Cross-sectional association between blood cholesterol and calcium levels in genetically diverse strains of mice

Genetically diverse outbred mice allow for the study of genetic variation in the context of high dietary and environmental control. Using a machine learning approach, we investigated clinical and morphometric factors that associate with serum cholesterol levels in 840 genetically unique Diversity Outbred mice of both sexes (n = 417 male and 423 female), and on both a control chow (% kcals in diet: protein 22%, carbohydrate 62%, fat 16%, no cholesterol) and high fat high sucrose (% kcals in diet: protein 15%, carbohydrate 41%, fat 45%, 0.05% cholesterol). We find expected elevations of cholesterol in male mice, as well as in mice with elevated serum triglycerides and/or fed a high fat high sucrose diet. The third strongest predictor was serum calcium which correlated with serum cholesterol across both diets and sexes (r = 0.39-0.48) in both Diversity Outbred (P = 3.0 x 10-43) and BXD (P = 0.005) mice. This is in-line with several human cohort studies which show associations between calcium and cholesterol, and calcium as an independent predictor of cardiovascular events. We used a machine learning approach using data from genetically diverse mice to identify predictors of serum cholesterol in mice. We reproduced well-established associations between diet and triglycerides on cholesterol levels, but identified a new diet-independent connection between serum calcium and cholesterol in Diversity Outbred mice.image