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

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

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Atherosclerosis. - 368 (2023) , 1-11, ISSN: 1879-1484

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2023
• Urheber: Schachtl-Riess, Johanna F. ; Schönherr, Sebastian ; Lamina, Claudia ; Forer, Lukas ; Coassin, Stefan ; Streiter, Gertraud ; Kheirkhah, Azin ; Li, Yong ; Meiselbach, Heike ; Di Maio, Silvia ; Eckardt, Kai-Uwe ; Köttgen, Anna ; Kronenberg, Florian ; Walz, Gerd ; Schultheiß, Ulla Teresa ; Kotsis, Fruzsina ; Meder, Simone ; Mitsch, Erna ; Reinhard, Ursula ; GCKD Investigators, [Study group]

Weitere Informationen

• DOI: 10.1016/j.atherosclerosis.2023.01.022
• URN: urn:nbn:de:bsz:25-freidok-2342263
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 14.08.2025, 10:52 MESZ