A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance

Background and aims The efficacy of statin therapy is hindered by intolerance to the therapy, leading to discontinuation. Variants in SLCO1B1, which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentrations of the drug and its metabolites. Current pharmacogenetic guidelines require sequencing of the SLCO1B1 gene, which is more expensive and less accessible than genotyping. In this study, we aimed to develop an easy, clinically implementable functional gene risk score (GRS) of common variants in SLCO1B1 to identify patients at risk of statin intolerance. Methods and results A GRS was developed from four common variants in SLCO1B1. In statin users from Tayside, Scotland, UK, those with a high-risk GRS had increased odds across three phenotypes of statin intolerance [general statin intolerance (GSI): ORGSI 2.42; 95% confidence interval (CI): 1.29–4.31, P = 0.003; statin-related myopathy: ORSRM 2.51; 95% CI: 1.28–4.53, P = 0.004; statin-related suspected rhabdomyolysis: ORSRSR 2.85; 95% CI: 1.03–6.65, P = 0.02]. In contrast, using the Val174Ala genotype alone or the recommended OATP1B1 functional phenotypes produced weaker and less reliable results. A meta-analysis with results from adjudicated cases of statin-induced myopathy in the PREDICTION-ADR Consortium confirmed these findings (ORVal174Ala 1.99; 95% CI: 1.01–3.95, P = 0.048; ORGRS 1.76; 95% CI: 1.16–2.69, P = 0.008). For those requiring high-dose statin therapy, the high-risk GRS was more consistently associated with the time to onset of statin intolerance amongst the three phenotypes compared with Val174Ala (GSI: HRVal174Ala 2.49; 95% CI: 1.09–5.68, P = 0.03; HRGRS 2.44; 95% CI: 1.46–4.08, P < 0.001). Finally, sequence kernel association testing confirmed that rare variants in SLCO1B1 are associated with the risk of intolerance (P = 0.02). Conclusion We provide evidence that a GRS based on four common SLCO1B1 variants provides an easily implemented genetic tool that is more reliable than the current recommended practice in estimating the risk and predicting early-onset statin intolerance

The Association of Cardiometabolic, Diet and Lifestyle Parameters With Plasma Glucagon-like Peptide-1: An IMI DIRECT Study

\ua9 The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.Context: The role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes (T2D) and obesity is not fully understood. Objective: We investigate the association of cardiometabolic, diet, and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D. Methods: We analyzed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1 (n = 2127) individuals at risk of diabetes; cohort 2 (n = 789) individuals with new-onset T2D. Results: Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin-resistant phenotype and observe a strong independent relationship with male sex, increased adiposity, and liver fat, particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycemia, higher adiposity, liver fat, male sex, and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit, and vegetables in people with prediabetes, and with a high intake of red meat and alcohol in people with diabetes. Conclusion: These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake, and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D