Background In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1... Show moreBackground In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods In this genome-wide analysis we included adults (aged >= 18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G -> A (Gly168Ser) in the GLP1R (0.08% [95% CI 0.04-0.12] or 0.9 mmol/mol lower reduction in HbA1c per serine, p=6.0 x 10(-5)) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6.7 x 10(-8)), largely driven by rs140226575G -> A (Thr370Met; 0.25% [SE 0.06] or 2.7 mmol/mol [SE 0.7] greater HbA1c reduction per methionine, p=5.2 x 10(-6)). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6-11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. Show less
Purpose: Parallel RF transmission (PTx) is one of the key technologies enabling high quality imaging at ultra-high fields (>= 7T). Compliance with regulatory limits on the local specific... Show morePurpose: Parallel RF transmission (PTx) is one of the key technologies enabling high quality imaging at ultra-high fields (>= 7T). Compliance with regulatory limits on the local specific absorption rate (SAR) typically involves over-conservative safety margins to account for intersubject variability, which negatively affect the utilization of ultra-high field MR. In this work, we present a method to generate a subject-specific body model from a single T1-weighted dataset for personalized local SAR prediction in PTx neuroimaging at 7T. Methods: Multi-contrast data were acquired at 7T (N = 10) to establish ground truth segmentations in eight tissue types. A 2.5D convolutional neural network was trained using the T1-weighted data as input in a leave-one-out cross-validation study. The segmentation accuracy was evaluated through local SAR simulations in a quadrature birdcage as well as a PTx coil model. Results: The network-generated segmentations reached Dice coefficients of 86.7% +/- 6.7% (mean +/- SD) and showed to successfully address the severe intensity bias and contrast variations typical to 7T. Errors in peak local SAR obtained were below 3.0% in the quadrature birdcage. Results obtained in the PTx configuration indicated that a safety margin of 6.3% ensures conservative local SAR estimates in 95% of the random RF shims, compared to an average overestimation of 34% in the generic "one-size-fits-all" approach. Conclusion: A subject-specific body model can be automatically generated from a single T1-weighted dataset by means of deep learning, providing the necessary inputs for accurate and personalized local SAR predictions in PTx neuroimaging at 7T. Show less
