Researchers have confirmed that HLA-B*52 is the strongest known genetic risk factor for Takayasu arteritis, a rare form of vasculitis, and uncovered additional susceptibility loci that provide insight into the disease’s underlying biology.
Takayasu arteritis (TAK) is a rare inflammatory disease of large arteries, particularly the aorta and its main branches. It most commonly affects women under age 50. The disease can lead to serious vascular complications, including aneurysms and arterial stenosis. Its estimated prevalence is 40 per million in Japan and 8.4 per million in the United States.
The study reviewed data from five genome-wide association studies (GWAS) of TAK, including one that analyzed 6,670 individuals from Turkish, Northern European, Han Chinese, South Asian, and Italian populations. This largest-ever GWAS in TAK confirmed that HLA-B*52 remains the most strongly associated variant with the disease.
Researchers calculated a cumulative genetic risk score (GRS) using genome-wide significant variants (P < 5 × 10⁻⁸) from GWAS. The GRS was significantly different across populations (ANOVA P < 1 × 10⁻⁴). The highest scores were observed in East Asian populations, followed by African and South Asian groups. Admixed American populations had the lowest risk scores. This variability partly reflects observed differences in disease prevalence.
Additional loci reaching genome-wide significance included IL6, IL12B, RPS9/LILRB3, SVEP1, DUSP22, PTK2B, VPS8, CFL2, and ETS2. Many of these genes are involved in immune regulation or inflammatory signaling.
To better understand how these genetic variants affect disease, researchers analyzed 311 single-nucleotide polymorphisms (SNPs), including those in high linkage disequilibrium (r² > 0.8). Among these, 85.9% modified expression of at least one gene, while 93.2% overlapped with histone marks associated with gene regulation. These marks included H3K4me1, H3K27ac, and H3K9ac.
Particularly notable was the chr21q22 region, where TAK-associated SNPs interacted with the ETS2 promoter in immune cells. This gene is involved in macrophage inflammation. Researchers found that TAK risk alleles were associated with increased ETS2 expression.
“This is of particular interest because it may provide evidence to guide functional studies, as is the case of ETS2, which showed changes in gene expression levels and chromatin interactions promoted by 11 SNPs associated with TAK or in high LD with them,” said Desiré Casares-Marfil and Dr. Amr H. Sawalha from the University of Pittsburgh School of Medicine.
Using HOMER, the team also identified 18 transcription factors enriched at TAK-related variants. These included members of the STAT and RUNX families, known for their involvement in cytokine signaling and immune cell development.
Pathway enrichment analysis revealed involvement in T cell–mediated immunity (P = 5.74 × 10⁻¹⁵), cytokine production regulation (P = 2.05 × 10⁻⁷), and natural killer cell activation (P = 2.03 × 10⁻⁵).
Although genetic factors play a role in TAK, the disease remains multifactorial. The authors emphasized that the presence of risk variants alone does not confirm disease. “>99.99% of individuals who carry HLA-B*52 will not develop Takayasu arteritis,” underscoring the importance of clinical context in interpreting genetic data.
Still, the findings mark a turning point. By mapping the genetic terrain of TAK, researchers are not just uncovering risk—they are illuminating paths toward future therapies. And in a disease where early detection is difficult and damage often silent, that kind of knowledge may prove essential.
Full disclosures can be found in the published study.
Source: ACR open rheumatology