Introduction & Objective: Insulin Resistance (IR) is heritable and predisposes to cardiometabolic disease, but few causes are known due to limited samples with direct measures of IR.

Methods: To increase power to identify IR-associated loci we carried out a genome wide association study (GWAS) of an indirect marker of IR, the triglyceride to high-density lipoprotein cholesterol ratio (TG:HDL-C) adjusted for BMI (TG:HDL-C adj BMI) in UK Biobank (N=401,090). We used a mixed linear model controlling for age, sex and principal components in SAIGE. Genome wide significant SNPs with effects (FDR < 0.05) on MAGIC Consortium fasting insulin, HOMA-IR and insulin sensitivity were deemed ‘high-confidence IR-associated’ loci (HCIRL). HCIRL tissue, pathway, and gene enrichment analyses were done using DEPICT. A HCIRC polygenic risk score (PRS) was tested for association with ICD-defined Phecodes from the Michigan Genetics Initiative (N=51,527) and results were Bonferroni-adjusted for multiple comparison. PheWAS/FUMA analysis of HCIRL across cardiometabolic traits with hierarchical clustering identified disease subtypes and their biology.

Results: 343 independent SNPs were genome-wide significantly associated with TG:HDL-C adj BMI (p<5e-08); 119 were HCIRL. HCIRL associated genes exhibited enrichment in adipose tissue and adipocytes (all p<3.79e-06) and metabolic syndrome (MetS) affected systems. A HCIRL PRS showed association with MetS-related phenotypes including hyperglyceridemia, hyperlipidemia, hypertension, T2D, coronary atherosclerosis, chronic liver disease and cirrhosis (all padj<5.29e-03). We identify 5 subtypes, highlighting familial hyperlipidemia type 4 and PI3KAKT signaling genes.

Conclusion: HCIRL identify new loci, genes, pathways and disease subtypes. This increases our understanding of the disease and opens up new avenues for identifying and treating subtypes and their complications.

Disclosure

A. Oliveri: None. R. Rebernick: None. E.K. Speliotes: Other Relationship; University of Michigan.

Funding

National Institutes of Health (R01DK106621, R01DK107904, R01DK128871, R01DK131787), The University of Michigan Department of Internal Medicine, MBIOFar

© 2024 by the American Diabetes Association
2024
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