Abstract
Aims/hypothesisAbnormal serum IGF-1 levels are associated with an increased risk of type 2 diabetes and cardiovascular disease. However, the causal role of IGF-1 levels within the normal range in cardiometabolic disease remains unclear. We employed Mendelian randomisation to explore the associations between genetically predicted serum IGF-1 levels and cardiometabolic diseases.MethodsSerum IGF-1 levels were predicted using 416 SNPs associated with IGF-1 levels among 358,072 individuals in UK Biobank. Genetic association estimates for the outcomes were obtained from consortia of type 2 diabetes (74,124 cases, 824,006 controls), coronary artery disease (60,801 cases, 123,504 controls), heart failure (47,309 cases, 930,014 controls), atrial fibrillation (65,446 cases, 522,744 controls), and ischaemic stroke (60,341 cases, 454,450 controls).ResultsGenetic predisposition to elevated serum IGF-1 levels was associated with higher risk of type 2 diabetes and coronary artery disease. The OR (95% CI) per SD increment in IGF-1 level was 1.14 (1.05, 1.24) for type 2 diabetes and 1.09 (1.02, 1.16) for coronary artery disease. The association between IGF-1 and coronary artery disease was attenuated after adjustment for type 2 diabetes (OR 1.06 [95% CI 1.00, 1.13]), suggesting that the association may be partly mediated via type 2 diabetes. There was limited evidence of associations between IGF-1 levels and heart failure, atrial fibrillation and ischaemic stroke.Conclusions/interpretationThis study found evidence that increased IGF-1 levels may be causally associated with higher risk of type 2 diabetes.Graphical abstract
Highlights
IGF-1 is a polypeptide hormone that is structurally similar to proinsulin
Cardiometabolic diseases Genetically predicted IGF-1 levels were positively associated with type 2 diabetes and coronary artery disease in the primary (IVW) analysis (Fig. 1)
The association with type 2 diabetes was confirmed when using data from a smaller dataset from the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium that did not include UK Biobank and in the FinnGen consortium
Summary
IGF-1 is synthesised primarily in the liver upon stimulation by growth hormone and is a key mediator of growth hormone-stimulated growth and other anabolic activities in many cells and tissues [1]. Both pathological excess, as in acromegaly, and deficiency of IGF-1 are associated with glucose intolerance, insulin resistance and increased risk of type 2 diabetes and cardiovascular morbidity and mortality [1, 2]. Because underlying disease may influence IGF-1 levels, and observational studies are vulnerable to confounding, causality cannot be inferred based on available data
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