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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

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...

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Detalles Bibliográficos
Autores principales: Hsu, Lung-An, Teng, Ming-Sheng, Wu, Semon, Chou, Hsin-Hua, Ko, Yu-Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499600/
https://www.ncbi.nlm.nih.gov/pubmed/36142332
http://dx.doi.org/10.3390/ijms231810418
Descripción
Sumario: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.