P1768Impact of inflammatory interleukin-1 genotypes on risk of infection in UK Biobank

Abstract

Background: The interleukin-1 (IL-1) pathway may offer promise as a target for the prevention of cardiovascular disease. For example, the impact of Canakinumab, a monoclonal antibody targeting IL-1beta, on cardiovascular events in those with raised C-reactive protein (CRP) post-myocardial infarction is soon to be reported. However, targeting the IL-1 pathway, which has a prominent role in the inflammatory cascade, may affect innate immunity and potentially increase the risk of serious infection. Mendelian randomization approaches allow us to explore the impact of IL-1 genotypes, with life-long effects on the IL-1 pathway, to elucidate the risk of potential adverse events of targeting IL-1. Purpose(s): To examine the impact of pro-inflammatory IL-1 genotypes on risk of hospital reported infection. Method(s): Among 115,894 genotyped participants of European ancestry in the UK Biobank (UKB), an IL-1(+) composite genotype, associated with overexpression of IL-1beta as well as elevated CRP, and IL-1(-) composite genotype, not associated with overexpression of IL-1beta, was constructed from three single nucleotide polymorphisms (rs16944 and rs1143634 [both in IL-1beta]:, and rs17561 [in IL-1alpha]). Incident reports of infection were identified from hospital episode statistics based on relevant ICD-10 codes, and considered by body system and infectious agent. Associations of the IL-1(+/-) composite genotypes with time to first incident infection were estimated using Cox proportional hazards models adjusted for age, sex, and 10 principle components. Result(s): A total of 68,528 (59.1%) UKB participants had IL-1(+) genotypes, previously associated with a pro-inflammatory response. There were no significant differences between the IL-1(+) and IL-1(-) groups in baseline characteristics, including age, gender, body mass index, diabetes, hypertension and pre-existing coronary disease (p>0.05). Among genotyped individuals, with an average followup of 6.2 years, 8393 individuals had an infection associated with admission to hospital (with infection being the primary cause of admission for 81.5%). There was no association between IL1(+/-) group and risk of infection (Hazard Ratio: 1.00; 95% CI: 0.96 to 1.04, p=0.96). This null association was consistent across different sites of infection including respiratory (n=2514), genitourinary (n=2936), and gastrointestinal (n=2428). Furthermore, there was no association of IL1(+/-) genotype with specific infectious agents, including bacterial (n=4207), viral (n=725) or fungal (n=543). Conclusion(s): This study suggests that lifelong predisposition to a proinflammatory response resulting from perturbation of the IL1 pathway is not associated with hospital reported infections. By contrast, Canakinumab has been associated with mildly increased rates of infection. Therefore, this genetic finding may reflect differences in pro-inflammatory versus inhibitory effects or potential biological compensation.