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Common and Rare PCSK9 Variants Associated with Low-Density Lipoprotein Cholesterol Levels and the Risk of Diabetes Mellitus: A Mendelian Randomization Study.
Hsu, Lung-An; Teng, Ming-Sheng; Wu, Semon; Chou, Hsin-Hua; Ko, Yu-Lin.
Afiliação
  • Hsu LA; The First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 33305, Taiwan.
  • Teng MS; Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan.
  • Wu S; Department of Life Science, Chinese Culture University, Taipei City 11114, Taiwan.
  • Chou HH; Cardiovascular Center, Division of Cardiology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan.
  • Ko YL; School of Medicine, Tzu Chi University, Hualien City 97004, Taiwan.
Int J Mol Sci ; 23(18)2022 Sep 08.
Article em En | MEDLINE | ID: mdl-36142332
PCSK9 is a candidate locus for low-density lipoprotein cholesterol (LDL-C) levels. The cause-effect relationship between LDL-C levels and diabetes mellitus (DM) has been suggested to be mechanism-specific. To identify the role of PCSK9 and genome-wide association study (GWAS)-significant variants in LDL-C levels and the risk of DM by using Mendelian randomization (MR) analysis, a total of 75,441 Taiwan Biobank (TWB) participants was enrolled for a GWAS to determine common and rare PCSK9 variants and their associations with LDL-C levels. MR studies were also conducted to determine the association of PCSK9 variants and LDL-C GWAS-associated variants with DM. A regional plot association study with conditional analysis of the PCSK9 locus revealed that PCSK9 rs10788994, rs557211, rs565436, and rs505151 exhibited genome-wide significant associations with serum LDL-C levels. Imputation data revealed that three rare nonsynonymous mutations-namely, rs151193009, rs768846693, and rs757143429-exhibited genome-wide significant association with LDL-C levels. A stepwise regression analysis indicated that seven variants exhibited independent associations with LDL-C levels. On the basis of two-stage least squares regression (2SLS), MR analyses conducted using weighted genetic risk scores (WGRSs) of seven PCSK9 variants or WGRSs of 41 LDL-C GWAS-significant variants revealed significant association with prevalent DM (p = 0.0098 and 5.02 × 10-7, respectively), which became nonsignificant after adjustment for LDL-C levels. A sensitivity analysis indicated no violation of the exclusion restriction assumption regarding the influence of LDL-C-level-determining genotypes on the risk of DM. Common and rare PCSK9 variants are independently associated with LDL-C levels in the Taiwanese population. The results of MR analyses executed using genetic instruments based on WGRSs derived from PCSK9 variants or LDL-C GWAS-associated variants demonstrate an inverse association between LDL-C levels and DM.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diabetes Mellitus / Pró-Proteína Convertase 9 / LDL-Colesterol Tipo de estudo: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Int J Mol Sci Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diabetes Mellitus / Pró-Proteína Convertase 9 / LDL-Colesterol Tipo de estudo: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Int J Mol Sci Ano de publicação: 2022 Tipo de documento: Article