Abstract 11599: Elevated Interleukin-6 and TMPRSS6 Genotype Are Associated with Worse Cardiovascular Outcomes

Abstract

Introduction: Elevated levels of plasma interleukin-6 (IL-6) and impaired iron homeostasis are associated with cardiovascular disease. IL-6 and matriptase-2, which is encoded by the TMPRSS6 gene, help regulate iron homeostasis. A nonsynonymous V736A substitution (rs855791) reduces the ability of matriptase-2 to inhibit hepcidin transcription, leading to iron-deficiency anemia that is refractory to iron administration. We assessed the hypothesis that patients with chronic kidney disease and elevated IL-6 and the rs855791 genotype have poorer cardiovascular outcomes. Methods: We used the clinical, genetic and biomarker data from 3031 Chronic Renal Insufficiency Cohort (CRIC) study participants with follow-up over 10 years. The genotype data was extracted from genome-wide association studies. The primary outcome of interest was all-cause mortality and a composite of myocardial infarction (MI), stroke, congestive heart failure (CHF) and peripheral arterial disease (PAD). We used a separate logistic regression model for each outcome, with covariates for genotype and IL-6 quintile, and the genotype x IL-6 interaction. These models were adjusted for the Pooled Cohort Equation 10-year atherosclerotic cardiovascular disease probability estimate, race, BMI, baseline eGFR and baseline albuminuria. Results: Among the study participants, 1569 (52%) and 1122 (37%) were homozygous for GG and AA alleles, and 1122 (37%) were heterozygous (AG). The rs855791 genotype and plasma level of IL-6 were significantly associated with lower hemoglobin levels, all-cause mortality and cardiovascular outcomes. In the adjusted model that included the rs855791 genotype, IL-6 remained significantly associated with all-cause mortality (1.36 (1.26-1.45), p<0.001) and the CVD composite (1.27 (1.19-1.36), p<0.001). The interaction of IL-6 quintile x rs855791 genotype was not significantly associated with outcomes. Conclusion: In conclusion, elevated plasma levels of IL-6 and the rs855791 genotype are both independently associated with anemia, all cause mortality and cardiovascular outcomes in patients with kidney disease.