Genetics of fasting indices of glucose homeostasis using GWIS unravels tight relationships with inflammatory markers

Abstract Purpose Homeostasis Model Assessment of β-cell function and Insulin Resistance (HOMA-B/-IR) indices are informative about the pathophysiological processes underlying type 2 diabetes (T2D). Data on both fasting glucose and insulin levels are required to calculate HOMA-B/-IR, leading to underpowered Genome-Wide Association studies (GWAS) of these traits. Methods We overcame such power loss issues by implementing Genome-Wide Inferred Statistics (GWIS) approach and subsequent dense genome-wide imputation of HOMA-B/-IR summary statistics with SS-imp to 1000 Genomes project variant density, reaching an analytical sample size of 75,240 European individuals without diabetes. We dissected mechanistic heterogeneity of glycaemic trait/T2D loci effects on HOMA-B/-IR and their relationships with 36 inflammatory and cardiometabolic phenotypes. Results We identified one/three novel HOMA-B ( FOXA2 )/HOMA-IR ( LYPLAL1, PER4, PPP1R3B ) loci. We detected novel strong genetic correlations between HOMA-IR/-B and Plasminogen Activator Inhibitor 1 (PAI-1, r g =0.92/0.78, P=2.13×10 -4 /2.54×10 -3 ). HOMA-IR/-B were also correlated with C-Reactive Protein ( r g =0.33/0.28, P=4.67×10 -3 /3.65×10 -3 ). HOMA-IR was additionally correlated with T2D ( r g =0.56, P=2.31×10 -9 ), glycated haemoglobin ( r g =0.28, P=0.024) and adiponectin ( r g =-0.30, P=0.012). Conclusion Using innovative GWIS approach for composite phenotypes we report novel evidence for genetic relationships between fasting indices of insulin resistance/beta-cell function and inflammatory markers, providing further support for the role of inflammation in T2D pathogenesis.