ArticleInternational journal of epidemiology2022
Clustered Mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus.
Article in International journal of epidemiology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 15 citations in OpenAlex.
- Associations between Sugar-Sweetened Beverage Intake and Metabolic Syndrome among Postmenopausal Black Women with Obesity and a Family History of Breast Cancer.Cancer research communications · 2026Article
- Likely causal effects of insulin resistance and IGF-1 bioaction on childhood and adult adiposity: a Mendelian randomization study.International journal of obesity (2005) · 2024Article
- Genetic Evidence for Distinct Biological Mechanisms That Link Adiposity to Type 2 Diabetes: Toward Precision Medicine.Diabetes · 2024Article
- Mammographic density mediates the protective effect of early-life body size on breast cancer risk.Nature communications · 2024Article
- Mendelian randomization analysis demonstrates the causal effects of IGF family members in diabetes.Frontiers in medicine · 2024Article
- The mediating role of mammographic density in the protective effect of early-life adiposity on breast cancer risk: a multivariable Mendelian randomization study.medRxiv : the preprint server for health sciences · 2023Article
- Investigating sex-specific associations of lipid traits with type 2 diabetes, glycemic traits and sex hormones using Mendelian randomization.Cardiovascular diabetology · 2023Article
- Metabolic diseases and healthy aging: identifying environmental and behavioral risk factors and promoting public health.Frontiers in public health · 2023Review
- Obesity, Fat Distribution and Risk of Cancer in Women and Men: A Mendelian Randomisation Study.Nutrients · 2022Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundThere is inconsistent evidence for the causal role of serum insulin-like growth factor-1 (IGF-1) concentration in the pathogenesis of human age-related diseases such as type 2 diabetes (T2D). Here, we investigated the association between IGF-1 and T2D using (clustered) Mendelian randomization (MR) analyses in the UK Biobank.
methodsWe conducted Cox proportional hazard analyses in 451 232 European-ancestry individuals of the UK Biobank (55.3% women, mean age at recruitment 56.6 years), among which 13 247 individuals developed type 2 diabetes during up to 12 years of follow-up. In addition, we conducted two-sample MR analyses based on independent single nucleotide polymorphisms (SNPs) associated with IGF-1. Given the heterogeneity between the MR effect estimates of individual instruments (P-value for Q statistic = 4.03e-145), we also conducted clustered MR analyses. Biological pathway analyses of the identified clusters were performed by over-representation analyses.
resultsIn the Cox proportional hazard models, with IGF-1 concentrations stratified in quintiles, we observed that participants in the lowest quintile had the highest relative risk of type 2 diabetes [hazard ratio (HR): 1.31; 95% CI: 1.23-1.39). In contrast, in the two-sample MR analyses, higher genetically influenced IGF-1 was associated with a higher risk of type 2 diabetes. Based on the heterogeneous distribution of MR effect estimates of individual instruments, six clusters of genetically determined IGF-1 associated either with a lower or a higher risk of type 2 diabetes were identified. The main clusters in which a higher IGF-1 was associated with a lower risk of type 2 diabetes consisted of instruments mapping to genes in the growth hormone signalling pathway, whereas the main clusters in which a higher IGF-1 was associated with a higher risk of type 2 diabetes consisted of instruments mapping to genes in pathways related to amino acid metabolism and genomic integrity.
conclusionsThe IGF-1-associated SNPs used as genetic instruments in MR analyses showed a heterogeneous distribution of MR effect estimates on the risk of type 2 diabetes. This was likely explained by differences in the underlying molecular pathways that increase IGF-1 concentration and differentially mediate the effects of IGF-1 on type 2 diabetes.
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