Presenter of 1 Presentation
GENOME-WIDE ASSOCIATION STUDY ON HDL-MEDIATED CHOLESTEROL EFFLUX CAPACITY
Abstract
Background and Aims
HDL-mediated cholesterol efflux capacity (CEC) measures the ability of HDL particles to induce efflux of cholesterol from macrophages. This functionality of HDL particles may protect from atherosclerosis. Indeed, several studies have shown an inverse association of CEC with prevalent and incident cardiovascular disease. However, to test for causality we need to know more about the genetic architecture of CEC.
Methods
We measured CEC in the German Chronic Kidney Disease (GCKD) study (n=5,171) using J774A.1 macrophages. Cells were labelled with BODIPY-cholesterol, stimulated with cAMP and efflux was performed for four hours to 2% apolipoprotein B-depleted serum. Multivariable regression analysis was performed to determine variables independently associated with CEC. Genome-wide association analysis (GWAS) was performed using REGENIE with the nf-gwas Nextflow pipeline (https://github.com/genepi/nf-gwas).
Results
HDL-cholesterol and triglyceride concentrations were the most important variables associated with CEC, explaining 11.8% and 12.9% of the variance in CEC values, respectively. In our main GWAS model adjusted for age, sex and principal components 1-10, the KLKB1 locus (chromosome 4) and APOE/C1 locus (chromosome 19) were significantly associated with CEC (p=8.8x10-10 and p=3.3x10-10, respectively). The association of the KLKB1 locus was independent of estimated glomerular filtration rate, albuminuria, HDL-cholesterol and triglycerides while the association with the APOE/C1 locus was mediated by triglycerides. Additional adjustment for triglycerides also revealed the CLSTN2 locus (chromosome 3) that was borderline significant in our main model (p=2.0x10-7).
Conclusions
We confirmed the previously reported association of the APOE/C1 locus and report two novel loci (KLKB1 and CLSTN2) that are associated with CEC.