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Comprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank.

ABSTRACT: Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.

SUBMITTER: Oliveri A

PROVIDER: S-EPMC10923176 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Comprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank.

Oliveri Antonino A Rebernick Ryan J RJ Kuppa Annapurna A Pant Asmita A Chen Yanhua Y Du Xiaomeng X Cushing Kelly C KC Bell Hannah N HN Raut Chinmay C Prabhu Ponnandy P Chen Vincent L VL Halligan Brian D BD Speliotes Elizabeth K EK

Nature genetics 20240110 2

Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of the ...[more]

PMID: 38200128

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Project description:BackgroundWhile evidence indicates that familial predisposition influences the risk of developing degenerative rotator cuff disease (RCD), knowledge of specific genetic markers is limited. We conducted a genome-wide association study of RCD surgery using the UK Biobank, a prospective cohort of 500,000 people (40 to 69 years of age at enrollment) with genotype data.MethodsCases with surgery for degenerative RCD were identified using linked hospital records. The cases were defined as an International Classification of Diseases, Tenth Revision (ICD-10) code of M75.1 determined by a trauma/orthopaedic specialist and surgery consistent with RCD treatment. Cases were excluded if a diagnosis of traumatic injury had been made during the same hospital visit. For each case, up to 5 controls matched by age, sex, and follow-up time were chosen from the UK Biobank. Analyses were limited to European-ancestry individuals who were not third-degree or closer relations. We used logistic regression to test for genetic association of 674,405 typed and >10 million imputed markers, after adjusting for age, sex, population principal components, and follow-up.ResultsWe identified 2,917 RCD surgery cases and 14,158 matched controls. We observed 1 genome-wide significant signal (p < 5 × 10-8) for a novel locus tagged by rs2237352 in the CREB5 gene on chromosome 7 (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.11 to 1.24). The single-nucleotide polymorphism (SNP) rs2237352 was imputed with a high degree of confidence (info score = 0.9847) and is common, with a minor allele frequency of 47%. After expanding the control sample to include additional unmatched non-cases, rs2237352 and another SNP in the CREB5 gene, rs12700903, were genome-wide significant. We did not detect genome-wide significant signals at loci associated with RCD in previous studies.ConclusionsWe identified a novel association between a variant in the CREB5 gene and RCD surgery. Validation of this finding in studies with imaging data to confirm diagnoses will be an important next step.Clinical relevanceIdentification of genetic RCD susceptibility markers can guide understanding of biological processes in rotator cuff degeneration and help inform disease risk in the clinical setting.Level of evidencePrognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Dataset Information

Comprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank.

Publications

Comprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank.

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