Pleiotropic Effects of Common and Rare <i>GCKR</i> Exonic Mutations on Cardiometabolic Traits
Background: The common non-synonymous mutation of the glucokinase regulator (<i>GCKR</i>) gene, namely rs1260326, is widely reported to have pleiotropic effects on cardio-metabolic traits and hematological parameters. Objective: This study aimed to identify whether other <i>GCKR<...
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MDPI AG
2022-03-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/13/3/491 |
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| author | Kuan-Hung Yeh Lung-An Hsu Ming-Sheng Teng Semon Wu Hsin-Hua Chou Yu-Lin Ko |
| author_facet | Kuan-Hung Yeh Lung-An Hsu Ming-Sheng Teng Semon Wu Hsin-Hua Chou Yu-Lin Ko |
| author_sort | Kuan-Hung Yeh |
| collection | DOAJ |
| description | Background: The common non-synonymous mutation of the glucokinase regulator (<i>GCKR</i>) gene, namely rs1260326, is widely reported to have pleiotropic effects on cardio-metabolic traits and hematological parameters. Objective: This study aimed to identify whether other <i>GCKR</i> variants may have pleiotropic effects independent of the rs1260326 genotypes. Methods: In total, 81,097 Taiwan Biobank participants were enrolled for the regional plot association studies and candidate variant analysis of the region around the <i>GCKR</i> gene. Results: The initial candidate variant approach showed the significant association of the rs1260326 genotypes with multiple phenotypes. Regional plot association analysis of the <i>GCKR</i> gene region further revealed genome-wide significant associations between <i>GCKR</i> variants and serum total and low-density lipoprotein cholesterol; triglyceride, uric acid, creatinine, aspartate aminotransferase, γ-Glutamyl transferase, albumin, and fasting plasma glucose levels; estimated glomerular filtration rate; leukocyte and platelet counts; microalbuminuria, and metabolic syndrome, with rs1260326 being the most common lead polymorphism. Serial conditional analysis identified genome-wide significant associations of two low-frequency exonic mutations, rs143881585 and rs8179206, with high serum triglyceride and albumin levels. In five rare <i>GCKR</i> exonic non-synonymous or nonsense mutations available for analysis, <i>GCKR</i> rs146175795 showed an independent association with serum triglyceride and albumin levels and rs150673460 showed an independent association with serum triglyceride levels. Weighted genetic risk scores from the combination of <i>GCKR</i> rs143881585 and rs146175795 revealed a significant association with metabolic syndrome. Conclusion: In addition to the rs1260326 variant, low-frequency and rare <i>GCKR</i> exonic mutations exhibit pleiotropic effects on serum triglyceride and albumin levels and the risk of metabolic syndrome. These results provide evidence that both common and rare <i>GCKR</i> variants may play a critical role in predicting the risk of cardiometabolic disorders. |
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| id | doaj.art-58413682ef704a35997661251b494b70 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T19:48:15Z |
| publishDate | 2022-03-01 |
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| spelling | doaj.art-58413682ef704a35997661251b494b702023-11-24T01:19:03ZengMDPI AGGenes2073-44252022-03-0113349110.3390/genes13030491Pleiotropic Effects of Common and Rare <i>GCKR</i> Exonic Mutations on Cardiometabolic TraitsKuan-Hung Yeh0Lung-An Hsu1Ming-Sheng Teng2Semon Wu3Hsin-Hua Chou4Yu-Lin Ko5Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, TaiwanThe First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 33305, TaiwanDepartment of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, TaiwanDepartment of Life Science, Chinese Culture University, Taipei 11114, TaiwanCardiovascular Center and Division of Cardiology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, TaiwanCardiovascular Center and Division of Cardiology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, TaiwanBackground: The common non-synonymous mutation of the glucokinase regulator (<i>GCKR</i>) gene, namely rs1260326, is widely reported to have pleiotropic effects on cardio-metabolic traits and hematological parameters. Objective: This study aimed to identify whether other <i>GCKR</i> variants may have pleiotropic effects independent of the rs1260326 genotypes. Methods: In total, 81,097 Taiwan Biobank participants were enrolled for the regional plot association studies and candidate variant analysis of the region around the <i>GCKR</i> gene. Results: The initial candidate variant approach showed the significant association of the rs1260326 genotypes with multiple phenotypes. Regional plot association analysis of the <i>GCKR</i> gene region further revealed genome-wide significant associations between <i>GCKR</i> variants and serum total and low-density lipoprotein cholesterol; triglyceride, uric acid, creatinine, aspartate aminotransferase, γ-Glutamyl transferase, albumin, and fasting plasma glucose levels; estimated glomerular filtration rate; leukocyte and platelet counts; microalbuminuria, and metabolic syndrome, with rs1260326 being the most common lead polymorphism. Serial conditional analysis identified genome-wide significant associations of two low-frequency exonic mutations, rs143881585 and rs8179206, with high serum triglyceride and albumin levels. In five rare <i>GCKR</i> exonic non-synonymous or nonsense mutations available for analysis, <i>GCKR</i> rs146175795 showed an independent association with serum triglyceride and albumin levels and rs150673460 showed an independent association with serum triglyceride levels. Weighted genetic risk scores from the combination of <i>GCKR</i> rs143881585 and rs146175795 revealed a significant association with metabolic syndrome. Conclusion: In addition to the rs1260326 variant, low-frequency and rare <i>GCKR</i> exonic mutations exhibit pleiotropic effects on serum triglyceride and albumin levels and the risk of metabolic syndrome. These results provide evidence that both common and rare <i>GCKR</i> variants may play a critical role in predicting the risk of cardiometabolic disorders.https://www.mdpi.com/2073-4425/13/3/491<i>GCKR</i> geneexonic mutationpleiotropic effectserum triglyceride levelserum albumin level |
| spellingShingle | Kuan-Hung Yeh Lung-An Hsu Ming-Sheng Teng Semon Wu Hsin-Hua Chou Yu-Lin Ko Pleiotropic Effects of Common and Rare <i>GCKR</i> Exonic Mutations on Cardiometabolic Traits Genes <i>GCKR</i> gene exonic mutation pleiotropic effect serum triglyceride level serum albumin level |
| title | Pleiotropic Effects of Common and Rare <i>GCKR</i> Exonic Mutations on Cardiometabolic Traits |
| title_full | Pleiotropic Effects of Common and Rare <i>GCKR</i> Exonic Mutations on Cardiometabolic Traits |
| title_fullStr | Pleiotropic Effects of Common and Rare <i>GCKR</i> Exonic Mutations on Cardiometabolic Traits |
| title_full_unstemmed | Pleiotropic Effects of Common and Rare <i>GCKR</i> Exonic Mutations on Cardiometabolic Traits |
| title_short | Pleiotropic Effects of Common and Rare <i>GCKR</i> Exonic Mutations on Cardiometabolic Traits |
| title_sort | pleiotropic effects of common and rare i gckr i exonic mutations on cardiometabolic traits |
| topic | <i>GCKR</i> gene exonic mutation pleiotropic effect serum triglyceride level serum albumin level |
| url | https://www.mdpi.com/2073-4425/13/3/491 |
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