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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.

ABSTRACT: Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

SUBMITTER: Scott RA

PROVIDER: S-EPMC5219001 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.

Scott Robert A RA Freitag Daniel F DF Li Li L Chu Audrey Y AY Surendran Praveen P Young Robin R Grarup Niels N Stancáková Alena A Chen Yuning Y Varga Tibor V TV Yaghootkar Hanieh H Luan Jian'an J Zhao Jing Hua JH Willems Sara M SM Wessel Jennifer J Wang Shuai S Maruthur Nisa N Michailidou Kyriaki K Pirie Ailith A van der Lee Sven J SJ Gillson Christopher C Al Olama Ali Amin AA Amouyel Philippe P Arriola Larraitz L Arveiler Dominique D Aviles-Olmos Iciar I Balkau Beverley B Barricarte Aurelio A Barroso Inês I Garcia Sara Benlloch SB Bis Joshua C JC Blankenberg Stefan S Boehnke Michael M Boeing Heiner H Boerwinkle Eric E Borecki Ingrid B IB Bork-Jensen Jette J Bowden Sarah S Caldas Carlos C Caslake Muriel M Cupples L Adrienne LA Cruchaga Carlos C Czajkowski Jacek J den Hoed Marcel M Dunn Janet A JA Earl Helena M HM Ehret Georg B GB Ferrannini Ele E Ferrieres Jean J Foltynie Thomas T Ford Ian I Forouhi Nita G NG Gianfagna Francesco F Gonzalez Carlos C Grioni Sara S Hiller Louise L Jansson Jan-Håkan JH Jørgensen Marit E ME Jukema J Wouter JW Kaaks Rudolf R Kee Frank F Kerrison Nicola D ND Key Timothy J TJ Kontto Jukka J Kote-Jarai Zsofia Z Kraja Aldi T AT Kuulasmaa Kari K Kuusisto Johanna J Linneberg Allan A Liu Chunyu C Marenne Gaëlle G Mohlke Karen L KL Morris Andrew P AP Muir Kenneth K Müller-Nurasyid Martina M Munroe Patricia B PB Navarro Carmen C Nielsen Sune F SF Nilsson Peter M PM Nordestgaard Børge G BG Packard Chris J CJ Palli Domenico D Panico Salvatore S Peloso Gina M GM Perola Markus M Peters Annette A Poole Christopher J CJ Quirós J Ramón JR Rolandsson Olov O Sacerdote Carlotta C Salomaa Veikko V Sánchez María-José MJ Sattar Naveed N Sharp Stephen J SJ Sims Rebecca R Slimani Nadia N Smith Jennifer A JA Thompson Deborah J DJ Trompet Stella S Tumino Rosario R van der A Daphne L DL van der Schouw Yvonne T YT Virtamo Jarmo J Walker Mark M Walter Klaudia K Abraham Jean E JE Amundadottir Laufey T LT Aponte Jennifer L JL Butterworth Adam S AS Dupuis Josée J Easton Douglas F DF Eeles Rosalind A RA Erdmann Jeanette J Franks Paul W PW Frayling Timothy M TM Hansen Torben T Howson Joanna M M JM Jørgensen Torben T Kooner Jaspal J Laakso Markku M Langenberg Claudia C McCarthy Mark I MI Pankow James S JS Pedersen Oluf O Riboli Elio E Rotter Jerome I JI Saleheen Danish D Samani Nilesh J NJ Schunkert Heribert H Vollenweider Peter P O'Rahilly Stephen S Deloukas Panos P Danesh John J Goodarzi Mark O MO Kathiresan Sekar S Meigs James B JB Ehm Margaret G MG Wareham Nicholas J NJ Waterworth Dawn M DM

Science translational medicine 20160601 341

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and f ...[more]

PMID: 27252175

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Project description:Abstract BACKGROUND: Glucagon-like peptide-1 (GLP-1) functions to increase insulin production in a glucose-dependent manner. Endogenous GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase 4 (DPP4), and GLP-1 receptor agonists and DPP4 inhibitors (DPP4Is) are now used in the treatment of diabetes. The GLP-1 receptor (GLP-1R) is a G-protein coupled receptor that is expressed widely, encoded for by GLP1R. The GLP1R variant rs6923761 (Gly168Ser) has been associated with increased weight loss in response to GLP-1 agonist therapy in some studies. This study tested the hypothesis that this variant would be associated with responsiveness to endogenous GLP-1 during DPP4I therapy. METHODS: Forty-seven subjects with hypertension and type 2 diabetes mellitus were assigned to one-week crossover therapy with placebo and the DPP4I sitagliptin (100 mg/d), and underwent a mixed meal study. Subjects were excluded for type 1 diabetes, poorly controlled diabetes with Hgb A1c ≥8.7%, use of an anti-diabetic medication other than metformin for last 12 months, or presence of secondary hypertension. RESULTS: Post-prandial GLP-1 levels were increased during sitagliptin (AUC 11413, 95% CI [7113, 15712]) as compared with placebo treatment (AUC 5101, 95% CI [2254, 7949], p<0.05), and did not significantly differ by genotype. Peak post-prandial glucose was significantly higher in placebo as compared with sitagliptin treatment (146.6 +/- 35.8 mg/dL versus 133.0 +/- 26.5 mg/dL, respectively; t=90 minutes, p<0.01). Subjects with one or two copies of the wild-type allele (Gly/Gly or Gly/Ser) had increased post-prandial glucose excursion as compared with Ser/Ser subjects, in both the placebo and sitagliptin treatments (plasma glucose at 90 minutes: placebo Gly/- 150.1 +/- 38.0 mg/dL vs Ser/Ser 132.6 +/- 13.7 mg/dL, p<0.05; sitagliptin Gly/- 135.8 +/- 27.3 mg/dL vs Ser/Ser 117.4 +/- 14.7 mg/dL, p<0.05). Post-prandial insulin levels were not different in the placebo versus sitagliptin treatments (AUC 13264, 95% CI [9296,17232] vs 11996, 95% CI [8278, 15714], respectively), but there was a genotype by drug treatment interaction (p<0.05) such that Ser/Ser subjects had higher post-prandial insulin in the placebo treatment as compared with other genotypes. This difference was eliminated with sitagliptin therapy. CONCLUSIONS: Homozygosity for the Ser variant of GLP1R is associated with decreased glucose after a mixed meal without altering the effect of sitagliptin on post prandial GLP-1 concentrations. Further studies are needed to assess whether this variant confers increased sensitivity at the GLP-1R and whether it affects the long-term response to DPP4I.

Project description:Adiponectin is the most abundant peptide secreted by adipocytes, being a key component in the interrelationship between adiposity, insulin resistance and inflammation. Central obesity accompanied by insulin resistance is a key factor in the development of metabolic syndrome (MS) and future macrovascular complications. Moreover, the remarkable correlation between coronary artery disease (CAD) and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes mellitus (T2DM) may share a common biological background. We summarize here the current knowledge about the influence of adiponectin on insulin sensitivity and endothelial function, discussing its forthcoming prospects and potential role as a therapeutic target for MS, T2DM, and cardiovascular disease. Adiponectin is present in the circulation as a dimer, trimer or protein complex of high molecular weight hexamers, >400 kDa. AdipoR1 and AdipoR2 are its major receptors in vivo mediating the metabolic actions. Adiponectin stimulates phosphorylation and AMP (adenosin mono phosphate) kinase activation, exerting direct effects on vascular endothelium, diminishing the inflammatory response to mechanical injury and enhancing endothelium protection in cases of apolipoprotein E deficiency. Hypoadiponectinemia is consistently associated with obesity, MS, atherosclerosis, CAD, T2DM. Lifestyle correction helps to favorably modify plasma adiponectin levels. Low adiponectinemia in obese patients is raised via continued weight loss programs in both diabetic and nondiabetic individuals and is also accompanied by reductions in pro-inflammatory factors. Diet modifications, like intake of fish, omega-3 supplementation, adherence to a Mediterranean dietary pattern and coffee consumption also increase adiponectin levels. Antidiabetic and cardiovascular pharmacological agents, like glitazones, glimepiride, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are also able to improve adiponectin concentration. Fibric acid derivatives, like bezafibrate and fenofibrate, have been reported to enhance adiponectin levels as well. T-cadherin, a membrane-associated adiponectin-binding protein lacking intracellular domain seems to be a main mediator of the antiatherogenic adiponectin actions. The finding of novel pharmacologic agents proficient to improve adiponectin plasma levels should be target of exhaustive research. Interesting future approaches could be the development of adiponectin-targeted drugs chemically designed to induce the activaton of its receptors and/or postreceptor signaling pathways, or the development of specific adiponectin agonists.

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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.

Publications

A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.

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