| 11. |
- Yuan, Shuai, et al.
(författare)
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Genetically predicted sex hormone levels and health outcomes : phenome-wide Mendelian randomization investigation.
- 2022
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 51:6, s. 1931-1942
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sex hormone-binding globulin (SHBG), testosterone and oestradiol have been associated with many diseases in observational studies; however, the causality of associations remains unestablished.METHODS: A phenome-wide Mendelian randomization (MR) association study was performed to explore disease outcomes associated with genetically proxied circulating SHBG, testosterone and oestradiol levels by using updated genetic instruments in 339 197 unrelated White British individuals (54% female) in the UK Biobank. Two-sample MR analyses with data from large genetic studies were conducted to replicate identified associations in phenome-wide MR analyses. Multivariable MR analyses were performed to investigate mediation effects of hormone-related biomarkers in observed associations with diseases.RESULTS: Phenome-wide MR analyses examined associations of genetically predicted SHBG, testosterone and oestradiol levels with 1211 disease outcomes, and identified 28 and 13 distinct phenotypes associated with genetically predicted SHBG and testosterone, respectively; 22 out of 28 associations for SHBG and 10 out of 13 associations for testosterone were replicated in two-sample MR analyses. Higher genetically predicted SHBG levels were associated with a reduced risk of hypertension, type 2 diabetes, diabetic complications, coronary atherosclerotic outcomes, gout and benign and malignant neoplasm of uterus, but an increased risk of varicose veins and fracture (mainly in females). Higher genetically predicted testosterone levels were associated with a lower risk of type 2 diabetes, coronary atherosclerotic outcomes, gout and coeliac disease mainly in males, but an increased risk of cholelithiasis in females.CONCLUSIONS: These findings suggest that sex hormones may causally affect risk of several health outcomes.
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| 12. |
- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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| 13. |
- Schmidt, Amand F., et al.
(författare)
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PCSK9 genetic variants and risk of type 2 diabetes : a mendelian randomisation study
- 2017
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Ingår i: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:2, s. 97-105
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Tidskriftsartikel (refereegranskat)abstract
- Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA 1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0.09 mmol/L, 95% CI 0.02 to 0.15), bodyweight (1.03 kg, 0.24 to 1.82), waist-to-hip ratio (0.006, 0.003 to 0.010), and an odds ratio for type diabetes of 1.29 (1.11 to 1.50). Based on the collected data, we did not identify associations with HbA 1c (0.03%, -0.01 to 0.08), fasting insulin (0.00%, -0.06 to 0.07), and BMI (0.11 kg/m(2), -0.09 to 0.30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefi ts of PCSK9 inhibitor treatment, as was previously done for statins.
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