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

TitleA genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsScott RA, Freitag DF, Li L, et al.
Secondary AuthorsWaterworth DM
Corporate AuthorsCVD50 consortium, GERAD_EC Consortium, Neurology Working Group of the Cohorts for Heart, Aging Research in Genomic Epidemiology(CHARGE), Alzheimer’s Disease Genetics Consortium, Pancreatic Cancer Cohort Consortium, European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease(EPIC-CVD), EPIC-InterAct, CHARGE Consortium, CHD Exome+ Consortium, CARDIOGRAM Exome Consortium
JournalSci Transl Med
Volume8
Issue341
Pagination341ra76
Date Published2016 06 01
ISSN1946-6242
KeywordsAlleles, Coronary Disease, Diabetes Mellitus, Type 2, Dipeptidyl Peptidase 4, Genotype, Glucagon-Like Peptide-1 Receptor, Humans, Obesity, Receptor, Cannabinoid, CB2, Receptor, Serotonin, 5-HT2C, Receptors, Somatostatin, Sodium-Glucose Transporter 1
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.

DOI10.1126/scitranslmed.aad3744
Alternate JournalSci Transl Med
PubMed ID27252175
PubMed Central IDPMC5219001
Grant ListG0800270 / MRC_ / Medical Research Council / United Kingdom
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
MR/L501517/1 / MRC_ / Medical Research Council / United Kingdom
R01 AG033193 / AG / NIA NIH HHS / United States
MR/L023784/1 / MRC_ / Medical Research Council / United Kingdom
K24 DK080140 / DK / NIDDK NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
MR/M008975/1 / MRC_ / Medical Research Council / United Kingdom
R01 DK093757 / DK / NIDDK NIH HHS / United States
R01 DK078616 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
MR/K013041/1 / MRC_ / Medical Research Council / United Kingdom
UL1 RR025005 / RR / NCRR NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
G0902227 / MRC_ / Medical Research Council / United Kingdom
UL1 TR001108 / TR / NCATS NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
9675 / CRUK_ / Cancer Research UK / United Kingdom
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01RC37004 / RC / CCR NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
MR/L010305/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL087641 / HL / NHLBI NIH HHS / United States
N01 CN045165 / CN / NCI NIH HHS / United States
MR/L023784/2 / MRC_ / Medical Research Council / United Kingdom