Abstract 2235: Epigenetic inflammation scores for C-Reactive protein and interleukin-6 associate with adverse cardiometabolic and cardiac outcomes among survivors of childhood cancer

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Abstract Background: Inflammaging, a chronic low-grade inflammation as individuals age, is measured by elevated levels of circulating markers of inflammation (e.g., C-reactive protein [CRP] and interleukin-6 [IL-6]) and is associated with age-related chronic health conditions (CHCs). We aim to evaluate epigenetic inflammation scores (EIS) for CRP and IL-6 and their associations with cardiometabolic and cardiac-based CHCs and epigenetic age acceleration (EAA) in childhood cancer survivors (CCS). Methods: Among 2,052 CCS (47.2% female; mean [SD] = 33.7 [9.3] years of age at blood draw) from the St Jude Lifetime Cohort, EIS of CRP and IL-6 were calculated as the weighted sum of the DNA methylation (DNAm) levels of CpGs that are associated with circulating levels of CRP or IL-6, where blood DNAm data were generated with Infinium EPIC BeadChip, and weights are regression coefficients from previously published EWAS studies. CHCs with a CTCAE (Common Terminology Criteria for Adverse Events) grade ≥2 were considered except for myocardial infarction (MI) where a minimum CTCAE grade of 3 was applied. Residuals of EIS were calculated by regressing EIS on age at blood draw and sex. A multivariable Cox proportional hazard regression model evaluated the associations between the EIS residuals and each CHC adjusting for sex and cancer treatments. The timeframe was years since age at blood draw. All participants alive at the last follow-up were censored. EAA was calculated as residuals from regressing epigenetic age (both GrimAge and PhenoAge) on age at blood draw. A linear regression model evaluated the association between the EIS residual and EAA adjusting for sex and treatments. Results: The incidence of cardiometabolic conditions (i.e., after the blood draw) included: abnormal glucose metabolism (AGM, 5.1%), hypertension (HTN, 16.6%), hypercholesterolemia (HCL, 3.9%), hypertriglyceridemia (HTG, 6.0%), and cardiomyopathy (CMP, 9.0%), MI (4.4%), and obesity (24.2%). CRP-EIS and IL6-EIS were correlated (r=0.62). The CRP-EIS residual was significantly associated with increased risk of AGM (Hazard Ratio [95% CI] = 1.33 [1.01-1.75], P=0.04) and CMP (1.44 [1.19-1.74], P=1.58 × 10−4) and suggestively associated with HTN (1.16 [0.99-1.36], P=0.07) and MI (1.55 [0.94-2.57], P=0.09). IL6-EIS residual was associated with CMP (1.25 [1.04-1.49], P=0.02). In addition, both CRP- and IL6-EIS were positively associated with PhenoAge-EAA (β = 0.53 and 0.50 years per SD increase of EIS) and GrimAge-EAA (β = 0.30 and 0.36 per SD increase of EIS). Conclusion: The CRP- and IL6-EIS are associated with increased risk of cardiometabolic and cardiac-based CHCs and EAA among CCS, suggesting that EIS may be used as clinical tools to identify survivors at higher risk of such CHCs and inflammation may be targeted for intervention to reduce the burden of CHCs. Citation Format: Qian Dong, Yan Chen, Xijun Zhang, John Easton, Heather Mulder, Emily Walker, Geoffrey Neale, Kyla Shelton, Stephanie B. Dixon, Jinghui Zhang, Gregory T. Armstrong, Melissa M. Hudson, Kirsten K. Ness, Zhaoming Wang. Epigenetic inflammation scores for C-Reactive protein and interleukin-6 associate with adverse cardiometabolic and cardiac outcomes among survivors of childhood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2235.