Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index.

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 further investigate 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 eleven GPR151 putative loss-of-function (plof) variants, three of which are present at homozygosity (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7), with a cumulative allele frequency of 2.2%. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits and find that GPR151 deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to Gpr151+/+ mice, Gpr151-/- animals exhibit no difference in body weight on normal chow and higher body weight on a high-fat diet. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach to treatment of obesity.

Déclaration de conflit d'intérêts

I have read the journal’s policy and the authors of this manuscript have the following competing interests: A.Gurt., J.D., S.C., T.C., S.R., L.L., and D.D. are employees of the Novartis Institutes for BioMedical Research (NIBR). L.V. is currently an employee of Alnylam. D.Sh. is currently an employee of Bristol Myers Squibb. D.Sa. has received funding from Novartis, Regeneron Pharmaceuticals, GSK, Genentech, AstraZeneca, Novo Nordisk, NGM, Eli Lilly and Variant Bio. A.V.K. has served as a scientific advisor to Sanofi, Amgen, Maze Therapeutics, Navitor Pharmaceuticals, Sarepta Therapeutics, Verve Therapeutics, Veritas International, Color Health, Third Rock Ventures, and Columbia University (NIH); received speaking fees from Illumina, MedGenome, Amgen, and NIBR; and received a sponsored research agreement from NIBR.