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Exploring the genetic intersection between obesity-associated genetic variants and insulin sensitivity indices
Sufyan Suleman1,2, Lars Ängquist1, Allan Linneberg3,4
1Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Scientific Reports
|May 6, 2025
Summary
This study reveals genetic variants influencing insulin sensitivity (IS) and obesity traits like BMI and WHR. Some variants impact IS and cardiometabolic disease risk, highlighting a shared genetic basis.
Area of Science:
- Genetics
- Metabolic Health
- Obesity Research
Background:
- Insulin sensitivity (IS) is crucial for metabolic health and shares genetic factors with obesity traits.
- Previous studies identified genetic variants for IS, body mass index (BMI), and waist-to-hip ratio (WHR), suggesting overlap.
- The genetic intersection between IS and obesity traits remains underexplored.
Purpose of the Study:
- To investigate the genetic associations between IS indices and variants linked to BMI and WHR.
- To determine the influence of these variants on IS and related cardiometabolic traits.
- To explore the relationship between IS-linked variants and risks for type 2 diabetes (T2D), coronary artery disease (CAD), and stroke.
Main Methods:
- Calculated six IS indices from fasting and oral glucose tolerance test (OGTT) data in 5,007 non-diabetic individuals.
- Analyzed 678 BMI-associated and 265 WHR-associated genetic variants using linear regression, adjusting for age and sex.
- Conducted sex-specific analyses for WHR and explored associations with T2D, CAD, and stroke.
Main Results:
- Among 678 BMI variants, 20 remained significant (p<0.05) for IS after multiple testing correction without BMI adjustment.
- After BMI adjustment, six BMI variants remained significant for IS.
- In females, 12 WHR variants showed significant associations with IS after BMI adjustment; none were significant in males.
- Variants linked to decreased IS (e.g., FTO, VPS13C) associated with increased T2D/stroke risk; IS-increasing variants (e.g., VPS13C, PPARG) linked to lower T2D/stroke risk.
Conclusions:
- Identified specific genetic variants influencing both insulin sensitivity and obesity-related traits.
- Revealed variants with both positive and negative effects on IS, impacting cardiometabolic health.
- Demonstrated a genetic link between obesity traits, insulin sensitivity, and risks for major cardiometabolic diseases.
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