Suleman Sufyan, Ängquist Lars, Linneberg Allan, Hansen Torben, Grarup Niels
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Biomedicine, Human Genetics, Aarhus University, Aarhus, 8000, Denmark.
Sci Rep. 2025 May 6;15(1):15761. doi: 10.1038/s41598-025-98507-w.
Insulin sensitivity (IS) is a key determinant of metabolic health and may share genetic factors with obesity-related traits. Previous large-scale genetic studies have identified variants associated with IS as well as obesity related traits like body mass index (BMI) and waist-to-hip ratio (WHR). Notably, many of these associations are shared across traits, indicating a potential genetic overlap. However, the genetic intersection between IS and obesity-related traits remains underexplored. To explore this gap, we investigated associations between six IS indices, including fasting and post-glucose load measures, and genetic variants linked to BMI and WHR to determine their influence on IS and related cardiometabolic traits. To achieve this, we calculated six IS indices using fasting and oral glucose tolerance test (OGTT) data from 5,007 non-diabetic individuals, grouping them into fasting, OGTT, and OGTT categories. A total of 678 BMI-associated and 265 WHR-associated genetic variants were analysed using linear regression, adjusting for age and sex, with sex-specific analyses for WHR. Analyses were conducted with and without BMI adjustments and corrected for multiple testing (p). Additionally, we explored the relationship between IS-linked variants and their associations with type 2 diabetes (T2D), coronary artery disease (CAD) and stroke. Among the 678 BMI-associated variants, 100 showed nominal associations (p < 0.05) with at least one IS index; and 20 remained significant after multiple testing correction (p < 0.05) when not adjusting for BMI. After adjusting for BMI, 70 variants retained nominal associations, and six remained significant (p < 0.05). In sex-specific analyses of the 265 WHR-associated variants, 12 variants were associated in females when adjusted for BMI, whereas no significant associations were observed in males. Furthermore, BMI- and WHR-associated variants linked to decreased IS, such as those in FTO and VPS13C loci, were also associated with increased T2D and stroke risk, whereas IS-increasing variants, including those in VPS13C and PPARG, were linked to lower T2D and stroke risk, with some, like THADA, showing opposing effects on CAD. This study offers insights into genetic variants that influence both IS and obesity-related traits, revealing BMI- and WHR-associated variants with both positive and negative effects on IS and their potential impact on cardiometabolic health.
胰岛素敏感性（IS）是代谢健康的关键决定因素，可能与肥胖相关性状共享遗传因素。以往的大规模基因研究已经确定了与IS以及肥胖相关性状（如体重指数（BMI）和腰臀比（WHR））相关的变异。值得注意的是，这些关联中有许多在不同性状之间是共享的，表明存在潜在的遗传重叠。然而，IS与肥胖相关性状之间的基因交集仍未得到充分探索。为了填补这一空白，我们研究了六个IS指标（包括空腹和葡萄糖负荷后测量值）与与BMI和WHR相关的基因变异之间的关联，以确定它们对IS及相关心脏代谢性状的影响。为实现这一目标，我们使用来自5007名非糖尿病个体的空腹和口服葡萄糖耐量试验（OGTT）数据计算了六个IS指标，并将其分为空腹、OGTT和OGTT类别。使用线性回归分析了总共678个与BMI相关和265个与WHR相关的基因变异，对年龄和性别进行了调整，对WHR进行了性别特异性分析。分析在调整和未调整BMI的情况下进行，并对多重检验（p值）进行了校正。此外，我们还探讨了与IS相关的变异及其与2型糖尿病（T2D）、冠状动脉疾病（CAD）和中风的关联。在678个与BMI相关的变异中，100个与至少一个IS指标存在名义关联（p < 0.05）；在未调整BMI时，经过多重检验校正后，20个变异仍然显著（p < 0.05）。调整BMI后，70个变异保留了名义关联，6个仍然显著（p < 0.05）。在对265个与WHR相关的变异进行的性别特异性分析中，调整BMI后，12个变异在女性中存在关联，而在男性中未观察到显著关联。此外，与IS降低相关的BMI和WHR相关变异（如FTO和VPS13C基因座中的变异）也与T2D和中风风险增加相关，而与IS增加相关的变异（包括VPS13C和PPARG中的变异）与较低的T2D和中风风险相关，其中一些变异（如THADA）对CAD有相反的影响。这项研究为影响IS和肥胖相关性状的基因变异提供了见解，揭示了与BMI和WHR相关的变异对IS既有正面影响也有负面影响，以及它们对心脏代谢健康的潜在影响。
