Session Title: Genetics, Genomics and Proteomics
Session Type: Abstract Submissions (ACR)
Inflammasomes are intra-cellular protein complexes important for the production of pro-inflammatory cytokines such as interleukin-(IL-)1β and IL-18. Cardiovascular disease is over-represented in patients with rheumatoid arthritis (RA), and chronic inflammation is believed, at least partly, to underlie this circumstance. Recent studies have suggested that the NLRP3 inflammasome influences both the severity of RA and development of atherosclerosis. NLRP3-Q705K and CARD8-C10X are functional polymorphisms which have been shown to influence inflammasome function, and to associate with plasma IL-1β levels in healthy individuals. Also, a number of reports have described synergistic effects between these polymorphism. Therefore, we sought to determine whether NLRP3-Q705K and CARD8-C10X influence the risk of cardiovascular disease (CVD) in patients with RA.
The incidence of CVD was assessed in 522 patients with established RA fulfilling the 1987 ACR criteria by a retrospective survey of medical records in combination with a 6 year prospective follow-up. CV events were defined as myocardial infarction (MI), severe verified angina pectoris treated with coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention, or stroke/transient ischaemic attack (TIA). NLRP3-Q705K and CARD8-C10X genotypes were analysed in relation to CVD by logistic regression analysis adjusting for traditional risk factors in addition to event preceding RA, treatment for RA, cumulative disease activity, and age at the onset of RA.
From the onset of RA to the 6-year follow-up, 121 patients were recorded as undergoing a CV event(s): 74 had suffered an MI, 20 had angina pectoris with intervention and 50 experienced a stroke/TIA. Carriage of the minor allele of NLRP3-Q705K was associated with an increased risk of stroke/TIA (Odds ratio (OR) = 2.01, 95% Confidence interval (CI) 1.0-4.1, p=0.05), whilst CARD8-C10X did not associate with any type of CV event. Patients with ≥1 variant allele in both polymorphisms had an increased risk of a CV event (OR 2.2, 95% CI 1.1-4.5, p=0.026) when compared with those homozygous for the major alleles of each polymorphism. Stratification showed that this risk was exclusively confined to stroke/TIA (OR 3.4, 95% CI 1.5-7.7, p=0.003) and not to MI and/or angina pectoris (OR, 1.5, 95% CI 0.6-3.4). Adjusting for traditional risk factors and RA severity yielded higher ORs regarding any CV event (OR 2.6, 95% CI 1.1-5.9, p=0.023) and stroke/TIA (OR 5.9, 95% CI 2.1-17, p=0.001). Stratification for sex consistently showed higher risk estimates among female patients.
Genetic variants of the NLRP3 inflammasome influence the risk of stroke/TIA, but not of MI/angina pectoris in patients with established RA. Future work should include genetic variants in upstream signaling pathways. Also, the possible clinical value of NLRP3 and CARD8 genotyping of RA patients, in relation to the risk of CVD and its prevention, calls for further attention in larger patient cohorts.
S. M. Rantapää-Dahlqvist,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-variants-of-the-nlrp3-inflammasome-are-associated-with-stroke-in-patients-with-rheumatoid-arthritis/