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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH
Diabetologia, Volume 66, No. 7, Year 2023
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Description
Aims/hypothesis: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes. Methods: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals. Results: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAFAfr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10−9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAFAfr=0.0536), was associated with a reduced response to metformin (p=2.4×10−8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA1c of 0.08% and non-carriers had an HbA1c increase of 0.01% after 1 year of treatment (p=3.3×10−3). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6×10−5), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology. Conclusions/interpretation: We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene–drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation. Data availability: The complete summary statistics from this study are available at the Common Metabolic Diseases Knowledge Portal (https://hugeamp.org) and the GWAS Catalog (www.ebi.ac.uk/gwas/ , accession IDs: GCST90269867 to GCST90269899). Graphical Abstract: [Figure not available: see fulltext.] © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Authors & Co-Authors
Huerta-Chagoya, Alicia
United States, Boston
Massachusetts General Hospital
United States, Cambridge
Massachusetts Institute of Technology
Chen, Ji
Unknown Affiliation
Spracklen, Cassandra N.
Unknown Affiliation
Marenne, Gaëlle
Unknown Affiliation
Varshney, Arushi
Unknown Affiliation
Corbin, Laura J.
Unknown Affiliation
Luan, Jian'fan N.An
Unknown Affiliation
Willems, Sara M.
Unknown Affiliation
Wu, Ying
Unknown Affiliation
Zhang, Xiaoshuai
Unknown Affiliation
Horikoshi, Momoko
Unknown Affiliation
Boutin, Thibaud S.
Unknown Affiliation
Mägi, Reedik
Unknown Affiliation
Waage, Johannes
Unknown Affiliation
Li-Gao, Ruifang
Unknown Affiliation
Chan, Kei Hang Katie
Unknown Affiliation
Yao, Jie
Unknown Affiliation
Anasanti, Mila Desi
Unknown Affiliation
Chu, Audrey Y.
Unknown Affiliation
Claringbould, Annique
Unknown Affiliation
Heikkinen, Jani
Unknown Affiliation
Hong, Jaeyoung
Unknown Affiliation
Hottenga, Jouke Jan
Unknown Affiliation
Huo, Shaofeng
Unknown Affiliation
Kaakinen, Marika A.
Unknown Affiliation
Louie, Tin L.
Unknown Affiliation
Mar̈z, Winfried
Unknown Affiliation
Moreno-Macías, Hortensia
Unknown Affiliation
Ndungu, Anne Wanjiru
Unknown Affiliation
Nelson, Sarah C.
Unknown Affiliation
Nolte, Ilja M.
Unknown Affiliation
North, Kari E.
Unknown Affiliation
Raulerson, Chelsea K.
Unknown Affiliation
Ray, Debashree
Unknown Affiliation
Rohde, Rebecca R.
Unknown Affiliation
Rybin, Denis V.
Unknown Affiliation
Schurmann, Claudia
Unknown Affiliation
Sim, Xueling
Unknown Affiliation
Southam, Loz
Unknown Affiliation
Stewart, Isobel D.
Unknown Affiliation
Wang, Carol A.
Unknown Affiliation
Wang, Yujie
Unknown Affiliation
Wu, Peitao
Unknown Affiliation
Zhang, Weihua
Unknown Affiliation
Ahluwalia, Tarunveer Singh
Unknown Affiliation
Appel, Emil Vincent Rosenbaum
Unknown Affiliation
Bielak, Lawrence F.
Unknown Affiliation
Brody, Jennifer A.
Unknown Affiliation
Burtt, Nöel P.
Unknown Affiliation
Cabrera, Claudia P.
Unknown Affiliation
Cade, Brian E.
Unknown Affiliation
Chai, Jinfang
Unknown Affiliation
Chai, Xiaoran
Unknown Affiliation
Chang, Liching
Unknown Affiliation
Chen, Chien Hsiun
Unknown Affiliation
Chen, Brian H.
Unknown Affiliation
Chitrala, Kumaraswamy Naidu
Unknown Affiliation
Chiu, Yen Feng
Unknown Affiliation
de Haan, Hugoline G.
Unknown Affiliation
Delgado, Graciela E.
Unknown Affiliation
Demirkan, Ayşe
Unknown Affiliation
Duan, Qing
Unknown Affiliation
Engmann, Jorgen E.L.
Unknown Affiliation
Fatumo, Segun A.
Unknown Affiliation
Gayán, Javier
Unknown Affiliation
Giulianini, Franco
Unknown Affiliation
Gong, Jung-ho
Unknown Affiliation
Gustafsson, Stefan
Unknown Affiliation
Hai, Yang
Unknown Affiliation
Hartwig, Fernando Pires
Unknown Affiliation
He, Jing
Unknown Affiliation
Heianza, Yoriko
Unknown Affiliation
Huang, Tao
Unknown Affiliation
Jensen, Richard A.
Unknown Affiliation
Kentistou, Katherine A.
Unknown Affiliation
Kleber, Marcus Edi
Unknown Affiliation
Kooner, Ishminder K.
Unknown Affiliation
Lai, Shuiqing
Unknown Affiliation
Lange, Leslie A.
Unknown Affiliation
Langefeld, Carl D.
Unknown Affiliation
Lauzon, Marie
Unknown Affiliation
Li, Man
Unknown Affiliation
Ligthart, Symen
Unknown Affiliation
Loh, Marie Chiew Shia
Unknown Affiliation
Long, Jirong
Unknown Affiliation
Lyssenko, Valeriya
Unknown Affiliation
Mangino, Massimo
Unknown Affiliation
Marzi, Carola S.
Unknown Affiliation
Montasser, May E.
Unknown Affiliation
Nag, Abhishek
Unknown Affiliation
Nakatochi, Masahiro
Unknown Affiliation
Noce, Damia
Unknown Affiliation
Noordam, Raymond
Unknown Affiliation
Pistis, Giorgio
Unknown Affiliation
Preuss, Michael H.
Unknown Affiliation
Raffield, Laura Marie
Unknown Affiliation
Rasmussen-Torvik, Laura J.
Unknown Affiliation
Rich, Stephen S.
Unknown Affiliation
Robertson, Neil R.
Unknown Affiliation
Rueedi, Rico
Unknown Affiliation
Sanna, Serena
Unknown Affiliation
Saxena, Richa
Unknown Affiliation
Schraut, Katharina E.
Unknown Affiliation
Sennblad, Bengt
Unknown Affiliation
Smith, Albert Vernon
Unknown Affiliation
Southam, Lorraine
Unknown Affiliation
Sparsø, Thomas
Unknown Affiliation
Strawbridge, Rona J.
Unknown Affiliation
Takeuchi, Fumihiko
Unknown Affiliation
Trompet, Stella
Unknown Affiliation
van den Akker, Erik Ben
Unknown Affiliation
van der Most, Peter J.
Unknown Affiliation
Verweij, Niek
Unknown Affiliation
Wang, Heming
Unknown Affiliation
Wang, Nan
Unknown Affiliation
Warren, Helen R.
Unknown Affiliation
Wilsgaard, Tom
Unknown Affiliation
Wood, Andrew R.
Unknown Affiliation
Zafarmand, Mohammad Hadi
Unknown Affiliation
Zhao, Jinghua
Unknown Affiliation
Zhao, Wei
Unknown Affiliation
Amin, Najaf A.
Unknown Affiliation
Astrup, Arne Vernon
Unknown Affiliation
Baldassarre, D.
Unknown Affiliation
Beekman, Marian
Unknown Affiliation
Bergman, Richard N.
Unknown Affiliation
Bertoni, Alain G.
Unknown Affiliation
Blüher, Matthias
Unknown Affiliation
Bonnycastle, Lori L.C.
Unknown Affiliation
Bowden, Donald W.
Unknown Affiliation
Campbell, Archie I.
Unknown Affiliation
Campbell, Harry
Unknown Affiliation
Eiríksdóttir, Gudný H.
Unknown Affiliation
Fuchsberger, Christian
Unknown Affiliation
Gao, Yutang
Unknown Affiliation
Gjesing, Anette Prior
Unknown Affiliation
Goel, Anuj
Unknown Affiliation
Han, Sohee
Unknown Affiliation
Hartman, Catharina Annette
Unknown Affiliation
Herder, Christian
Unknown Affiliation
Hicks, Andrew A.
Unknown Affiliation
Ichihara, Sahoko
Unknown Affiliation
Ikram, Mohammad Arfan
Unknown Affiliation
Johnson, William Craig
Unknown Affiliation
Joshi, Peter K.
Unknown Affiliation
Kandeel, Fouad R.
Unknown Affiliation
Khor, Chiea Chuen
Unknown Affiliation
Kiess, Wieland
Unknown Affiliation
Kolcic, Ivana
Unknown Affiliation
Läll, Kristi
Unknown Affiliation
Lawlor, Deborah A.
Unknown Affiliation
Mayol, Nanette L.
Unknown Affiliation
Lemaitre, Rozenn N.
Unknown Affiliation
Lindstr̈om, Jaana
Unknown Affiliation
Lorenzo, Carlos
Unknown Affiliation
Matsuda, Fumihiko
Unknown Affiliation
Mooijaart, Simon P.
Unknown Affiliation
Nabika, Tohru
Unknown Affiliation
Nadkarni, Girish N.
Unknown Affiliation
Nelis, Mari
Unknown Affiliation
Neville, Matt J.
Unknown Affiliation
Norris, Jill M.
Unknown Affiliation
Peters, Annette
Unknown Affiliation
Peyser, Patricia A.
Unknown Affiliation
Polašek, Ozren
Unknown Affiliation
Qi, Qibin
Unknown Affiliation
Reilly, Dermot F.
Unknown Affiliation
Reiner, Alexander Paul
Unknown Affiliation
Rudan, Igor
Unknown Affiliation
Sattar, Naveed
Unknown Affiliation
Stringham, Heather M.
Unknown Affiliation
Taylor, Kent D.
Unknown Affiliation
Teslovich, Tanya M.
Unknown Affiliation
Thuesen, Betina Heinsbæk
Unknown Affiliation
Timmers, Paul R.H.J.
Unknown Affiliation
Tremoli, Elena
Unknown Affiliation
Tsai, Michael Y.
Unknown Affiliation
Uitterlinden, Andre G.
Unknown Affiliation
van Heemst, Diana
Unknown Affiliation
van Hylckama-Vlieg, Astrid
Unknown Affiliation
Wang, Tao
Unknown Affiliation
van Dijk, Ko Willems
Unknown Affiliation
Zemunik, T.
Unknown Affiliation
Adair, Linda S.
Unknown Affiliation
Alarcón-Riquelme, Marta Eugenia
Unknown Affiliation
An, Ping
Unknown Affiliation
Beilin, Lawerence Joseph
Unknown Affiliation
Bisgaard, Hans
Unknown Affiliation
Boehnke, Michael
Unknown Affiliation
Boerwinkle, Eric A.
Unknown Affiliation
Böhm, Bernhard O.
Unknown Affiliation
Bønnelykke, Klaus
Unknown Affiliation
Böttinger, Erwin P.
Unknown Affiliation
Buchanan, Thomas A.
Unknown Affiliation
Canouil, Mickaël
Unknown Affiliation
Caulfield, Mark J.
Unknown Affiliation
Chambers, John Campbell
Unknown Affiliation
Chasman, Daniel I.
Unknown Affiliation
Chen, Yii Der Ida
Unknown Affiliation
Correa, Adolfo
Unknown Affiliation
Cucca, Francesco
Unknown Affiliation
de Silva, Hithanadura Janaka
Unknown Affiliation
Dedoussis, George V.Z.
Unknown Affiliation
Elmstähl, Sölve I.
Unknown Affiliation
Evans, Michele Kim
Unknown Affiliation
Ferrannini, Ele
Unknown Affiliation
Florez, Jose C.
Unknown Affiliation
Franks, Paul W.
Unknown Affiliation
Frayling, Tim M.
Unknown Affiliation
Froguel, Philippe
Unknown Affiliation
Gigante, Bruna
Unknown Affiliation
Goodarzi, Mark O.
Unknown Affiliation
Grallert, Harald
Unknown Affiliation
Grarup, Niels
Unknown Affiliation
Groop, Leif C.
Unknown Affiliation
Guo, Xiuqing
Unknown Affiliation
Hamsten, Anders
Unknown Affiliation
Hansen, Torben
Unknown Affiliation
Hayward, Caroline
Unknown Affiliation
Heckbert, Susan R.
Unknown Affiliation
Horta, Bernardo Lessa
Unknown Affiliation
Jonas, Jost Bruno
Unknown Affiliation
Jukema, Johan Wouter
Unknown Affiliation
Kaleebu, Pontiano P.
Unknown Affiliation
Deloukas, Panos C.
Unknown Affiliation
Kardia, Sharon L.R.
Unknown Affiliation
Kato, Norihiro
Unknown Affiliation
Keinänen-Kiukaanniemi, Sirkka M.
Unknown Affiliation
Kim, Bongjo
Unknown Affiliation
Kivimaki, Mika Shipley
Unknown Affiliation
Koistinen, Heikki A.
Unknown Affiliation
Kooner, Jaspal Singh
Unknown Affiliation
Kor̈ner, Antje
Unknown Affiliation
Kovács, Péter F.
Unknown Affiliation
Kumari, Meena
Unknown Affiliation
Kutalik, Zoltán
Unknown Affiliation
Lakka, Timo Antero
Unknown Affiliation
Launer, Lenore J.
Unknown Affiliation
Leander, Karin
Unknown Affiliation
Lind, Lars L.
Unknown Affiliation
Lindgren, Cecilia M.
Unknown Affiliation
Liu, Simin
Unknown Affiliation
Magnusson, Patrik K.E.
Unknown Affiliation
Mahajan, Anubha
Unknown Affiliation
Mook-Kanamori, Dennis Owen
Unknown Affiliation
Mori, Trevor A.
Unknown Affiliation
Munroe, Patricia B.
Unknown Affiliation
NjØlstad, Inger
Unknown Affiliation
Oldehinkel, Albertine J.(Tineke)
Unknown Affiliation
Ong, Ken K.L.
Unknown Affiliation
Padmanabhan, Sandosh
Unknown Affiliation
Palmer, Colin Neil Alexander
Unknown Affiliation
Pedersen, Oluf Borbye
Unknown Affiliation
Pennell, Craig Edward
Unknown Affiliation
Porteous, David John
Unknown Affiliation
Pramstaller, Peter P.
Unknown Affiliation
Province, Michael A.
Unknown Affiliation
Psaty, Bruce M.
Unknown Affiliation
Qi, Lu
Unknown Affiliation
Rauramaa, Rainer
Unknown Affiliation
Redline, Susan
Unknown Affiliation
Ridker, Paul M.
Unknown Affiliation
Saaristo, Timo E.
Unknown Affiliation
Sandhu, Manjinder Singh
Unknown Affiliation
Saramies, Jouko L.
Unknown Affiliation
Schwarz, Peter Ee H.
Unknown Affiliation
Scott, Laura J.
Unknown Affiliation
Selvin, Elizabeth
Unknown Affiliation
Sever, Peter S.
Unknown Affiliation
Shu, Xiaoou
Unknown Affiliation
Slagboom, Pieternella Eline
Unknown Affiliation
Small, Kerrin S.
Unknown Affiliation
Smith, Blair H.
Unknown Affiliation
Snieder, Harold
Unknown Affiliation
Sofer, Tamar
Unknown Affiliation
Sorensen, Thorkild I.A.
Unknown Affiliation
Stanton, Alice V.
Unknown Affiliation
Steves, Claire J.
Unknown Affiliation
Stumvoll, Michael W.
Unknown Affiliation
Tai, E. Shyong
Unknown Affiliation
Timpson, Nicholas J.
Unknown Affiliation
Tönjes, Anke
Unknown Affiliation
Tuomilehto, Jaakko O.I.
Unknown Affiliation
Uusitupa, Matti
Unknown Affiliation
van der Harst, Pim
Unknown Affiliation
van Duijn, Cornelia M.
Unknown Affiliation
Vitart, Véronique
Unknown Affiliation
Vollenweider, Peter K.
Unknown Affiliation
Wagenknecht, Lynne E.
Unknown Affiliation
Walker, Mark A.
Unknown Affiliation
Wang, Yaxing
Unknown Affiliation
Wareham, Nicholas J.
Unknown Affiliation
Watanabe, Richard M.
Unknown Affiliation
Watkins, Hugh C.
Unknown Affiliation
Wickramasinghe, Ananda Rajitha
Unknown Affiliation
Willemsen, Gonneke A.H.M.
Unknown Affiliation
Wilson, James F.
Unknown Affiliation
Wong, Tienyin
Unknown Affiliation
Wu, Jeryuarn
Unknown Affiliation
Xiang, Anny Hui
Unknown Affiliation
Yanek, Lisa R.
Unknown Affiliation
Yengo, Loic
Unknown Affiliation
Zeggini, Eleftheria
Unknown Affiliation
Zheng, Wei
Unknown Affiliation
Zonderman, Alan B.
Unknown Affiliation
Rotter, Jerome I.
Unknown Affiliation
Gloyn, Anna L.
Unknown Affiliation
McCarthy, Mark I.
Unknown Affiliation
Dupuis, Josée
Unknown Affiliation
Meigs, James B.
Unknown Affiliation
Scott, Robert A.
Unknown Affiliation
Prokopenko, Inga
Unknown Affiliation
Leong, Aaron
United States, Boston
Massachusetts General Hospital
United States, Cambridge
Massachusetts Institute of Technology
United States, Boston
Harvard Medical School
Liu, Chingti
Unknown Affiliation
Mohlke, Karen
Unknown Affiliation
Langenberg, Claudia C.
Unknown Affiliation
Wheeler, Eleanor
Unknown Affiliation
Morris, Andrew Paul
Unknown Affiliation
Champagne, Catherine M.
Unknown Affiliation
Greenway, Frank Lyons
Unknown Affiliation
Polonsky, Kenneth S.
Unknown Affiliation
Goldberg, Ronald B.
Unknown Affiliation
Flórez, Hermes Jose
Unknown Affiliation
Haffner, Steven M.
Unknown Affiliation
Dabelea, Dana M.
Unknown Affiliation
Anderson, Denise R.
Unknown Affiliation
Boxer, Rebecca S.
Unknown Affiliation
Jortberg, Bonnie T.
Unknown Affiliation
Horton, Edward S.
Unknown Affiliation
Kahn, Steven E.
Unknown Affiliation
Fujimoto, Wilfred Y.
Unknown Affiliation
Applegate, William B.
Unknown Affiliation
Nyenwe, Ebenezer A.
Unknown Affiliation
Metzger, Boyd E.
Unknown Affiliation
Wallia, Amisha
Unknown Affiliation
Fitzgibbon, Marian L.
Unknown Affiliation
Stevens, Christine R.
Unknown Affiliation
Araneta, Maria Rosario G.
Unknown Affiliation
Edelman, Steven V.
Unknown Affiliation
Polonsky, William H.
Unknown Affiliation
Allison, David B.
Unknown Affiliation
Marrero, David G.
Unknown Affiliation
Ratner, Robert E.
Unknown Affiliation
Aroda, Vanita R.
Unknown Affiliation
Uwaifo, Gabriel Ikponmosa
Unknown Affiliation
Waters, Debra Lynn
Unknown Affiliation
White, Neil H.
Unknown Affiliation
Brown, Angela L.
Unknown Affiliation
Golden, Sherita Hill
Unknown Affiliation
Brancati, Frederick L.
Unknown Affiliation
Charleston, Jeanne B.
Unknown Affiliation
Kalyani, Rita Rastogi
Unknown Affiliation
Mathioudakis, Nestoras Nicolas
Unknown Affiliation
Wing, Rena R.
Unknown Affiliation
Culyba, Rebecca J.
Unknown Affiliation
Knowler, William C.
Unknown Affiliation
Shah, Vallabh O.
Unknown Affiliation
Bennett, Peter H.
Unknown Affiliation
Curtis, Jeffrey L.
Unknown Affiliation
Jablonski, Kathleen A.
Unknown Affiliation
Christophi, Costas A.
Unknown Affiliation
Hoffman, Heather J.
Unknown Affiliation
Jones, Steven J.M.
Unknown Affiliation
Pan, Qing
Unknown Affiliation
Kriska, Andrea P.
Unknown Affiliation
Marcovina, Santica Marija
Unknown Affiliation
Albers, John J.
Unknown Affiliation
Lee, Christine G.
Unknown Affiliation
Gregg, Edward W.
Unknown Affiliation
Zhang, Ping
Unknown Affiliation
Budoff, Matthew J.
Unknown Affiliation
Schwartz, Ann V.
Unknown Affiliation
Rautaharju, Pentti M.
Unknown Affiliation
Prineas, Ronald J.
Unknown Affiliation
Soliman, Elsayed Z.
Unknown Affiliation
Li, Yabing
Unknown Affiliation
Mills, Margaret G.
Unknown Affiliation
Statistics
Authors: 377
Affiliations: 3
Identifiers
Doi:
10.1007/s00125-023-05922-7
ISSN:
0012186X
Research Areas
Genetics And Genomics
Health System And Policy
Noncommunicable Diseases