NEW YORK – Researchers have identified additional variants that contribute to risk of Takayasu arteritis, a rare inflammatory disease.
Takayasu arteritis is marked by inflammation affecting the aorta and other large arteries and can lead to heart attack, stroke, or blood loss and organ damage. It is more common among women and among East Asian populations, and there is evidence that genetic factors, including an allele in the HLA region, contribute to the disease.
An international team of researchers conducted a genome-wide association study of Takayasu arteritis drawing on data from individuals from five diverse ancestries to uncover additional susceptibility loci, which they used to develop a genetic risk score, as they reported Friday in the American Journal of Human Genetics. The researchers additionally found Takayasu arteritis to be genetically related to inflammatory bowel disease and to involve monocytes and B cells, shedding additional light on the processes involved in disease development.
"Many of us who treat patients with Takayasu arteritis are frustrated because we don't really know how the disease works," senior author Amr Sawalha, a pediatric rheumatologist at the University of Pittsburgh School of Medicine, said in a statement. "We don't have good tools to predict a disease flare-up. Some parents have very active disease without clear symptoms or an increase in inflammatory markers."
He and his colleagues conducted a GWAS of 1,226 individuals with Takayasu arteritis from five different populations — people of Turkish, Northern European, Han Chinese, South Asian, and Italian ancestry — and 5,444 ancestry-matched controls.
The most robust signal they identified was within the HLA region and they further homed in on five SNPs in the region with independent associations with Takayasu arteritis, including three near a well-known susceptibility locus in HLA-B. Another four independent HLA classical alleles were also linked to Takayasu arteritis risk.
The researchers further found loci linked to Takayasu arteritis beyond the HLA region. They implicated loci at SVEP1, VPS8, CFL2, and chr13q21 in disease risk. SVEP1, for instance, encodes a cell-adhesion molecule that has been found to have a role in the development of autoimmune diseases like rheumatoid arthritis. They additionally confirmed that genetic loci at IL12B, PTPK2B, and at chr21q22 were shared across genetic backgrounds.
The loci at PTPK2B, the researchers noted, was previously identified as a genetic susceptibility factor for inflammatory bowel disease, and the two polymorphisms at IL12B have been linked to IBD and psoriasis, respectively. By further comparing Takayasu arteritis to hundreds of other traits, they found it was most closely genetically related to IBD.
Additionally, the researchers found that disease-linked variants in PTPK2B were linked to gene expression changes in other nearby genes, and a chromatin interaction analysis found ties between it and promoter regions of EPHX2 and CHRNA1.
Further chromatin interaction maps, epigenomic annotations, and eQTL analyses underscored the link between IL12B and Takayasu arteritis as well as highlighted ties between the chr21q22 region and ETS expression, particularly in monocytes and macrophages. Analyses of active chromatin marks affected by risk loci further implicated monocyte and B cells in disease processes.
The researchers bundled these and other loci with suggestive links to Takayasu arteritis into a genetic risk score. The score suggests that some differences in disease prevalence could have a genetic basis.
The findings additionally hint at potential treatment avenues. "We found that, generally speaking, Takayasu arteritis was closest to Crohn's disease," Sawalha added. "This suggests that we can try developing treatments based on what we know works for inflammatory bowel disease, which is a much more common condition."