Genetic interleukin-6 receptor blockade, Chronic Disease Risk and Longevity. Results from the Women's Health Initiative.

Abstract

Background: Interleukin-6 (IL-6) levels have been related to increased risk of chronic disease and mortality. Whether genetic IL-6 receptor (IL6R) blockade is associated with lower chronic disease risk or greater longevity is unknown.

Methods: The analytic cohort consisted of 38,807 Women's Health Initiative participants that had available genotyping information, of which 23,464 were eligible to survive to 90 years of age through February 19, 2023. Carrier status of the IL6R variant (rs8192284; p.Asp358Ala) was determined via genotyping. Chronic disease outcome data were available through February 19, 2023 for coronary heart disease (CHD), heart failure (HF), stroke and invasive cancer events. Prospective associations of IL6R carrier status with chronic disease outcomes were assessed with the Cox proportional hazards models, and logistic regression was used to evaluate survival to 90 years of age during follow-up.

Results: During a median follow-up of 20 years, 12,181 of 23,464 women (52.0%) survived to age 90. No significant difference in likelihood of surviving to age 90 was detected between women with 2 alleles of the IL6R gene variant compared to women without any allele (Odds Ratio, 1.00; 95% confidence interval, 0.91-1.09). The risks of CHD, HF, stroke, or cancer did not differ among IL6R variant carriers. High-sensitive C-reactive Protein (hsCRP) levels ≥2 mg/L compared to <2mg/L were associated with a modest increase in all-cause mortality and CHD risk independent of IL6R allele carrier status.

Conclusion: Genetic IL6R blockade was not associated with incident chronic disease risk including invasive cancer and longevity in a large, ethnically diverse cohort of postmenopausal women. No significant interaction with hsCRP levels was observed. While pharmacological blockade of IL6R has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease, these long-term data on genetic IL6R blockade do not indicate an altered likelihood for survival to very old age.