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Pharmacogenomics of...
Pharmacogenomics of GLP-1 receptor agonists : a genome- wide analysis of observational data and large randomised controlled trials
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- Dawed, Adem Y. (author)
- Univ Dundee, Sch Med, Div Populat Hlth & Genom, Dundee, Scotland.;Univ Dundee, Sch Med, Div Populat Hlth & Genom, Dundee DD1 9SY, Scotland.
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- Mari, Andrea (author)
- CNR, Inst Neurosci, Padua, Italy.,Natl Res Council Inst Neurosci, Padua, Italy.
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- Brown, Andrew (author)
- Univ Dundee, Sch Med, Div Populat Hlth & Genom, Dundee, Scotland.
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- McDonald, Timothy J. (author)
- Univ Exeter, Inst Biomed & Clin Sci, Exeter, England.
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- Li, Lin (author)
- BioStat Solut, Frederick, MD USA.
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- Wang, Shuaicheng (author)
- BioStat Solut, Frederick, MD USA.
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- Hong, Mun-Gwan (author)
- Stockholms universitet,KTH,Science for Life Laboratory, SciLifeLab,Proteinvetenskap,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, Stockholm, Sweden.
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- Sharma, Sapna (author)
- Helmholtz Zentrum Muenchen, Inst Epidemiol 2, Res Unit Mol Epidemiol, Neuherberg, Germany.,Helmholtz Zent Muenchen, Inst Epidemiol II, Res Unit Mol Epidemiol, Neuherberg, Germany.
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- Robertson, Neil R. (author)
- Univ Oxford, WellcomeTrust Ctr Human Genet, Oxford, England.,Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
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- Mahajan, Anubha (author)
- Univ Oxford, WellcomeTrust Ctr Human Genet, Oxford, England.,Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
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- Wang, Xuan, 1984- (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi,Science for Life Laboratory, SciLifeLab
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- Walker, Mark (author)
- Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, England.
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- Gough, Stephen (author)
- Novo Nordisk, Global Chief Med Off, Soborg, Denmark.
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- Hart, Leen M. 't (author)
- Leiden Univ, Med Ctr, Dept Cell & Chem Biol, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Biomed Data Sci, Sect Mol Epidemiol, Leiden, Netherlands.;Univ Amsterdam, Med Ctr, Locat VUMC, Amsterdam Publ Hlth Inst,Dept Epidemiol & Data Sci, Amsterdam, Netherlands.
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- Zhou, Kaixin (author)
- Univ Dundee, Sch Med, Div Populat Hlth & Genom, Dundee, Scotland.
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- Forgie, Ian (author)
- Univ Dundee, Sch Med, Div Populat Hlth & Genom, Dundee, Scotland.
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- Ruetten, Hartmut (author)
- TMED, Sanofi Aventis Deutschland Frankfurt, Frankfurt, Germany.
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- Pavo, Imre (author)
- Eli Lilly Res Labs, Indianapolis, IN USA.
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- Bhatnagar, Pallav (author)
- Eli Lilly Res Labs, Indianapolis, IN USA.
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- Jones, Angus G. (author)
- Univ Exeter, Inst Biomed & Clin Sci, Exeter, England.
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- Pearson, Ewan R. (author)
- Univ Dundee, Sch Med, Div Populat Hlth & Genom, Dundee, Scotland.;Univ Dundee, Sch Med, Div Populat Hlth & Genom, Dundee DD1 9SY, Scotland.
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Consortium, D I R E C T (author)
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Univ Dundee, Sch Med, Div Populat Hlth & Genom, Dundee, Scotland;Univ Dundee, Sch Med, Div Populat Hlth & Genom, Dundee DD1 9SY, Scotland. CNR, Inst Neurosci, Padua, Italy. (creator_code:org_t)
- ELSEVIER SCIENCE INC, 2023
- 2023
- English.
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In: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 11:1, s. 33-41
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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Abstract
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- 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 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 & GE;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 & RARR;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 & RARR;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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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- Fredrick
- MD
- USA
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- Stockholm
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Dawed, Adem Y.
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Mari, Andrea
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Brown, Andrew
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McDonald, Timoth ...
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Li, Lin
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Wang, Shuaicheng
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Hong, Mun-Gwan
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Sharma, Sapna
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Robertson, Neil ...
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Mahajan, Anubha
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Wang, Xuan, 1984 ...
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Walker, Mark
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Gough, Stephen
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Hart, Leen M. 't
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Zhou, Kaixin
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Forgie, Ian
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Ruetten, Hartmut
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Pavo, Imre
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Bhatnagar, Palla ...
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Jones, Angus G.
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Pearson, Ewan R.
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Consortium, D I ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
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The Lancet Diabe ...
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Royal Institute of Technology
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Stockholm University
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Uppsala University