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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 associati...

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Main Authors: Broadaway, K. Alaine (Author) , Yin, Xianyong (Author) , Williamson, Alice (Author) , Parsons, Victoria A. (Author) , Wilson, Emma P. (Author) , Moxley, Anne H. (Author) , Vadlamudi, Swarooparani (Author) , Varshney, Arushi (Author) , Jackson, Anne U. (Author) , Ahuja, Vasudha (Author) , Bornstein, Stefan R. (Author) , Corbin, Laura J. (Author) , Delgado Gonzales de Kleber, Graciela (Author) , Dwivedi, Om P. (Author) , Fernandes Silva, Lilian (Author) , Frayling, Timothy M. (Author) , Grallert, Harald (Author) , Gustafsson, Stefan (Author) , Hakaste, Liisa (Author) , Hammar, Ulf (Author) , Herder, Christian (Author) , Herrmann, Sandra (Author) , Højlund, Kurt (Author) , Hughes, David A. (Author) , Kleber, Marcus E. (Author) , Lindgren, Cecilia M. (Author) , Liu, Ching-Ti (Author) , Luan, Jian’an (Author) , Malmberg, Anni (Author) , Moissl-Blanke, Angela P. (Author) , Morris, Andrew P. (Author) , Perakakis, Nikolaos (Author) , Peters, Annette (Author) , Petrie, John R. (Author) , Roden, Michael (Author) , Schwarz, Peter E. H. (Author) , Sharma, Sapna (Author) , Silveira, Angela (Author) , Strawbridge, Rona J. (Author) , Tuomi, Tiinamaija (Author) , Wood, Andrew R. (Author) , Wu, Peitao (Author) , Zethelius, Björn (Author) , Baldassarre, Damiano (Author) , Eriksson, Johan G. (Author) , Fall, Tove (Author) , Florez, Jose C. (Author) , Fritsche, Andreas (Author) , Gigante, Bruna (Author) , Hamsten, Anders (Author) , Kajantie, Eero (Author) , Laakso, Markku (Author) , Lahti, Jari (Author) , Lawlor, Deborah A. (Author) , Lind, Lars (Author) , März, Winfried (Author) , Meigs, James B. (Author) , Sundström, Johan (Author) , Timpson, Nicholas J. (Author) , Wagner, Róbert (Author) , Walker, Mark (Author) , Wareham, Nicholas J. (Author) , Watkins, Hugh (Author) , Barroso, Inês (Author) , O’Rahilly, Stephen (Author) , Grarup, Niels (Author) , Parker, Stephen CJ. (Author) , Boehnke, Michael (Author) , Langenberg, Claudia (Author) , Wheeler, Eleanor (Author) , Mohlke, Karen L. (Author)
Format: Article (Journal)
Language:English
Published: 2 February 2023
In: The American journal of human genetics
Year: 2023, Volume: 110, Issue: 2, Pages: 284-299
ISSN:1537-6605
DOI:10.1016/j.ajhg.2023.01.002
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ajhg.2023.01.002
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0002929723000022
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Author Notes:K. Alaine Broadaway, Xianyong Yin, Alice Williamson, Victoria A. Parsons, Emma P. Wilson, Anne H. Moxley, Swarooparani Vadlamudi, Arushi Varshney, Anne U. Jackson, Vasudha Ahuja, Stefan R. Bornstein, Laura J. Corbin, Graciela E. Delgado, Om P. Dwivedi, Lilian Fernandes Silva, Timothy M. Frayling, Harald Grallert, Stefan Gustafsson, Liisa Hakaste, Ulf Hammar, Christian Herder, Sandra Herrmann, Kurt Højlund, David A. Hughes, Marcus E. Kleber, Cecilia M. Lindgren, Ching-Ti Liu, Jian’an Luan, Anni Malmberg, Angela P. Moissl, Andrew P. Morris, Nikolaos Perakakis, Annette Peters, John R. Petrie, Michael Roden, Peter E. H. Schwarz, Sapna Sharma, Angela Silveira, Rona J. Strawbridge, Tiinamaija Tuomi, Andrew R. Wood, Peitao Wu, Björn Zethelius, Damiano Baldassarre, Johan G. Eriksson, Tove Fall, Jose C. Florez, Andreas Fritsche, Bruna Gigante, Anders Hamsten, Eero Kajantie, Markku Laakso, Jari Lahti, Deborah A. Lawlor, Lars Lind, Winfried März, James B. Meigs, Johan Sundström, Nicholas J. Timpson, Robert Wagner, Mark Walker, Nicholas J. Wareham, Hugh Watkins, Inês Barroso, Stephen O’Rahilly, Niels Grarup, Stephen CJ. Parker, Michael Boehnke, Claudia Langenberg, Eleanor Wheeler, Karen L. Mohlke
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Summary: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.
Item Description:Online verfügbar: 23. Januar 2023, Artikelversion: 2. Februar 2023
Gesehen am 12.09.2024
Physical Description:Online Resource
ISSN:1537-6605
DOI:10.1016/j.ajhg.2023.01.002

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