Abstract
Background: Statins are prescribed to reduce LDL-cholesterol (LDL-c) and the risk of cardiovascular disease. Statins may influence other outcomes such as dementia through pleiotropic effects unrelated to lipid metabolism. We compared the proteome of statin users and nonusers. We hypothesized that statin use would be associated with proteins in biological pathways unrelated to lipid metabolism. Methods: Among 11,471 participants enrolled in the ARIC study at visit 3 (1993-95), plasma concentrations of 4,638 proteins were determined using the SOMAlogic DNA aptamer-based capture array. We identified 402 participants who initiated statin use within the 2 years prior. Propensity scores (PS) were calculated based on visit 2 (1990-92) LDL-c levels and visit 3 demographic characteristics, CVD risk factors and medications, kidney function, and prevalent CVD. Statin users were matched to nonusers (controls) based on PS similarity, yielding 382 matched pairs. Log2-transformed and standardized protein levels were compared between statin users and controls using t-tests. The false discovery rate (FDR) adjusted for multiple comparisons. Ingenuity Pathway Analysis (IPA) was used to identify potentially altered biological pathways. Results: After PS matching, LDL-c levels at visit 3 were lower in statin users vs controls (125.4 vs 147.1 mg/dL; p <.0001), but all other covariates were balanced. We identified 344 enriched and 298 depleted proteins in statin users (p <.05). After FDR adjustment, 12 proteins were enriched and 17 were depleted. Proteins involved in lipid metabolism were altered in statin users, including proteins in the mevalonate pathway. Proteins unrelated to lipid metabolism also differed between groups (Figure). IPA analysis suggested 20 pathways were altered among statin users. Conclusion: Several proteins unrelated to lipid metabolism differed by statin use. Pending external validation, exploring the biological functions of these proteins could elucidate pleiotropic effects of statins.
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