GWAS Identifies New Genetic Associations of Takayasu Arteritis

Researchers identified new genetic associations that can predict individuals’ susceptibility to Takayasu arteritis, a rare type of vasculitis. The study, published in the American Journal of Human Genetics, was conducted by a group of international investigators led by individuals at the University of Pittsburgh School of Medicine.

“Takayasu arteritis is a rare inflammatory disease affecting large arteries, most frequently the aorta and its major branches,” authors explained. Clinical manifestations of the disease result from vascular complications including occlusions and aneurysms. Takayasu arteritis is more common among women and typically occurs within the second or third decade of life while disease prevalence is the highest in East Asia.

"Many of us who treat patients with Takayasu arteritis are frustrated because we don't really know how the disease works," said Amr Sawalha, MD, professor of pediatrics and medicine at the University of Pittsburg, who conceived the study. "We don't have good tools to predict a disease flare-up. Some patients have very active disease without clear symptoms or an increase in inflammatory markers."

The etiology of the disease is not completely understood but previous studies have indicated genetic factors play a role in disease pathophysiology. However, “knowledge of the genetic component of Takayasu arteritis remains significantly limited compared to other immune-mediated diseases.”

In order to gain insights into the pathogenesis of the disease, researchers conducted a large genome-wide association study (GWAS) using cases from 5 diverse ancestries.

A total of 1226 individuals with Takayasu arteritis of Turkish, Northern European, Han Chinese, South Asian, and Italian descent were included in the study along with 5444 ancestry-matched healthy controls, marking the largest collection of theses samples in the world.

Genotyping data from 591 individuals with the disease were generated using Infinium Global Screening Array-24 v2.0 and Infinium OmniZhongHua-8 v1.3. The remaining patients’ and control data were gleaned from a previously published GWAS, the database of Genotypes and Phenotypes (dbGAP), and the 1000 Genome Project.

Samples with a genotyping call rate <95% and single nucleotide polymorphisms (SNPs) with a genotyping call rate <98% were not included in the analyses. Researchers also investigated whether an accumulative genetic risk score (GRS) for Takayasu arteritis varied across populations by examining the GRS of 2504 individuals included in the 1000 Genome project.

An association between the disease and HLA-B*52 had previously been established. Overall, the current analyses revealed:

• 4 novel genetic susceptibility non-HLA loci in Takayasu arteritis with a GWAS level of significance (SVEP1, CFL2, VPS8 and chr13q21)
• >60 genetic loci with a suggestive level of association with the disease
• Strongest association signals observed within the HLA region
• 5 variants showing independent associations with the disease: 3 located near the well-known susceptibility locus HLA-B (rs12524487-HLA-B/MICA, rs17193507-HLA-B/MICA and rs12526858-HLA-B) and 2 variants which may indicate previously unreported risk loci for Takayasu arteritis (rs2844678-MUC21 and rs28749167-HLA-G)
• 4 independent HLA classical alleles identified as susceptibility factors for Takayasu arteritis (HLA-B*52:01, HLA-B*13:02, HLA-B*15:01, and HLA-DQB1*05:02)

In addition, “The most significant biological process identified among genetic risk loci detected in our study was lymphocyte differentiation, which includes key specific pathways such as leukocyte differentiation, T cell activation, inflammatory response to antigenic stimulus, cytokine production, among others,” researchers explained.

The analysis found Takayasu arteritis was genetically closest to Crohn disease, meaning researchers can try developing treatments based on what is already known for this more common condition.

Future studies ought to be carried out to functionally characterize the complex effects identified, authors wrote. Investigators hope to use the data to find out which individuals are more likely to develop severe disease and which patients are more likely to carry the disease without presenting easily identifiable molecular markers.

Reference

Ortiz-Fernandez L, Saruhan-Direskeneli G, Alibaz-Oner F, et al. Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study. Am J Hum Genet. Published online December 11, 2020.