Differential Genetic Architecture of Insulin Resistance (HOMA-IR) Based on Obesity Status: Evidence from a Large-Scale GWAS of Koreans
Insulin resistance (IR) is a key mechanism underlying type 2 diabetes mellitus and is closely associated with obesity. Although numerous genome-wide association studies (GWASs) have identified variants that influence IR-related traits, it remains unclear whether the genetic architecture of IR differ...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
|
| Series: | Current Issues in Molecular Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1467-3045/47/6/461 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Insulin resistance (IR) is a key mechanism underlying type 2 diabetes mellitus and is closely associated with obesity. Although numerous genome-wide association studies (GWASs) have identified variants that influence IR-related traits, it remains unclear whether the genetic architecture of IR differs according to obesity status. We conducted a stratified GWAS of the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in 8906 Korean individuals from the Korean Genome and Epidemiology Study. Participants were categorized into a normal-weight group (Body Mass Index (BMI) ≤ 23 kg/m<sup>2</sup>) and an overweight or obese group (BMI > 23 kg/m<sup>2</sup>), and the GWAS was performed separately within each group. No significant genome-wide variants were identified in the normal-weight group; however, seven loci showed suggestive associations. In contrast, in the overweight and obese group, two loci, rs662799 in Apolipoprotein A5 (<i>APOA5</i>) and rs671 in Aldehyde Dehydrogenase 2 (<i>ALDH2</i>), showed genome-wide significance, with seven loci showing suggestive associations. The risk allele of rs662799 was associated with increased HOMA-IR values, with a stronger effect observed in the overweight and obese group. This finding aligns with the known role of <i>APOA5</i> in triglyceride metabolism, suggesting that a higher BMI may exacerbate its effect on IR. These results highlight obesity-specific genetic susceptibility to IR and the need to consider obesity status in genetic studies of metabolic traits. |
|---|---|
| ISSN: | 1467-3037 1467-3045 |