Low "quotient" Lp(a) Concentration Mediates Autoimmune Activation and Independently Predicts Cardiometabolic Risk

Objective: We determined whether U-shaped relationships exist between serum lipoprotein[Lp](a) and cardiometabolic risk. Methods: In population-based nondiabetic and diabetic middle-aged adults (n=1428 and 241, respectively) who had been genotyped for the LPA rs10455872 A>G polymorphism, we adjusted the Lp(a) concentration for the effects of genotype and other covariates. Via sex-specific equations we estimated expected Lp(a) concentration in each participant, and the quotient between observed to expected Lp(a) values was determined. Lp(a) and Lp(a) quotient tertiles served to identify non-linear associations with outcomes. Results: Incident 81 cases of diabetes and 128 of coronary heart disease (CHD) developed at 5.1 years' follow-up. Lp(a) concentration was linearly associated with the LPA genotype, gender, total cholesterol, (inversely) fasting insulin, which together with age formed the variables to derive the equations. In logistic regression for incident diabetes, the low Lp(a) quotient tertile was a predictor (RR 1.95 [95%CI 1.10; 3.47]) alike the low Lp(a) tertile, additively to major confounders. Cox regression models comprising sex, age, LPA genotype, smoking status, systolic pressure and serum HDL-cholesterol disclosed that, compared with the mid-tertile, both low (HR 1.77) and high Lp(a) quotient tertiles significantly predicted incident CHD, especially in women. Conclusion: Elevated cardiometabolic risk is conferred by apparently reduced circulating Lp(a) assays supporting the notion that low serum Lp(a), mediating autoimmune activation, is a major determinant of cardiometabolic risk.