Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)
Authors: Li Josephine H. , Perry James A. , Jablonski Kathleen A. , Srinivasan Shylaja , Chen Ling , Todd Jennifer N. , Harden Maegan , Mercader Josep M. , Pan Qing , Dawed Adem Y. , Yee Sook Wah , Pearson Ewan R. , Giacomini Kathleen M. , Giri Ayush , Hung Adriana M. , Xiao Shujie , Williams L. Keoki , Franks Paul W. , Hanson Robert L. , Kahn Steven E. , Knowler William C. , Pollin Toni I. , Florez Jose C. ,   Diabetes Prevention Program Research Group:, Bray George A. , Gadde Kishore M. , Culbert Iris W. , Chatellier Annie , Arceneaux Jennifer , Dragg Amber , Champagne Catherine M. , Duncan Crystal , Eberhardt Barbara , Greenway Frank , Guillory Fonda G. , Herbert April A. , Jeffirs Michael L. , Kennedy Betty M. , Levy Erma , Lockett Monica , Lovejoy Jennifer C. , Morris Laura H. , Melancon Lee E. , Ryan Donna H. , Sanford Deborah A. , Smith Kenneth G. , Smith Lisa L. , St. Amant Julia A. , Tulley Richard T. , Vicknair Paula C. , Williamson Donald , Zachwieja Jeffery J. , Polonsky Kenneth S. , Tobian Janet , Ehrmann David A. , Matulik Margaret J. , Temple Karla A. , Clark Bart , Czech Kirsten , DeSandre Catherine , Dotson Brittnie , Hilbrich Ruthanne , McNabb Wylie , Quinn Michael T. , Semenske Ann R. , Caro Jose F. , Furlong Kevin , Goldstein Barry J. , Watson Pamela G. , Smith Kellie A. , Mendoza Jewel , Wildman Wendi , Simmons Marsha , Jensen Genine , Liberoni Renee , Spandorfer John , Pepe Constance , Donahue Richard P. , Goldberg Ronald B. , Prineas Ronald , Rowe Patricia , Giannella Anna , Calles Jeanette , Sanguily Juliet , Cassanova-Romero Paul , Castillo-Florez Sumaya , Florez Hermes J. , Garg Rajesh , Kirby Lascelles , Lara Olga , Larreal Carmen , McLymont Valerie , Mendez Jadell , Perry Arlette , Saab Patrice , Veciana Bertha , Haffner Steven M. , Hazuda Helen P. , Montez Maria G. , Isaac Juan , Hattaway Kathy , Lorenzo Carlos , Martinez Arlene , Salazar Monica , Walker Tatiana , Hamman Richard F. , Dabelea Dana , Nash Patricia V. , Steinke Sheila C. , Testaverde Lisa , Truong Jennifer , Anderson Denise R. , Ballonoff Larry B. , Bouffard Alexis , Boxer Rebecca S. , Bucca Brian , Calonge B. Ned , Delve Lynne , Farago Martha , Hill James O. , Hoyer Shelley R. , Jenkins Tonya , Jortberg Bonnie T. , Lenz Dione , Miller Marsha , Nilan Thomas , Perreault Leigh , Price David W. , Regensteiner Judith G. , Schroeder Emily B. , Seagle Helen , Smith Carissa M. , VanDorsten Brent , Horton Edward S. , Munshi Medha , Lawton Kathleen E. , Poirier Catherine S. , Swift Kati , Jackson Sharon D. , Arky Ronald A. , Bryant Marybeth , Burke Jacqueline P. , Caballero Enrique , Callaphan Karen M. , Fargnoli Barbara , Franklin Therese , Ganda Om P. , Guidi Ashley , Guido Mathew , Jacobsen Alan M. , Kula Lyn M. , Kocal Margaret , Lambert Lori , Lawton Kathleen E. , Ledbury Sarah , Malloy Maureen A. , Middelbeek Roeland J.W. , Nicosia Maryanne , Oldmixon Cathryn F. , Pan Jocelyn , Quitingon Marizel , Rainville Riley , Rubtchinsky Stacy , Seely Ellen W. , Sansoucy Jessica , Schweizer Dana , Simonson Donald , Smith Fannie , Solomon Caren G. , Spellman Jeanne , Warram James , Kahn Steven E. , Montgomery Brenda K. , Fattaleh Basma , Colegrove Celeste , Fujimoto Wilfred , Knopp Robert H. , Lipkin Edward W. , Marr Michelle , Morgan-Taggart Ivy , Murillo Anne , O’Neal Kayla , Trence Dace , Taylor Lonnese , Thomas April , Tsai Elaine C. , Kitabchi Abbas E. , Dagogo-Jack Samuel , Murphy Mary E. , Taylor Laura , Dolgoff Jennifer , Hampton Ethel Faye , Applegate William B. , Bryer-Ash Michael , Clark Debra , Frieson Sandra L. , Ibebuogu Uzoma , Imseis Raed , Lambeth Helen , Lichtermann Lynne C. , Oktaei Hooman , Ricks Harriet , Rutledge Lily M.K. , Sherman Amy R. , Smith Clara M. , Soberman Judith E. , Williams-Cleaves Beverly , Patel Avnisha , Nyenwe Ebenezer A. , Hampton Ethel Faye , Metzger Boyd E. , Molitch Mark E. , Wallia Amisha , Johnson Mariana K. , VanderMolen Sarah , Adelman Daphne T. , Behrends Catherine , Cook Michelle , Fitzgibbon Marian , Giles Mimi M. , Hartmuller Monica , Johnson Cheryl K.H. , Larsen Diane , Lowe Anne , Lyman Megan , McPherson David , Penn Samsam C. , Pitts Thomas , Reinhart Renee , Roston Susan , Schinleber Pamela A. , Nathan David M. , McKitrick Charles , Turgeon Heather , Larkin Mary , Mugford Marielle , Thangthaeng Nopporn , Leander Fernelle , Abbott Kathy , Anderson Ellen , Bissett Laurie , Bondi Kristy , Cagliero Enrico , Florez Jose C. , Delahanty Linda , Goldman Valerie , Grassa Elaine , Gurry Lindsey , D’Anna Kali , Leandre Fernelle , Lou Peter , Poulos Alexandra , Raymond Elyse , Ripley Valerie , Stevens Christine , Tseng Beverly , Olefsky Jerrold M. , Barrett-Connor Elizabeth , Mudaliar Sunder , Rosario Araneta Maria , Carrion-Petersen Mary Lou , Vejvoda Karen , Bassiouni Sarah , Beltran Madeline , Claravall Lauren N. , Dowden Jonalle M. , Edelman Steven V. , Garimella Pranav , Henry Robert R. , Horne Javiva , Lamkin Marycie , Szerdi Janesch Simona , Leos Diana , Polonsky William , Ruiz Rosa , Smith Jean , Torio-Hurley Jennifer , Pi-Sunyer F. Xavier , Laferrere Blandine , Lee Jane E. , Hagamen Susan , Kelly-Dinham Kim , Allison David B. , Agharanya Nnenna , Aronoff Nancy J. , Baldo Maria , Crandall Jill P. , Foo Sandra T. , Luchsinger Jose A. , Pal Carmen , Parkes Kathy , Pena Mary Beth , Roman Julie , Rooney Ellen S. , Van Wye Gretchen E.H. , Viscovich Kristine A. , Prince Melvin J. , Marrero David G. , Mather Kieren J. , de Groot Mary , Kelly Susie M. , Jackson Marcia A. , McAtee Gina , Putenney Paula , Ackermann Ronald T. , Cantrell Carolyn M. , Dotson Yolanda F. , Fineberg Edwin S. , Fultz Megan , Guare John C. , Hadden Angela , Ignaut James M. , Kirkman Marion S. , O’Kelly Phillips Erin , Pinner Kisha L. , Porter Beverly D. , Roach Paris J. , Rowland Nancy D. , Wheeler Madelyn L. , Ratner Robert E. , Aroda Vanita , Magee Michelle , Youssef Gretchen , Shapiro Sue , Andon Natalie , Bavido-Arrage Catherine , Boggs Geraldine , Bronsord Marjorie , Brown Ernestine , Love Burkott Holly , Cheatham Wayman W. , Cola Susan , Evans Cindy , Gibbs Peggy , Kellum Tracy , Leon Lilia , Lagarda Milvia , Levatan Claresa , Lindsay Milajurine , Nair Asha K. , Park Jean , Passaro Maureen , Silverman Angela , Uwaifo Gabriel , Wells-Thayer Debra , Wiggins Renee , Saad Mohammed F. , Watson Karol , Budget Maria , Jinagouda Sujata , Botrous Medhat , Sosa Anthony , Tadros Sameh , Akbar Khan , Conzues Claudia , Magpuri Perpetua , Ngo Kathy , Rassam Amer , Waters Debra , Xapthalamous Kathy , Santiago Julio V. , Dagogo-Jack Samuel , White Neil H. , Brown Angela L. , Santiago Ana , Das Samia , Khare-Ranade Prajakta , Stich Tamara , Fisher Edwin , Hurt Emma , Jones Jackie , Jones Tracy , Kerr Michelle , McCowan Sherri , Ryder Lucy , Wernimont Cormarie , Saudek Christopher D. , Hill Golden Sherita , Bradley Vanessa , Sullivan Emily , Whittington Tracy , Abbas Caroline , Allen Adrienne , Brancati Frederick L. , Cappelli Sharon , Clark Jeanne M. , Charleston Jeanne B. , Freel Janice , Horak Katherine , Greene Alicia , Jiggetts Dawn , Johnson Delois , Joseph Hope , Kalyani Rita , Loman Kimberly , Mathioudakis Nestoras , Maruthur Nisa , Mosley Henry , Reusing John , Rubin Richard R. , Samuels Alafia , Shields Thomas , Stephens Shawne , Stewart Kerry J. , Thomas LeeLana , Utsey Evonne , Williamson Paula , Schade David S. , Adams Karwyn S. , Johannes Carolyn , Hemphill Claire , Hyde Penny , Canady Janene L. , Atler Leslie F. , Boyle Patrick J. , Burge Mark R. , Chai Lisa , Colleran Kathleen , Fondino Ateka , Gonzales Ysela , Hernandez-McGinnis Doris A. , Katz Patricia , King Carolyn , Middendorf Julia , Rassam Amer , Rubinchik Sofya , Senter Willette , Waters Debra , Shamoon Harry , Crandall Jill , Brown Janet O. , Trandafirescu Gilda , Powell Danielle , Adorno Elsie , Cox Liane , Duffy Helena , Engel Samuel , Friedler Allison , Goldstein Angela , Howard-Century Crystal J. , Lukin Jennifer , Kloiber Stacey , Longchamp Nadege , Martinez Helen , Pompi Dorothy , Scheindlin Jonathan , Tomuta Norica , Violino Elissa , Walker Elizabeth A. , Wylie-Rosett Judith , Zimmerman Elise , Zonszein Joel , Wing Rena R. , Orchard Trevor , Venditti Elizabeth , Koenning Gaye , Kramer M. Kaye , Smith Marie , Jeffries Susan , Weinzierl Valarie , Barr Susan , Benchoff Catherine , Boraz Miriam , Clifford Lisa , Culyba Rebecca , Frazier Marlene , Gilligan Ryan , Guimond Stephanie , Harrier Susan , Harris Louann , Kriska Andrea , Manjoo Qurashia , Mullen Monica , Noel Alicia , Otto Amy , Pettigrew Jessica , Rockette-Wagner Bonny , Rubinstein Debra , Semler Linda , Smith Cheryl F. , Williams Katherine V. , Wilson Tara , Arakaki Richard F. , Mau Marjorie K. , Latimer Renee W. , Isonaga Mae K. , Baker-Ladao Narleen K. , Beddow Ralph , Bermudez Nina E. , Dias Lorna , Inouye Jillian , Melish John S. , Mikami Kathy , Mohideen Pharis , Odom Sharon K. , Perry Raynette U. , Yamamoto Robin E. , Knowler William C. , Hanson Robert L. , Shah Vallabh , Dodge Charlotte , Hoskin Mary A. , Percy Carol A. , Cooeyate Norman , Natewa Camille , Dodge Charlotte , Enote Alvera , Anderson Harelda , Acton Kelly J. , Andre Vickie L. , Barber Rosalyn , Begay Shandiin , Bennett Peter H. , Benson Mary Beth , Bird Evelyn C. , Broussard Brenda A. , Bucca Brian C. , Chavez Marcella , Cook Sherron , Curtis Jeff , Dacawyma Tara , Doughty Matthew S. , Duncan Roberta , Edgerton Cyndy , Ghahate Jacqueline M. , Glass Justin , Glass Martia , Gohdes Dorothy , Grant Wendy , Horse Ellie , Ingraham Louise E. , Jackson Merry , Jay Priscilla , Kaskalla Roylen S. , Kavena Karen , Kessler David , Kobus Kathleen M. , Krakoff Jonathan , Kurland Jason , Manus Catherine , McCabe Cherie , Michaels Sara , Morgan Tina , Nashboo Yolanda , Nelson Julie A. , Poirier Steven , Polczynski Evette , Piromalli Christopher , Reidy Mike , Roumain Jeanine , Rowse Debra , Roy Robert J. , Sangster Sandra , Sewenemewa Janet , Smart Miranda , Spencer Chelsea , Tonemah Darryl , Williams Rachel , Wilson Charlton , Yazzie Michelle , Bain Raymond , Fowler Sarah , Larsen Michael D. , Jablonski Kathleen , Temprosa Marinella , Brenneman Tina , Edelstein Sharon L. , Abebe Solome , Bamdad Julie , Barkalow Melanie , Bethepu Joel , Bezabeh Tsedenia , Bowers Anna , Butler Nicole , Callaghan Jackie , Carter Caitlin E. , Christophi Costas , Dwyer Gregory M. , Foulkes Mary , Gao Yuping , Gooding Robert , Gottlieb Adrienne , Grimes Kristina L. , Grover-Fairchild Nisha , Haffner Lori , Hoffman Heather , Jones Steve , Jones Tara L. , Katz Richard , Kolinjivadi Preethy , Lachin John M. , Ma Yong , Mucik Pamela , Orlosky Robert , Pan Qing , Reamer Susan , Rochon James , Sapozhnikova Alla , Sherif Hanna , Stimpson Charlotte , Hogan Tjaden Ashley , Walker-Murray Fredricka , Venditti Elizabeth M. , Kriska Andrea M. , Semler Linda , Weinzierl Valerie , Marcovina Santica , Aldrich F. Alan , Harting Jessica , Albers John , Strylewicz Greg , Killeen Anthony , Gabrielson Deanna , Eastman R. , Fradkin Judith , Garfield Sanford , Lee Christine , Gregg Edward , Zhang Ping , O’Leary Dan , Evans Gregory , Budoff Matthew , Dailing Chris , Stamm Elizabeth , Schwartz Ann , Navy Caroline , Palermo Lisa , Rautaharju Pentti , Prineas Ronald J. , Soliman Elsayed Z. , Alexander Teresa , Campbell Charles , Hall Sharon , Li Yabing , Mills Margaret , Pemberton Nancy , Rautaharju Farida , Zhang Zhuming , Hu Julie , Hensley Susan , Keasler Lisa , Taylor Tonya , Blodi Barbara , Danis Ronald , Davis Matthew , Hubbard Larry , Blodi Barbara , Endres Ryan , Elsas Deborah , Johnson Samantha , Myers Dawn , Barrett Nancy , Baumhauer Heather , Benz Wendy , Cohn Holly , Corkery Ellie , Dohm Kristi , Domalpally Amitha , Gama Vonnie , Goulding Anne , Ewen Andy , Hurtenbach Cynthia , Lawrence Daniel , McDaniel Kyle , Pak Jeong , Reimers James , Shaw Ruth , Swift Maria , Vargo Pamela , Watson Sheila , Luchsinger Jose A. , Manly Jennifer , Mayer-Davis Elizabeth , Moran Robert R. , Ganiats Ted , David Kristin , Sarkin Andrew J. , Groessl Erik , Katzir Naomi , Chong Helen , Herman William H. , Brändle Michael , Brown Morton B. , Florez Jose C. , Altshuler David , Billings Liana K. , Chen Ling , Harden Maegan , Hanson Robert L. , Knowler William C. , Pollin Toni I. , Shuldiner Alan R. , Jablonski Kathleen , Franks Paul W. , Hivert Marie-France , Li Josephine H. , Perry James A. , Srinivasan Shylaja , Mercader Josep M. , Todd Jennifer N. 
Published: December 2022

Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been replicated in the Diabetes Prevention Program (DPP). To assess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes incidence. We identified four genome-wide significant variants after correcting for correlated traits (P &lt; 9 × 10−9). In the MET arm, rs144322333 near ENOSF1 (minor allele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, β = 0.39 [95% CI 0.28, 0.50]; P = 2.8 × 10−12). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, β = −7.55 [95% CI −9.88, −5.22]; P = 3.2 × 10−10) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) &lt; 1.0 × 10−4]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.