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Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH

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Abstract

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).

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Abbreviations

AOC:

Area over the curve

DPP:

Diabetes Prevention Program

EAF:

Effect allele frequency

gePS:

Global extended polygenic score

GLP-1:

Glucagon-like peptide 1

GWAS:

Genome-wide association study

LD:

Linkage disequilibrium

MAF:

Minor allele frequency

PC:

Principal component

PP:

Posterior probability

pPS:

Process-specific polygenic score

SUGAR-MGH:

Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans

V1:

Visit 1

V2:

Visit 2

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Author information

Author notes

  1. Josephine H. Li, Laura N. Brenner and Varinderpal Kaur contributed equally to this work.

Authors and Affiliations

  1. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Josephine H. Li, Laura N. Brenner, Varinderpal Kaur, Katherine Figueroa, Philip Schroeder, Alicia Huerta-Chagoya, Miriam S. Udler, Aaron Leong, Josep M. Mercader & Jose C. Florez

  2. Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA

    Josephine H. Li, Varinderpal Kaur, Philip Schroeder, Alicia Huerta-Chagoya, Miriam S. Udler, Aaron Leong, Josep M. Mercader & Jose C. Florez

  3. Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Josephine H. Li, Laura N. Brenner, Varinderpal Kaur, Katherine Figueroa, Philip Schroeder, Alicia Huerta-Chagoya, Miriam S. Udler, Aaron Leong, Josep M. Mercader & Jose C. Florez

  4. Harvard Medical School, Boston, MA, USA

    Josephine H. Li, Laura N. Brenner, Miriam S. Udler, Aaron Leong, Josep M. Mercader & Jose C. Florez

  5. Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA

    Laura N. Brenner

  6. Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA

    Aaron Leong

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  • , Hans Bisgaard
  • , Corri Black
  • , Michael Boehnke
  • , Eric Boerwinkle
  • , Bernhard O. Böhm
  • , Klaus Bønnelykke
  • , D.I. Boomsma
  • , Erwin P. Bottinger
  • , Thomas A. Buchanan
  • , Mickaël Canouil
  • , Mark J. Caulfield
  • , John C. Chambers
  • , Daniel I. Chasman
  • , Yii-Der Ida Chen
  • , Ching-Yu Cheng
  • , Francis S. Collins
  • , Adolfo Correa
  • , Francesco Cucca
  • , H. Janaka de Silva
  • , George Dedoussis
  • , Sölve Elmståhl
  • , Michele K. Evans
  • , Ele Ferrannini
  • , Luigi Ferrucci
  • , Jose C. Florez
  • , Paul W. Franks
  • , Timothy M. Frayling
  • , Philippe Froguel
  • , Bruna Gigante
  • , Mark O. Goodarzi
  • , Penny Gordon-Larsen
  • , Harald Grallert
  • , Niels Grarup
  • , Sameline Grimsgaard
  • , Leif Groop
  • , Vilmundur Gudnason
  • , Xiuqing Guo
  • , Anders Hamsten
  • , Torben Hansen
  • , Caroline Hayward
  • , Susan R. Heckbert
  • , Bernardo L Horta
  • , Wei Huang
  • , Erik Ingelsson
  • , Pankow S. James
  • , Marjo-Ritta Jarvelin
  • , Jost B. Jonas
  • , J. Wouter Jukema
  • , Pontiano Kaleebu
  • , Robert Kaplan
  • , Sharon L.R. Kardia
  • , Norihiro Kato
  • , Sirkka M. Keinanen-Kiukaanniemi
  • , Bong-Jo Kim
  • , Mika Kivimaki
  • , Heikki A. Koistinen
  • , Jaspal S. Kooner
  • , Antje Körner
  • , Peter Kovacs
  • , Diana Kuh
  • , Meena Kumari
  • , Zoltan Kutalik
  • , Markku Laakso
  • , Timo A. Lakka
  • , Lenore J. Launer
  • , Karin Leander
  • , Huaixing Li
  • , Xu Lin
  • , Lars Lind
  • , Cecilia Lindgren
  • , Simin Liu
  • , Ruth J.F. Loos
  • , Patrik K.E. Magnusson
  • , Anubha Mahajan
  • , Andres Metspalu
  • , Dennis O. Mook-Kanamori
  • , Trevor A. Mori
  • , Patricia B. Munroe
  • , Inger Njølstad
  • , Jeffrey R. O’Connell
  • , Albertine J. Oldehinkel
  • , Ken K. Ong
  • , Sandosh Padmanabhan
  • , Colin N.A. Palmer
  • , Nicholette D. Palmer
  • , Oluf Pedersen
  • , Craig E. Pennell
  • , David J. Porteous
  • , Peter P. Pramstaller
  • , Michael A. Province
  • , Bruce M. Psaty
  • , Lu Qi
  • , Leslie J. Raffel
  • , Rainer Rauramaa
  • , Susan Redline
  • , Paul M. Ridker
  • , Frits R. Rosendaal
  • , Timo E. Saaristo
  • , Manjinder Sandhu
  • , Jouko Saramies
  • , Neil Schneiderman
  • , Peter Schwarz
  • , Laura J. Scott
  • , Elizabeth Selvin
  • , Peter Sever
  • , Xiao-ou Shu
  • , P. Eline Slagboom
  • , Kerrin S. Small
  • , Blair H. Smith
  • , Harold Snieder
  • , Tamar Sofer
  • , Thorkild I.A. Sørensen
  • , Tim D. Spector
  • , Alice Stanton
  • , Claire J. Steves
  • , Michael Stumvoll
  • , Liang Sun
  • , Yasuharu Tabara
  • , E. Shyong Tai
  • , Nicholas J. Timpson
  • , Anke Tönjes
  • , Jaakko Tuomilehto
  • , Teresa Tusie
  • , Matti Uusitupa
  • , Pim van der Harst
  • , Cornelia van Duijn
  • , Veronique Vitart
  • , Peter Vollenweider
  • , Tanja G.M. Vrijkotte
  • , Lynne E. Wagenknecht
  • , Mark Walker
  • , Ya X. Wang
  • , Nick J. Wareham
  • , Richard M. Watanabe
  • , Hugh Watkins
  • , Wen B. Wei
  • , Ananda R. Wickremasinghe
  • , Gonneke Willemsen
  • , James F. Wilson
  • , Tien-Yin Wong
  • , Jer-Yuarn Wu
  • , Anny H. Xiang
  • , Lisa R. Yanek
  • , Loïc Yengo
  • , Mitsuhiro Yokota
  • , Eleftheria Zeggini
  • , Wei Zheng
  • , Alan B. Zonderman
  • , Jerome I. Rotter
  • , Anna L. Gloyn
  • , Mark I. McCarthy
  • , Josée Dupuis
  • , James B. Meigs
  • , Robert A. Scott
  • , Inga Prokopenko
  • , Aaron Leong
  • , Ching-Ti Liu
  • , Stephen C.J. Parker
  • , Karen L. Mohlke
  • , Claudia Langenberg
  • , Eleanor Wheeler
  • , Andrew P. Morris
  •  & Inês Barroso

Diabetes Prevention Program (DPP) Research Group

  • George A. Bray
  • , Kishore M. Gadde
  • , Iris W. Culbert
  • , Annie Chatellier
  • , Jennifer Arceneaux
  • , Amber Dragg
  • , Catherine M. Champagne
  • , Crystal Duncan
  • , Barbara Eberhardt
  • , Frank Greenway
  • , Fonda G. Guillory
  • , April A. Herbert
  • , Michael L. Jeffirs
  • , Betty M. Kennedy
  • , Erma Levy
  • , Monica Lockett
  • , Jennifer C. Lovejoy
  • , Laura H. Morris
  • , Lee E. Melancon
  • , Donna H. Ryan
  • , Deborah A. Sanford
  • , Kenneth G. Smith
  • , Lisa L. Smith
  • , Julia A. St.Amant
  • , Richard T. Tulley
  • , Paula C. Vicknair
  • , Donald Williamson
  • , Jeffery J. Zachwieja
  • , Kenneth S. Polonsky
  • , Janet Tobian
  • , David A. Ehrmann
  • , Margaret J. Matulik
  • , Karla A. Temple
  • , Bart Clark
  • , Kirsten Czech
  • , Catherine DeSandre
  • , Brittnie Dotson
  • , Ruthanne Hilbrich
  • , Wylie McNabb
  • , Michael T. Quinn
  • , Ann R. Semenske
  • , Jose F. Caro
  • , Pamela G. Watson
  • , Barry J. Goldstein
  • , Kevin Furlong
  • , Kellie A. Smith
  • , Jewel Mendoza
  • , Wendi Wildman
  • , Marsha Simmons
  • , Genine Jensen
  • , Renee Liberoni
  • , John Spandorfer
  • , Constance Pepe
  • , Richard P. Donahue
  • , Ronald B. Goldberg
  • , Ronald Prineas
  • , Patricia Rowe
  • , Anna Giannella
  • , Jeanette Calles
  • , Juliet Sanguily
  • , Paul Cassanova-Romero
  • , Sumaya Castillo-Florez
  • , Hermes J. Florez
  • , Rajesh Garg
  • , Lascelles Kirby
  • , Olga Lara
  • , Carmen Larreal
  • , Valerie McLymont
  • , Jadell Mendez
  • , Arlette Perry
  • , Patrice Saab
  • , Bertha Veciana
  • , Steven M. Haffner
  • , Helen P. Hazuda
  • , Maria G. Montez
  • , Juan Isaac
  • , Kathy Hattaway
  • , Carlos Lorenzo
  • , Arlene Martinez
  • , Monica Salazar
  • , Tatiana Walker
  • , Richard F. Hamman
  • , Dana Dabelea
  • , Patricia V. Nash
  • , Sheila C. Steinke
  • , Lisa Testaverde
  • , Jennifer Truong
  • , Denise R. Anderson
  • , Larry B. Ballonoff
  • , Alexis Bouffard
  • , Rebecca S. Boxer
  • , Brian Bucca
  • , B. Ned Calonge
  • , Lynne Delve
  • , Martha Farago
  • , James O. Hill
  • , Shelley R. Hoyer
  • , Tonya Jenkins
  • , Bonnie T. Jortberg
  • , Dione Lenz
  • , Marsha Miller
  • , Thomas Nilan
  • , Leigh Perreault
  • , David W. Price
  • , Judith G. Regensteiner
  • , Emily B. Schroeder
  • , Helen Seagle
  • , Carissa M. Smith
  • , Brent VanDorsten
  • , Edward S. Horton
  • , Medha Munshi
  • , Kathleen E. Lawton
  • , Catherine S. Poirier
  • , Kati Swift
  • , Sharon D. Jackson
  • , Ronald A. Arky
  • , Marybeth Bryant
  • , Jacqueline P. Burke
  • , Enrique Caballero
  • , Karen M. Callaphan
  • , Barbara Fargnoli
  • , Therese Franklin
  • , Om P. Ganda
  • , Ashley Guidi
  • , Mathew Guido
  • , Alan M. Jacobsen
  • , Lyn M. Kula
  • , Margaret Kocal
  • , Lori Lambert
  • , Kathleen E. Lawton
  • , Sarah Ledbury
  • , Maureen A. Malloy
  • , Roeland J. W. Middelbeek
  • , Maryanne Nicosia
  • , Cathryn F. Oldmixon
  • , Jocelyn Pan
  • , Marizel Quitingon
  • , Riley Rainville
  • , Stacy Rubtchinsky
  • , Ellen W. Seely
  • , Jessica Sansoucy
  • , Dana Schweizer
  • , Donald Simonson
  • , Fannie Smith
  • , Caren G. Solomon
  • , Jeanne Spellman
  • , James Warram
  • , Steven E. Kahn
  • , Brenda K. Montgomery
  • , Basma Fattaleh
  • , Celeste Colegrove
  • , Wilfred Fujimoto
  • , Robert H. Knopp
  • , Edward W. Lipkin
  • , Michelle Marr
  • , Ivy Morgan-Taggart
  • , Anne Murillo
  • , Kayla O’Neal
  • , Dace Trence
  • , Lonnese Taylor
  • , April Thomas
  • , Elaine C. Tsai
  • , Abbas E. Kitabchi
  • , Samuel Dagogo-Jack
  • , Mary E. Murphy
  • , Laura Taylor
  • , Jennifer Dolgoff
  • , Ethel Faye Hampton
  • , William B. Applegate
  • , Michael Bryer-Ash
  • , Debra Clark
  • , Sandra L. Frieson
  • , Uzoma Ibebuogu
  • , Raed Imseis
  • , Helen Lambeth
  • , Lynne C. Lichtermann
  • , Hooman Oktaei
  • , Harriet Ricks
  • , Lily M. K. Rutledge
  • , Amy R. Sherman
  • , Clara M. Smith
  • , Judith E. Soberman
  • , Beverly Williams-Cleaves
  • , Avnisha Patel
  • , Ebenezer A. Nyenwe
  • , Boyd E. Metzger
  • , Mark E. Molitch
  • , Amisha Wallia
  • , Mariana K. Johnson
  • , Sarah VanderMolen
  • , Daphne T. Adelman
  • , Catherine Behrends
  • , Michelle Cook
  • , Marian Fitzgibbon
  • , Mimi M. Giles
  • , Monica Hartmuller
  • , Cheryl K. H. Johnson
  • , Diane Larsen
  • , Anne Lowe
  • , Megan Lyman
  • , David McPherson
  • , Samsam C. Penn
  • , Thomas Pitts
  • , Renee Reinhart
  • , Susan Roston
  • , Pamela A. Schinleber
  • , David M. Nathan
  • , Charles McKitrick
  • , Heather Turgeon
  • , Mary Larkin
  • , Marielle Mugford
  • , Nopporn Thangthaeng
  • , Fernelle Leander
  • , Kathy Abbott
  • , Ellen Anderson
  • , Laurie Bissett
  • , Kristy Bondi
  • , Enrico Cagliero
  • , Jose C. Florez
  • , Linda Delahanty
  • , Valerie Goldman
  • , Elaine Grassa
  • , Lindsey Gurry
  • , Kali D’Anna
  • , Fernelle Leandre
  • , Peter Lou
  • , Alexandra Poulos
  • , Elyse Raymond
  • , Valerie Ripley
  • , Christine Stevens
  • , Beverly Tseng
  • , Jerrold M. Olefsky
  • , Elizabeth Barrett-Connor
  • , Sunder Mudaliar
  • , Maria Rosario Araneta
  • , Mary Lou Carrion-Petersen
  • , Karen Vejvoda
  • , Sarah Bassiouni
  • , Madeline Beltran
  • , Lauren N. Claravall
  • , Jonalle M. Dowden
  • , Steven V. Edelman
  • , Pranav Garimella
  • , Robert R. Henry
  • , Javiva Horne
  • , Marycie Lamkin
  • , Simona Szerdi Janesch
  • , Diana Leos
  • , William Polonsky
  • , Rosa Ruiz
  • , Jean Smith
  • , Jennifer Torio-Hurley
  • , F. Xavier Pi-Sunyer
  • , Blandine Laferrere
  • , Jane E. Lee
  • , Susan Hagamen
  • , Kim Kelly-Dinham
  • , David B. Allison
  • , Nnenna Agharanya
  • , Nancy J. Aronoff
  • , Maria Baldo
  • , Jill P. Crandall
  • , Sandra T. Foo
  • , Jose A. Luchsinger
  • , Carmen Pal
  • , Kathy Parkes
  • , Mary Beth Pena
  • , Julie Roman
  • , Ellen S. Rooney
  • , Gretchen E. H. Van Wye
  • , Kristine A. Viscovich
  • , Melvin J. Prince
  • , David G. Marrero
  • , Kieren J. Mather
  • , Mary de Groot
  • , Susie M. Kelly
  • , Marcia A. Jackson
  • , Gina McAtee
  • , Paula Putenney
  • , Ronald T. Ackermann
  • , Carolyn M. Cantrell
  • , Yolanda F. Dotson
  • , Edwin S. Fineberg
  • , Megan Fultz
  • , John C. Guare
  • , Angela Hadden
  • , James M. Ignaut
  • , Marion S. Kirkman
  • , Erin O’Kelly Phillips
  • , Kisha L Pinner
  • , Beverly D. Porter
  • , Paris J. Roach
  • , Nancy D. Rowland
  • , Madelyn L. Wheeler
  • , Robert E. Ratner
  • , Vanita Aroda
  • , Michelle Magee
  • , Gretchen Youssef
  • , Sue Shapiro
  • , Natalie Andon
  • , Catherine Bavido-Arrage
  • , Geraldine Boggs
  • , Marjorie Bronsord
  • , Ernestine Brown
  • , Holly Love Burkott
  • , Wayman W. Cheatham
  • , Susan Cola
  • , Cindy Evans
  • , Peggy Gibbs
  • , Tracy Kellum
  • , Lilia Leon
  • , Milvia Lagarda
  • , Claresa Levatan
  • , Milajurine Lindsay
  • , Asha K. Nair
  • , Jean Park
  • , Maureen Passaro
  • , Angela Silverman
  • , Gabriel Uwaifo
  • , Debra Wells-Thayer
  • , Renee Wiggins
  • , Mohammed F. Saad
  • , Karol Watson
  • , Maria Budget
  • , Sujata Jinagouda
  • , Medhat Botrous
  • , Anthony Sosa
  • , Sameh Tadros
  • , Khan Akbar
  • , Claudia Conzues
  • , Perpetua Magpuri
  • , Kathy Ngo
  • , Amer Rassam
  • , Debra Waters
  • , Kathy Xapthalamous
  • , Julio V. Santiago
  • , Samuel Dagogo-Jack
  • , Neil H. White
  • , Angela L. Brown
  • , Ana Santiago
  • , Samia Das
  • , Prajakta Khare-Ranade
  • , Tamara Stich
  • , Edwin Fisher
  • , Emma Hurt
  • , Jackie Jones
  • , Tracy Jones
  • , Michelle Kerr
  • , Sherri McCowan
  • , Lucy Ryder
  • , Cormarie Wernimont
  • , Christopher D. Saudek
  • , Sherita Hill Golden
  • , Vanessa Bradley
  • , Emily Sullivan
  • , Tracy Whittington
  • , Caroline Abbas
  • , Adrienne Allen
  • , Frederick L. Brancati
  • , Sharon Cappelli
  • , Jeanne M. Clark
  • , Jeanne B. Charleston
  • , Janice Freel
  • , Katherine Horak
  • , Alicia Greene
  • , Dawn Jiggetts
  • , Delois Johnson
  • , Hope Joseph
  • , Rita Kalyani
  • , Kimberly Loman
  • , Nestoras Mathioudakis
  • , Nisa Maruthur
  • , Henry Mosley
  • , John Reusing
  • , Richard R. Rubin
  • , Alafia Samuels
  • , Thomas Shields
  • , Shawne Stephens
  • , Kerry J. Stewart
  • , LeeLana Thomas
  • , Evonne Utsey
  • , Paula Williamson
  • , David S. Schade
  • , Karwyn S. Adams
  • , Carolyn Johannes
  • , Claire Hemphill
  • , Penny Hyde
  • , Janene L. Canady
  • , Leslie F. Atler
  • , Patrick J. Boyle
  • , Mark R. Burge
  • , Lisa Chai
  • , Kathleen Colleran
  • , Ateka Fondino
  • , Ysela Gonzales
  • , Doris A. Hernandez-McGinnis
  • , Patricia Katz
  • , Carolyn King
  • , Julia Middendorf
  • , Amer Rassam
  • , Sofya Rubinchik
  • , Willette Senter
  • , Debra Waters
  • , Harry Shamoon
  • , Jill Crandall
  • , Janet O. Brown
  • , Gilda Trandafirescu
  • , Danielle Powell
  • , Elsie Adorno
  • , Liane Cox
  • , Helena Duffy
  • , Samuel Engel
  • , Allison Friedler
  • , Angela Goldstein
  • , Crystal J. Howard-Century
  • , Jennifer Lukin
  • , Stacey Kloiber
  • , Nadege Longchamp
  • , Helen Martinez
  • , Dorothy Pompi
  • , Jonathan Scheindlin
  • , Norica Tomuta
  • , Elissa Violino
  • , Elizabeth A. Walker
  • , Judith Wylie-Rosett
  • , Elise Zimmerman
  • , Joel Zonszein
  • , Rena R. Wing
  • , Trevor Orchard
  • , Elizabeth Venditti
  • , Gaye Koenning
  • , M. Kaye Kramer
  • , Marie Smith
  • , Susan Jeffries
  • , Valarie Weinzierl
  • , Susan Barr
  • , Catherine Benchoff
  • , Miriam Boraz
  • , Lisa Clifford
  • , Rebecca Culyba
  • , Marlene Frazier
  • , Ryan Gilligan
  • , Stephanie Guimond
  • , Susan Harrier
  • , Louann Harris
  • , Andrea Kriska
  • , Qurashia Manjoo
  • , Monica Mullen
  • , Alicia Noel
  • , Amy Otto
  • , Jessica Pettigrew
  • , Bonny Rockette-Wagner
  • , Debra Rubinstein
  • , Linda Semler
  • , Cheryl F. Smith
  • , Katherine V. Williams
  • , Tara Wilson
  • , Richard F. Arakaki
  • , Marjorie K. Mau
  • , Renee W. Latimer
  • , Mae K. Isonaga
  • , Narleen K. Baker-Ladao
  • , Ralph Beddow
  • , Nina E. Bermudez
  • , Lorna Dias
  • , Jillian Inouye
  • , John S. Melish
  • , Kathy Mikami
  • , Pharis Mohideen
  • , Sharon K. Odom
  • , Raynette U. Perry
  • , Robin E. Yamamoto
  • , William C. Knowler
  • , Robert L. Hanson
  • , Vallabh Shah
  • , Mary A. Hoskin
  • , Carol A. Percy
  • , Norman Cooeyate
  • , Camille Natewa
  • , Charlotte Dodge
  • , Alvera Enote
  • , Harelda Anderson
  • , Kelly J. Acton
  • , Vickie L. Andre
  • , Rosalyn Barber
  • , Shandiin Begay
  • , Peter H. Bennett
  • , Mary Beth Benson
  • , Evelyn C. Bird
  • , Brenda A. Broussard
  • , Brian C. Bucca
  • , Marcella Chavez
  • , Sherron Cook
  • , Jeff Curtis
  • , Tara Dacawyma
  • , Matthew S. Doughty
  • , Roberta Duncan
  • , Cyndy Edgerton
  • , Jacqueline M. Ghahate
  • , Justin Glass
  • , Martia Glass
  • , Dorothy Gohdes
  • , Wendy Grant
  • , Ellie Horse
  • , Louise E. Ingraham
  • , Merry Jackson
  • , Priscilla Jay
  • , Roylen S. Kaskalla
  • , Karen Kavena
  • , David Kessler
  • , Kathleen M. Kobus
  • , Jonathan Krakoff
  • , Jason Kurland
  • , Catherine Manus
  • , Cherie McCabe
  • , Sara Michaels
  • , Tina Morgan
  • , Yolanda Nashboo
  • , Julie A. Nelson
  • , Steven Poirier
  • , Evette Polczynski
  • , Christopher Piromalli
  • , Mike Reidy
  • , Jeanine Roumain
  • , Debra Rowse
  • , Robert J. Roy
  • , Sandra Sangster
  • , Janet Sewenemewa
  • , Miranda Smart
  • , Chelsea Spencer
  • , Darryl Tonemah
  • , Rachel Williams
  • , Charlton Wilson
  • , Michelle Yazzie
  • , Raymond Bain
  • , Sarah Fowler
  • , Michael D. Larsen
  • , Kathleen Jablonski
  • , Marinella Temprosa
  • , Tina Brenneman
  • , Sharon L. Edelstein
  • , Solome Abebe
  • , Julie Bamdad
  • , Melanie Barkalow
  • , Joel Bethepu
  • , Tsedenia Bezabeh
  • , Anna Bowers
  • , Nicole Butler
  • , Jackie Callaghan
  • , Caitlin E. Carter
  • , Costas Christophi
  • , Gregory M. Dwyer
  • , Mary Foulkes
  • , Yuping Gao
  • , Robert Gooding
  • , Adrienne Gottlieb
  • , Kristina L. Grimes
  • , Nisha Grover-Fairchild
  • , Lori Haffner
  • , Heather Hoffman
  • , Steve Jones
  • , Tara L. Jones
  • , Richard Katz
  • , Preethy Kolinjivadi
  • , John M. Lachin
  • , Yong Ma
  • , Pamela Mucik
  • , Robert Orlosky
  • , Qing Pan
  • , Susan Reamer
  • , James Rochon
  • , Alla Sapozhnikova
  • , Hanna Sherif
  • , Charlotte Stimpson
  • , Ashley Hogan Tjaden
  • , Fredricka Walker-Murray
  • , Elizabeth M. Venditti
  • , Andrea M. Kriska
  • , Linda Semler
  • , Valerie Weinzierl
  • , Santica Marcovina
  • , F. Alan Aldrich
  • , Jessica Harting
  • , John Albers
  • , Greg Strylewicz
  • , Anthony Killeen
  • , Deanna Gabrielson
  • , R. Eastman
  • , Judith Fradkin
  • , Sanford Garfield
  • , Christine Lee
  • , Edward Gregg
  • , Ping Zhang
  • , Dan O’Leary
  • , Gregory Evans
  • , Matthew Budoff
  • , Chris Dailing
  • , Elizabeth Stamm
  • , Ann Schwartz
  • , Caroline Navy
  • , Lisa Palermo
  • , Pentti Rautaharju
  • , Ronald J. Prineas
  • , Elsayed Z. Soliman
  • , Teresa Alexander
  • , Charles Campbell
  • , Sharon Hall
  • , Yabing Li
  • , Margaret Mills
  • , Nancy Pemberton
  • , Farida Rautaharju
  • , Zhuming Zhang
  • , Julie Hu
  • , Susan Hensley
  • , Lisa Keasler
  • , Tonya Taylor
  • , Ronald Danis
  • , Matthew Davis
  • , Larry Hubbard
  • , Barbara Blodi
  • , Ryan Endres
  • , Deborah Elsas
  • , Samantha Johnson
  • , Dawn Myers
  • , Nancy Barrett
  • , Heather Baumhauer
  • , Wendy Benz
  • , Holly Cohn
  • , Ellie Corkery
  • , Kristi Dohm
  • , Amitha Domalpally
  • , Vonnie Gama
  • , Anne Goulding
  • , Andy Ewen
  • , Cynthia Hurtenbach
  • , Daniel Lawrence
  • , Kyle McDaniel
  • , Jeong Pak
  • , James Reimers
  • , Ruth Shaw
  • , Maria Swift
  • , Pamela Vargo
  • , Sheila Watson
  • , Jose A. Luchsinger
  • , Jennifer Manly
  • , Elizabeth Mayer-Davis
  • , Robert R. Moran
  • , Ted Ganiats
  • , Kristin David
  • , Andrew J. Sarkin
  • , Erik Groessl
  • , Naomi Katzir
  • , Helen Chong
  • , William H. Herman
  • , Michael Brändle
  • , Morton B. Brown
  • , Jose C. Florez
  • , David Altshuler
  • , Liana K. Billings
  • , Ling Chen
  • , Maegan Harden
  • , Robert L. Hanson
  • , William C. Knowler
  • , Toni I. Pollin
  • , Alan R. Shuldiner
  • , Kathleen Jablonski
  • , Paul W. Franks
  • , Marie-France Hivert
  • , Josephine H. Li
  • , James A. Perry
  • , Shylaja Srinivasan
  • , Josep M. Mercader
  •  & Jennifer N. Todd

Corresponding author

Correspondence to Jose C. Florez.

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Acknowledgements

We would like to thank J. Del Rio (freelance graphic designer, Cambridge, MA, USA) for his support with Fig. 1 generation. Portions of this study were previously presented as an oral presentation at the 81st Virtual Scientific Sessions of the American Diabetes Association, 25–29 June 2021.

Data availability

The complete summary statistics from this study will be deposited and made 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) following article publication. Related study documents, including the original study protocol and informed consent forms, are available [14]. Additional data requests should be sent by email to the corresponding author.

Funding

This work was conducted with support from National Institutes of Health/NIDDK awards R01 GM117163, R01 DK088214, R03 DK077675 and P30 DK036836; from the Joslin Clinical Research Center from its philanthropic donors; and from the Harvard Catalyst: the Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH Awards M01-RR-01066, 1 UL1 RR025758-04 and 8UL1TR000170-05, and financial contributions from Harvard University and its affiliated academic healthcare centres). JHL received individual support from NIH T32DK007028 and NIDDK K23DK131345. LNB is supported by NIDDK K23DK125839. MSU is supported by NIDDK K23DK114551. AL is supported by grant 2020096 from the Doris Duke Charitable Foundation and the American Diabetes Association grant 7-22-ICTSPM-23. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1-19-ICTS-068, American Diabetes Association grant #11-22-ICTSPM-16, and by NHGRI U01HG011723. JCF is supported by NHLBI K24HL157960.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

All authors took part in designing the experiments presented in this manuscript. VK, LNB, MSU, AL and JCF recruited participants in SUGAR-MGH. VK supervised participant recruitment, data collection, and IRB review and approval, and performed DNA extractions and managed GWAS genotyping. Quality control, imputation of the genetic data and GWAS analyses were performed by JMM. JHL, LNB, VK, KF, PS, AH-C and JMM performed follow-up of GWAS data analysis. JHL, LNB, VK, JMM and JCF contributed to the interpretation of the results. JHL, LNB, VK and JMM wrote and prepared the manuscript. All authors revised and approved the final manuscript. JMM and JCF jointly supervised this study. JCF is the guarantor of this work.

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Josep M. Mercader and Jose C. Florez jointly directed this work.

Members of the MAGIC Consortium and the DPP Research Group are included as collaborators and listed in the electronic supplementary material (ESM) text.

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Li, J.H., Brenner, L.N., Kaur, V. et al. Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH. Diabetologia 66, 1260–1272 (2023). https://doi.org/10.1007/s00125-023-05922-7

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