Researchers have discovered two common genetic variants that offer protection against pericarditis, paving the way towards more targeted and personalized treatments.
The dual discovery at a gene locus for interleukin (IL)-1 cytokines could help tailor therapy with a group of drugs that block the action of these proteins, which recently received regulatory clearance for recurrent pericarditis.
The findings, by Rosa Thorolfsdottir, PhD, from DeCODE genetics and colleagues are published in the journal JAMA Cardiology.
“The present study by Thorolfsdottir and colleagues represents an important first step toward understanding the genetic architecture of pericarditis,” note Brittany Weber, PhD, and Michael Honigberg, PhD, from Harvard Medical School, in a Commentary article accompanying the study.
“These results provide important corroboratory data supporting the use of targeted anti–IL-1 biologics in pericardial disease given that these therapies have only been recently approved after small, albeit strong, clinical trials.”
Pericarditis is characterized by inflammation of a thin tissue sac surrounding the heart, which can cause sharp chest pain and is recurrent in up to 30 percent of patients.
Colchicine combined with nonsteroidal anti-inflammatory drugs (NSAIDs) is standard first-line therapy for acute pericarditis.
While this is frequently successful, traditional treatment for recurrent pericarditis—with the addition of prednisone to NSAIDs and colchicine—is often ineffective and can lead to steroid dependence and associated glucocorticoid adverse effects.
U.S. regulators approved the IL-1α and IL-1β cytokine trap rilonacept for recurrent pericarditis in 2021, following the landmark, RHAPSODY phase III trial and these results were further confirmed with another IL-1 trap receptor, goflikicept.
While biologics have been transformative for treatment, the rapid paradigm shift in the therapeutic landscape leaves many unanswered questions—particularly as biologics have been associated with small but significant increases in risk of sepsis and other infections.
Weber and Honigberg summarize that “while the time for targeted biologic therapy to treat a challenging cardiovascular condition has arrived, important questions remain to define precision management approaches for pericardial disease.”
In an attempt to gain greater understanding of the genes and pathways involved, Thorolfsdottir et al. conducted a genome-wide association study meta-analysis that incorporated individuals with European genetic ancestry from five countries.
This included 4894 patients with pericarditis, of whom 22.6 percent had recurrent pericarditis, and 1,457,822 control individuals.
The analysis identified two independent common genetic variants associated with protection from pericarditis at chromosome 2q14, which includes genes for the majority of IL-1 cytokines. The strongest association was observed with rs12992780, which sits approximately 10 kilobases downstream of the gene encoding IL-1β and had an odds ratio of 0.83 for pericarditis. This lead variant had an effect allele frequency of 31–40 percent and a stronger association with recurrent than acute pericarditis, with odds ratios of 0.76 and 0.86, respectively.
The second association was with rs7575402, which sits close to both genes encoding IL1RN, the IL-1 receptor antagonist protein, and the IL-1 family member 10. This had an effect allele frequency of 45–55 percent and an odds ratio of 0.89.
The rs7575402 variant was associated with CpG methylation overlapping binding sites of four transcription factors known to regulate IL-1 production.
The researchers note that there was a significant association for the variants among individuals without documented recurrences of pericarditis.
“Thus, given that the results implicate the IL-1 pathway, they would also support a broader indication for IL-1 inhibition than currently recommended, such as for patients with first recurrence that do not tolerate colchicine,” the team suggests.
“Furthermore, the possibility of personalized treatment based on genotype may be addressed in future studies comparing response and adverse effects of the drugs among carriers and non-carriers of the pericarditis-associated sequence variants.”
