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Novel association between CDKAL1 and cholesterol efflux capacity: Replication after GWAS-based discovery

  • Author Footnotes
    1 These authors contributed equally to this work.
    Eun Jeong Cheon
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Do Hyeon Cha
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Yonsei University College of Medicine, Seoul, South Korea
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  • Sung Kweon Cho
    Affiliations
    Department of Clinical Research Design & Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
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  • Hye-Min Noh
    Affiliations
    Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea
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  • Sungha Park
    Affiliations
    Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea

    Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
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  • Seok-Min Kang
    Affiliations
    Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea

    Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
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  • Heon Yung Gee
    Correspondence
    Corresponding author. Department of Pharmacology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-752, South Korea.
    Affiliations
    Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, South Korea
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  • Sang-Hak Lee
    Correspondence
    Corresponding author. Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-752, South Korea.
    Affiliations
    Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea

    Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
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  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • We identified and replicated genetic variants associated with cholesterol efflux capacity (CEC).
      • One variant was located near LOC541471 on 2q13, and four were in CDKAL1 on 6p22.3
      • The association between any CDKAL1 variant and CEC was significant after adjustment.

      Abstract

      Background and aims

      Although the importance of the functional properties of high-density lipoprotein (HDL) has been increasingly emphasized, studies on the genetic factors associated with HDL function are highly limited. The aim of this study was to identify genetic variants associated with an individual's cholesterol efflux capacity (CEC) using a genome-wide association study approach.

      Methods

      This study included a discovery group of 607 subjects with coronary artery disease and an independent replication group of 158 subjects. CEC was assessed using a radioisotope and ApoB-depleted serum. Genome-wide associations between the adjusted CEC and genotyped and imputed variants were examined with linear regression, assuming an additive genetic model. Finally, adjustments were made for confounding parameters to assess the independence of associations and to determine R2 of overall model on CEC.

      Results

      In the discovery group, 631 variants showed significant association with CEC, and five of them were found to correlate with CEC in the replication group. One of them was located near LOC541471 in 2q13, whereas the other four (rs117835232, rs117252933, rs118064592, and rs150434350) were located in CDKAL1 in 6p22.3. The association between the presence of any CDKAL1 variant and CEC was significant after adjustment for clinical and laboratory variables. High-density lipoprotein-cholesterol levels also showed a very significant association with CEC. Body mass index, current alcohol use, triglycerides levels, low-density lipoprotein-cholesterol levels and statin use showed borderline associations with CEC.

      Conclusions

      We identified and replicated genetic variants associated with CEC using a genome-wide association study-based approach. CDKAL1 variants showed correlations with CEC independent of HDL-cholesterol levels and other clinical characteristics.

      Keywords

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