UC San Diego

Insulin resistance is implicated in multiple prevalent metabolic disorders, such as type 2 diabetes, cardiovascular disease, and fatty liver disease. While genome-wide association studies (GWAS) have been employed to identify genes associated with insulin resistance, the difficulty in measuring insulin resistance has led to limited sample sizes and reduced statistical power in previous GWAS studies. Conducting an expansive GWAS with a large sample size is essential to identify novel insulin resistance genes. The triglyceride to high-density lipoprotein ratio (TG/HDL) demonstrates a high correlation with insulin resistance phenotypes and is available in large cohorts, making it a potential surrogate marker for insulin resistance. Performing a GWAS of TG/HDL on 382,129 individuals in the UK Biobank, we identified 251 genomic risk loci, among which 62 displayed heightened significance compared to individual markers (TG or HDL), suggesting them as potential insulin resistance loci. We developed a systematic approach for the comprehensive analysis of these loci, prioritizing those that remain undiscovered and exhibit differential associations across different sexes. Through this analysis, we highlighted TNFAIP8, a gene involved in the regulation of apoptosis and immune responses, as a novel sex-dimorphic factor influencing insulin resistance. Our findings contribute to the genetic understanding of insulin resistance and identify potential sex-specific genes as therapeutic targets.