KLKB1 and CLSTN2 are associated with HDL-mediated cholesterol efflux capacity in a genome-wide association study. (March 2023) - Schachtl-Riess, Johanna F.
Abstract: 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. Graphical abstract: Image 1 Highlights: HDL-C and triglycerides are the main biochemical determinants of cholesterol efflux capacity each explaining >11% of variance. In a GWAS, 2 novel genetic loci ( KLKB1 & CLSTN2 ) and the known APOE/C1 locus are associated with cholesterol efflux capacity. The KLKB1 locus is significant irrespective of adjustment for kidney function, HDL-C, triglycerides and apolipoprotein A-IV. The association with the CLSTN2 locus is suggestive and reaches genome-wide significance with adjustment for triglycerides.