Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10 ^-8 ), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
Competing Interests: Declaration of interests J.B.M. is an academic associate for Quest Diagnostics Endocrine R&D. M.E.K. is employed by SYNLAB Holding Deutschland GmbH. C.M.L. receives grants from Bayer Ag and Novo Nordisk and her husband works for Vertex. B.Z. is employed at the Swedish Medical Products Agency, SE-751 03 Uppsala, Sweden; the views expressed in this paper are the personal views of the authors and not necessarily the views of the Swedish government agency. B.Z. has not received any funding or benefits from any sponsor for the present work. J.C.F. receives consulting honoraria from Goldfinch Bio and AstraZeneca and speaker honoraria from Novo Nordisk, AstraZeneca, and Merck for research lectures over which he had full control on content. D.A.L. has received support from Medtronics Ltd and Roche Diagnostics for research unrelated to this paper. W.M. reports grants and personal fees from Siemens Diagnostics, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants and personal fees from AstraZeneca, grants and personal fees from Danone Research, grants and personal fees from Sanofi, personal fees from Hoffmann LaRoche, personal fees from MSD, grants and personal fees from Pfizer, personal fees from Synageva, grants and personal fees from BASF, grants from Abbott Diagnostics, and grants and personal fees from Numares, outside the submitted work. W.M. is employed by Synlab Holding Deutschland GmbH. R.W. reports lecture fees from Novo Nordisk and Sanofi and served on an advisory board for Akcea Therapeutics, Daiichi Sankyo, Sanofi, and Novo Nordisk. E.W. is now an employee of AstraZeneca.
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