limited to Turkish, European-American, and Japanese populations, which may be a limiting factor in gene-disease association [2].…”