Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index
Year: 2021
Type: preprint
Study design: Observational Study
Abstract: Novel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we follow up on GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify 3 GPR151 putative loss-of-function (plof) variants (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7) with a cumulative allele frequency of 2.2% and present at homozygosity. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits. GPR151 deficiency in complete human knockouts is not associated with a clinically significant difference in BMI. Moreover, loss of GPR151 confers a nominally significant increase in risk of T2D (odds ratio = 1.2, p value = 0.03). Relative to wild-type mice, Gpr151 -/- animals exhibit no difference in body weight on normal chow, and higher body weight on a high-fat diet, consistent with the findings in humans. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach for obesity.
Source: medRxiv
Authors: Allan Gurtan, John Dominy, Shareef Khalid, Linh Vong, Shari Caplan, Treeve Currie, Sean Richards, Lindsey Lamarche, Daniel Denning, Diana Shpektor, Anastasia Gurinovich, Asif Rasheed, Shahid Hameed, Subhan Saeed, Imran Saleem, Anjum Jalal, Shahid Abbas, Raffat Sultana, Syed Zahed Rasheed, Fazal-ur-Rehman Memon, Nabi Shah, Mohammad Ishaq, Amit Khera, John Danesh, Sekar Kathiresan, Philippe Frossard, Danish Saleheen
Institutions: Columbia University Irving Medical Center, Center for Non-Communicable Diseases, Tufts Medical Center, Punjab Institute of Cardiology, Karachi Institute of Heart Diseases, COMSATS University Islamabad, Massachusetts General Hospital, University of Cambridge, Wellcome Sanger Institute, Health Data Research UK
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Large-scale integrative genomic studies of high-dimensional traits in cardiovascular diseases (renewal), The BHF Chair of Epidemiology and Medicine, Comprehensive biomarker study to capitalize on existing GWAS in 10K South Asians, Markers of the metabolic syndrome linking type 2 diabetes and MI in South Asia
OpenAlex ID: W3208201436