KLKB1 and CLSTN2 are associated with HDL-mediated cholesterol efflux capacity in a genome-wide association study

Background and aims: HDL-mediated cholesterol efflux capacity (CEC) may protect from cardiovascular disease. Thus, we aimed to identify its genetic and non-genetic determinants.

Methods: We measured CEC to 2% apolipoprotein B-depleted serum using BODIPY-cholesterol and cAMP-stimulated J774A.1 macrophages using serum samples from 4,981 participants in the German Chronic Kidney Disease (GCKD) study. Variance of CEC explained by clinical and biochemical parameters in a multivariable linear regression model was calculated by proportional marginal variance decomposition. A genome-wide association study with 7,746,917 variants was performed based on an additive genetic model. The main model was adjusted for age, sex and principal components 1-10. Further models were selected for sensitivity analysis and to reduce residual variance by known CEC pathways.

Results: Variables that explained 1% and more of the variance of CEC were concentrations of triglycerides (12.9%), HDL-cholesterol (11.8%), LDL-cholesterol (3.0%), apolipoprotein A-IV (2.8%), PCSK9 (1.0%), and eGFR (1.0%). The KLKB1 (chr4) and APOE/C1 (chr19) loci were genome-wide significantly (p < 5x10^-8) associated with CEC in our main model (p = 8.8x10^-10 and p = 3.3x10^-10, respectively). KLKB1 remained significantly associated after additional adjustment for either kidney parameters, HDL-cholesterol, triglycerides or apolipoprotein A-IV concentrations, while the APOE/C1 locus was not significantly associated anymore after adjustment for triglycerides. Adjustment for triglycerides also revealed an association with the CLSTN2 locus (chr3; p = 6.0x10^-9).

Conclusions: We identified HDL-cholesterol and triglycerides as the main determinants of CEC. Furthermore, we newly found a significant association of CEC with the KLKB1 and the CLSTN2 locus and confirmed the association with the APOE/C1 locus, likely mediated by triglycerides.