Takayasu arteritis: Aortic root enhancement on a PET-CT scan. A 30-year-old woman with long-standing Takayasu arteritis on infliximab and methotrexate developed chest pain and left arm claudication. PET scan showed 18-fluorodeoxyglucose avidity of the wall of the aortic root and arch indicative of active aortitis. (Click to enlarge.)
The rare systemic inflammatory disease known as Takayasu arteritis primarily targets the aorta and its major branches, such as the carotid arteries that direct oxygenated blood to the brain. Chronic inflammation of the arteries can yield complications, such as aneurysms and stenosis, or a narrowing and blocking of blood vessels that can prevent parts of the body from receiving enough blood and oxygen. This ischemia can lead to tissue damage.
Researchers remain in the dark about the underlying cause of Takayasu arteritis, adding to the challenges of identifying and managing the disease. “We still don’t understand, for example, how much genetics, relative to non-genetic factors, contribute to the disease etiology,” says Amr H. Sawalha, MD, chair of the Department of Pediatric Rheumatology and director of the Comprehensive Lupus Center of Excellence at the University of Pittsburgh Medical Center.
Over the past decade, however, multiple large-scale genetic studies have revealed some important details about genetic susceptibility to Takayasu arteritis. In a recent review and analysis in ACR Open Rheumatology, Dr. Sawalha and post-doctoral fellow Desiré Casares-Marfil, PhD, have built upon that evidence with genetic associations that could help uncover pivotal molecular pathways, potential therapeutic targets and promising drug candidates.1 From the data, they devised a cumulative genetic risk score that confirmed differences in risk among people with different genetic ancestries, and developed a practical guide for communicating the risk to patients and their families.
New Susceptibility Clues
Takayasu arteritis is much less common than another type of large vessel vasculitis known as giant cell arteritis. The Takayasu type also tends to strike younger patients—primarily women, with a typical onset between the ages of 20 and 40. It is most prevalent in Asia, with about 40 cases per million people, whereas its prevalence in the U.S. is roughly fivefold lower. “It is a challenge because when it starts, it tends to be insidious in onset,” Dr. Sawalha says. “Basically, patients might not have very specific symptoms when they first present.” Some clinical clues can point toward Takayasu arteritis, however, like ischemic changes and symptoms related to blood vessel inflammation. Immunosuppressive medications are the usual first line of treatment.
Dr. Sawalha
In the 1970s, Japanese researchers reported that Takayasu arteritis is associated with the human leukocyte antigen (HLA) region of chromosome 6, which encodes a variety of cell-surface proteins that help regulate the immune system.2 Subsequently, researchers linked the disease to a specific variant of the HLA class B gene, known as the HLA-B*52 allele, which encodes one of these immune system-regulating cell-surface proteins.
“There was always a question whether or not other genes outside the HLA region might be contributing,” Dr. Sawalha says. Then in 2013, he and colleagues conducted a genome-wide association study that used an unbiased approach to scan the genomes of more than 450 patients and look for differences compared with healthy controls.3 The study searched for genetic variants, mainly in the form of single-letter changes in the DNA known as single nucleotide polymorphisms (SNPs), which occur with a significantly higher frequency in people with Takayasu arteritis than in healthy counterparts.
The study not only confirmed the Takayasu arteritis association with HLA-B*52 but also identified several new associations with small parts of the human genome beyond that HLA region. Akin to neighborhoods, these genetic susceptibility loci are stretches of DNA that may include multiple genes. From that initial effort and another four large-scale genetic studies, researchers have found Takayasu arteritis associations with 18 genetic susceptibility loci so far.
“So we’ve gone a long way from only having the HLA-B*52 connection to now having a number of genetic susceptibility loci within the HLA and also outside of the HLA,” Dr. Sawalha says. “That helps us understand the disease better, especially from the immunologic standpoint, but we are still not there yet. We still have much more work to do.”
Closer Genetic Associations
One pressing task has been figuring out which genes within each genetic susceptibility loci are truly associated with Takayasu arteritis. “We take these regions and try to identify, as much as we can, what might be the causal variant—the causal gene—and how it might affect the cause of the disease,” Dr. Sawalha says. In the review paper, he and Dr. Casares-Marfil used several methods to help determine these causal relationships with more precision. Within each genetic neighborhood, or locus, the researchers tried to determine which genetic variants were consistently associated with Takayasu arteritis. From those candidates, they asked which were associated with unusually higher or lower gene activity in disease-relevant cells and tissues, like in immune cells and tissue from the aorta.
Another tool allowed them to make note of functional similarities among the genes whose activity was altered by Takayasu arteritis-associated variants. “What do these genes have in common? What pathways? What cell types are enriched within these genes that induces susceptibility to Takayasu?” Dr. Sawalha asks. “By knowing that, we know what pathways in the immune system might be involved in the disease pathogenesis and also what pathways we can target for therapy.”
Yet another analysis let the researchers explore disease-associated epigenetic changes, or physical modifications to the DNA structure that alter a gene’s activity without actually changing its DNA sequence. About 90% of the Takayasu arteritis-linked variants are enriched in these epigenetic changes, he notes, bolstering the idea that they may play regulatory roles.
The DNA-protein complex, called chromatin, that makes up human chromosomes can also mediate physical changes by forming large loops, allowing some regulatory regions to interact with and control genes that would otherwise be far away. In Takayasu arteritis, Dr. Sawalha says, emerging evidence suggests at least two disease-associated loci may use this regulatory strategy to alter the activity of distant genes, including the promoter of the ETS2 gene, previously identified as a key regulator of inflammation in macrophage immune cells. By studying which genes are being controlled in this way, the researchers can glean further clues about how they may relate to disease processes and whether they might represent potential therapeutic targets.
Finally, the researchers found that members of at least two big families of transcription factors, or proteins that control how and when genes are turned off and on, were significantly more enriched in Takayasu arteritis-associated genetic sites than in other random sites on the genome. These specific transcription factors, part of the STAT and RUNX families, are known to help regulate immune functions and inflammatory responses. What the new research finding means, Dr. Sawalha says, is that these transcription factors may play a role in Takayasu arteritis as well, and thus offer additional therapeutic targets.
The growing list of functional pathways, transcription factors and causal genes can help the researchers piece together a better understanding of the cellular functions and cell types involved in the disease. The next step, Dr. Sawalha says, is to experimentally determine whether and how the associated genetic variants are pathogenic to cell cultures grown in vitro. He and colleagues are also conducting high-throughput analyses to narrow down the SNPs that merit further study.
Measuring & Communicating Risk
Based on the growing evidence, Dr. Sawalha and Dr. Casares-Marfil developed what’s known as a cumulative genetic risk score for Takayasu arteritis. “Basically the idea is that we now have a number of genetic susceptibility loci that we are confident about,” says Dr. Sawalha. “These are common genetic variants, so they are present in the general population. It’s just they happen to be enriched more in people who end up developing Takayasu.”
Considered one at a time, each genetic variant may not do much to increase an individual’s relative risk for developing the disease. But because everyone carries two copies of every SNP, the researchers can consider the additive effect of having none, one or two copies of every allele associated with a higher risk for Takayasu arteritis, multiplied by the estimated effect size of each of those alleles. Some alleles, like HLA-B*52 for example, have considerably larger effects than others. In sum, they can produce an estimate of someone’s cumulative genetic risk for Takayasu arteritis, similar to estimates produced for other diseases.
That risk score is unlikely to be useful diagnostically, Dr. Sawalha cautions, given that it’s based primarily on common genetic variants. It could, however, help explain differences or variability in disease prevalence among genetic ancestry groups. Using DNA samples donated by healthy individuals of African, East Asian, South Asian, European and mixed American genetic ancestry enrolled in the 1000 Genomes Project, the researchers found that the cumulative genetic risk partially explains the variability in disease prevalence seen across populations. The East Asian population, they found, had the highest cumulative risk score, while the mixed American population had the lowest score.
Given the caveats and unknowns, the researchers have developed a practical guide for communicating the genetic information to patients and their families. One of the most common questions asked by someone diagnosed with a rare disease is, “Are my children going to get it?” Dr. Sawalha says. To help put someone’s susceptibility in perspective, the two biggest considerations are the disease’s rarity and the relative risk for people who have disease-associated alleles that their healthy counterparts lack. In this case, he says, because Takayasu arteritis is quite rare, a two- or fourfold increase in relative risk would still yield a low overall risk.
To improve how the disease is treated, far more research into the underlying mechanisms of Takayasu arteritis will be necessary. For rheumatologists, Dr. Sawalha says, one big take-home lesson is the necessity of working together across institutions to conduct such research, including sharing data, providing samples and recruiting patients. “For rare diseases like Takayasu, it’s important that the community gets together to collaborate,” he says. “We cannot do any of this work without extensive international collaboration.”
Bryn Nelson, PhD, is a medical journalist based in Seattle.
References
- Casares-Marfil D, Sawalha AH. Functional and practical insights into the genetic basis of Takayasu arteritis. ACR Open Rheumatol. 2025 Jan;7(1):e11766.
- Naito S, Arakawa K, Saito S, et al. Takayasu’s disease: Association with HLA-B5. Tissue Antigens. 1978 Aug;12(2):143–145.
- Saruhan-Direskeneli G, Hughes T, Aksu K, et al. Identification of multiple genetic susceptibility loci in Takayasu arteritis. Am J Hum Genet. 2013 Aug 8;93(2):298–305.
