Random glucose GWAS in 493,036 individuals provides insights into diabetes pathophysiology, complications and treatment stratification

Abstract

Homeostatic control of blood glucose requires different physiological responses in the fasting and post-prandial states. We reasoned that glucose measurements under non-standardised conditions (random glucose, RG) may capture diverse glucoregulatory processes more effectively than previous genome-wide association studies (GWAS) of fasting glycaemia or after standardised glucose loads. Through GWAS meta-analysis of RG in 493,036 individuals without diabetes of diverse ethnicities we identified 128 associated loci represented by 162 distinct signals, including 14 with sex-dimorphic effects, 9 discovered through trans-ethnic analysis, and 70 novel signals for glycaemic traits. Novel RG loci were particularly enriched in expression in the ileum and colon, indicating a prominent role for the gastrointestinal tract in the control of blood glucose. Functional studies and molecular dynamics simulations of coding variants of GLP1R, a well-established type 2 diabetes treatment target, provided a genetic framework for optimal selection of GLP-1R agonist therapy. We also provided new evidence from Mendelian randomisation that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Thus, our approach based on RG GWAS provided wide-ranging insights into the biology of glucose regulation, diabetes complications and the potential for treatment stratification.

Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

“…10 It is interesting that a study found that the Gly168Ser variant does not alter the function of GLP1R. 18 However, previous reports in transfected Chinese hamster cell lines show that association of the 168Ser variant with reduced cell surface expression of the GLP1R and reduced intracellular calcium mobilisation following GLP1 stimulation. 19 The worse response seen with the Gly168Ser variant could also be due to reduced gene expression of GLP1R in the pancreas.…”

Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes

“…Notably, relative GLP-1 resistance and impairment of the gut-brain GLP-1 axis has been described in preclinical studies. 14 Clinically, genetic variation in the GLP1R has been associated with changes in receptor signaling and glycemia 27 and differential responses to GLP-1RA in some human studies. 28,29 Variables such as local tissue expression of the GLP-1R, interindividual differences in GLP-1 receptor binding, receptor structure, or downstream signaling activity are difficult to measure in the context of large clinical trials.…”

Bifidobacterium Is Enriched in Gut Microbiome of Kashmiri Women with Polycystic Ovary Syndrome

“…However, as for Collinsella , we see a shared genetic link with genus in larger population based studies; in our recent report on genetics of random glucose in humans, we suggest that ABO/FUT2 genetic locus potentially orchestrates the correlation between Collinsella and the host glucose level [ 73 ]. Another piece of supporting evidence from a shared genetic background concerns family Peptococcaceae; rs7574352 associated with the family Peptococcaceae [ 39 ] is located in the intergenic region in the proximity (220kb apart) of IRF1 , which is involved in insulin resistance and susceptibility to T2DM, also suggested as a risk loci for PCOS [ 74 , 75 ].…”