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<p>Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype (‘mvIR’), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (<i>AKT1</i>, <i>ERBB3</i>, <i>FCGR1A</i>, <i>FGFR1</i>, <i>LPL</i>, <i>NR1H3</i>) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity.</p>

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Multivariate genome-wide analyses of insulin resistance unravel novel loci and therapeutic targets for cardiometabolic health

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月17日

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  • Chaojie Ye,
  • Chun Dou,
  • Dong Liu,
  • Lijie Kong,
  • Mingling Chen,
  • Min Xu,
  • Yu Xu,
  • Mian Li,
  • Zhiyun Zhao,
  • Jie Zheng,
  • Jieli Lu,
  • Yuhong Chen,
  • Guang Ning,
  • Weiqing Wang,
  • Yufang Bi,
  • Tiange Wang

摘要

Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype (‘mvIR’), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (AKT1, ERBB3, FCGR1A, FGFR1, LPL, NR1H3) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity.