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
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Anmerkungen
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Atherosclerosis. - 368 (2023) , 1-11, ISSN: 1879-1484
- Ereignis
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Veröffentlichung
- (wo)
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Freiburg
- (wer)
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Universität
- (wann)
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2023
- Urheber
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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]
- DOI
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10.1016/j.atherosclerosis.2023.01.022
- URN
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urn:nbn:de:bsz:25-freidok-2342263
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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25.03.2025, 13:46 MEZ
Datenpartner
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Beteiligte
- 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]
- Universität
Entstanden
- 2023