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

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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Title	Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH.
Date	July 1st, 2023
Issue name	Diabetologia
Issue number	v66.7:1260-1272
DOI	10.1007/s00125-023-05922-7
PubMed	37233759
Authors	Li JH, Brenner LN, Kaur V, Figueroa K, Schroeder P, Huerta-Chagoya A, Udler MS, Leong A, Mercader JM & Florez JC
Info	Chen J, Spracklen CN, Marenne G, Varshney A, Corbin LJ, Luan J, Willems SM, Wu Y, Zhang X, Horikoshi M, Boutin TS, Mägi R, Waage J, Li-Gao R, Chan KHK, Yao J, Anasanti MD, Chu AY, Claringbould A, Heikkinen J, Hong J, Hottenga JJ, Huo S, Kaakinen MA, Louie T, März W, Moreno-Macias H, Ndungu A, Nelson SC, Nolte IM, North KE, Raulerson CK, Ray D, Rohde R, Rybin D, Schurmann C, Sim X, Southam L, Stewart ID, Wang CA, Wang Y, Wu P, Zhang W, Ahluwalia TS, Appel EVR, Bielak LF, Brody JA, Burtt NP, Cabrera CP, Cade BE, Chai JF, Chai X, Chang LC, Chen CH, Chen BH, Chitrala KN, Chiu YF, de Haan HG, Delgado GE, Demirkan A, Duan Q, Engmann J, Fatumo SA, Gayán J, Giulianini F, Gong JH, Gustafsson S, Hai Y, Hartwig FP, He J, Heianza Y, Huang T, Huerta-Chagoya A, Hwang MY, Jensen RA, Kawaguchi T, Kentistou KA, Kim YJ, Kleber ME, Kooner IK, Lai S, Lange LA, Langefeld CD, Lauzon M, Li M, Ligthart S, Liu J, Loh M, Long J, Lyssenko V, Mangino M, Marzi C, Montasser ME, Nag A, Nakatochi M, Noce D, Noordam R, Pistis G, Preuss M, Raffield L, Rasmussen-Torvik LJ, Rich SS, Robertson NR, Rueedi R, Ryan K, Sanna S, Saxena R, Schraut KE, Sennblad B, Setoh K, Smith AV, Southam L, Sparsø T, Strawbridge RJ, Takeuchi F, Tan J, Trompet S, van den Akker E, van der Most PJ, Verweij N, Vogel M, Wang H, Wang C, Wang N, Warren HR, Wen W, Wilsgaard T, Wong A, Wood AR, Xie T, Zafarmand MH, Zhao JH, Zhao W, Amin N, Arzumanyan Z, Astrup A, Bakker SJL, Baldassarre D, Beekman M, Bergman RN, Bertoni A, Blüher M, Bonnycastle LL, Bornstein SR, Bowden DW, Cai Q, Campbell A, Campbell H, Chang YC, de Geus EJC, Dehghan A, Du S, Eiriksdottir G, Farmaki AE, Frånberg M, Fuchsberger C, Gao Y, Gjesing AP, Goel A, Han S, Hartman CA, Herder C, Hicks AA, Hsieh CH, Hsueh WA, Ichihara S, Igase M, Ikram MA, Johnson WC, Jørgensen ME, Joshi PK, Kalyani RR, Kandeel FR, Katsuya T, Khor CC, Kiess W, Kolcic I, Kuulasmaa T, Kuusisto J, Läll K, Lam K, Lawlor DA, Lee NR, Lemaitre RN, Li H, Lin SY, Lindström J, Linneberg A, Liu J, Lorenzo C, Matsubara T, Matsuda F, Mingrone G, Mooijaart S, Moon S, Nabika T, Nadkarni GN, Nadler JL, Nelis M, Neville MJ, Norris JM, Ohyagi Y, Peters A, Peyser PA, Polasek O, Qi Q, Raven D, Reilly DF, Reiner A, Rivideneira F, Roll K, Rudan I, Sabanayagam C, Sandow K, Sattar N, Schürmann A, Shi J, Stringham HM, Taylor KD, Teslovich TM, Thuesen B, Timmers PRHJ, Tremoli E, Tsai MY, Uitterlinden A, van Dam RM, van Heemst D, van Hylckama Vlieg A, Van Vliet-Ostaptchouk JV, Vangipurapu J, Vestergaard H, Wang T, van Dijk KW, Zemunik T, Abecasis GR, Adair LS, Aguilar-Salinas CA, Alarcón-Riquelme ME, An P, Aviles-Santa L, Becker DM, Beilin LJ, Bergmann S, Bisgaard H, Black C, Boehnke M, Boerwinkle E, Böhm BO, Bønnelykke K, Boomsma DI, Bottinger EP, Buchanan TA, Canouil M, Caulfield MJ, Chambers JC, Chasman DI, Chen YI, Cheng CY, Collins FS, Correa A, Cucca F, de Silva HJ, Dedoussis G, Elmståhl S, Evans MK, Ferrannini E, Ferrucci L, Florez JC, Franks PW, Frayling TM, Froguel P, Gigante B, Goodarzi MO, Gordon-Larsen P, Grallert H, Grarup N, Grimsgaard S, Groop L, Gudnason V, Guo X, Hamsten A, Hansen T, Hayward C, Heckbert SR, Horta BL, Huang W, Ingelsson E, James PS, Jarvelin MR, Jonas JB, Jukema JW, Kaleebu P, Kaplan R, Kardia SLR, Kato N, Keinanen-Kiukaanniemi SM, Kim BJ, Kivimaki M, Koistinen HA, Kooner JS, Körner A, Kovacs P, Kuh D, Kumari M, Kutalik Z, Laakso M, Lakka TA, Launer LJ, Leander K, Li H, Lin X, Lind L, Lindgren C, Liu S, Loos RJF, Magnusson PKE, Mahajan A, Metspalu A, Mook-Kanamori DO, Mori TA, Munroe PB, Njølstad I, O'Connell JR, Oldehinkel AJ, Ong KK, Padmanabhan S, Palmer CNA, Palmer ND, Pedersen O, Pennell CE, Porteous DJ, Pramstaller PP, Province MA, Psaty BM, Qi L, Raffel LJ, Rauramaa R, Redline S, Ridker PM, Rosendaal FR, Saaristo TE, Sandhu M, Saramies J, Schneiderman N, Schwarz P, Scott LJ, Selvin E, Sever P, Shu XO, Slagboom PE, Small KS, Smith BH, Snieder H, Sofer T, Sørensen TIA, Spector TD, Stanton A, Steves CJ, Stumvoll M, Sun L, Tabara Y, Tai ES, Timpson NJ, Tönjes A, Tuomilehto J, Tusie T, Uusitupa M, van der Harst P, van Duijn C, Vitart V, Vollenweider P, Vrijkotte TGM, Wagenknecht LE, Walker M, Wang YX, Wareham NJ, Watanabe RM, Watkins H, Wei WB, Wickremasinghe AR, Willemsen G, Wilson JF, Wong TY, Wu JY, Xiang AH, Yanek LR, Yengo L, Yokota M, Zeggini E, Zheng W, Zonderman AB, Rotter JI, Gloyn AL, McCarthy MI, Dupuis J, Meigs JB, Scott RA, Prokopenko I, Leong A, Liu CT, Parker SCJ, Mohlke KL, Langenberg C, Wheeler E, Morris AP, Barroso I, Bray GA, Gadde KM, Culbert IW, Chatellier A, Arceneaux J, Dragg A, Champagne CM, Duncan C, Eberhardt B, Greenway F, Guillory FG, Herbert AA, Jeffirs ML, Kennedy BM, Levy E, Lockett M, Lovejoy JC, Morris LH, Melancon LE, Ryan DH, Sanford DA, Smith KG, Smith LL, St Amant JA, Tulley RT, Vicknair PC, Williamson D, Zachwieja JJ, Polonsky KS, Tobian J, Ehrmann DA, Matulik MJ, Temple KA, Clark B, Czech K, DeSandre C, Dotson B, Hilbrich R, McNabb W, Quinn MT, Semenske AR, Caro JF, Watson PG, Goldstein BJ, Furlong K, Smith KA, Mendoza J, Wildman W, Simmons M, Jensen G, Liberoni R, Spandorfer J, Pepe C, Donahue RP, Goldberg RB, Prineas R, Rowe P, Giannella A, Calles J, Sanguily J, Cassanova-Romero P, Castillo-Florez S, Florez HJ, Garg R, Kirby L, Lara O, Larreal C, McLymont V, Mendez J, Perry A, Saab P, Veciana B, Haffner SM, Hazuda HP, Montez MG, Isaac J, Hattaway K, Lorenzo C, Martinez A, Salazar M, Walker T, Hamman RF, Dabelea D, Nash PV, Steinke SC, Testaverde L, Truong J, Anderson DR, Ballonoff LB, Bouffard A, Boxer RS, Bucca B, Calonge BN, Delve L, Farago M, Hill JO, Hoyer SR, Jenkins T, Jortberg BT, Lenz D, Miller M, Nilan T, Perreault L, Price DW, Regensteiner JG, Schroeder EB, Seagle H, Smith CM, VanDorsten B, Horton ES, Munshi M, Lawton KE, Poirier CS, Swift K, Jackson SD, Arky RA, Bryant M, Burke JP, Caballero E, Callaphan KM, Fargnoli B, Franklin T, Ganda OP, Guidi A, Guido M, Jacobsen AM, Kula LM, Kocal M, Lambert L, Lawton KE, Ledbury S, Malloy MA, Middelbeek RJW, Nicosia M, Oldmixon CF, Pan J, Quitingon M, Rainville R, Rubtchinsky S, Seely EW, Sansoucy J, Schweizer D, Simonson D, Smith F, Solomon CG, Spellman J, Warram J, Kahn SE, Montgomery BK, Fattaleh B, Colegrove C, Fujimoto W, Knopp RH, Lipkin EW, Marr M, Morgan-Taggart I, Murillo A, O'Neal K, Trence D, Taylor L, Thomas A, Tsai EC, Kitabchi AE, Dagogo-Jack S, Murphy ME, Taylor L, Dolgoff J, Hampton EF, Applegate WB, Bryer-Ash M, Clark D, Frieson SL, Ibebuogu U, Imseis R, Lambeth H, Lichtermann LC, Oktaei H, Ricks H, Rutledge LMK, Sherman AR, Smith CM, Soberman JE, Williams-Cleaves B, Patel A, Nyenwe EA, Metzger BE, Molitch ME, Wallia A, Johnson MK, VanderMolen S, Adelman DT, Behrends C, Cook M, Fitzgibbon M, Giles MM, Hartmuller M, Johnson CKH, Larsen D, Lowe A, Lyman M, McPherson D, Penn SC, Pitts T, Reinhart R, Roston S, Schinleber PA, Nathan DM, McKitrick C, Turgeon H, Larkin M, Mugford M, Thangthaeng N, Leander F, Abbott K, Anderson E, Bissett L, Bondi K, Cagliero E, Florez JC, Delahanty L, Goldman V, Grassa E, Gurry L, D'Anna K, Leandre F, Lou P, Poulos A, Raymond E, Ripley V, Stevens C, Tseng B, Olefsky JM, Barrett-Connor E, Mudaliar S, Araneta MR, Carrion-Petersen ML, Vejvoda K, Bassiouni S, Beltran M, Claravall LN, Dowden JM, Edelman SV, Garimella P, Henry RR, Horne J, Lamkin M, Janesch SS, Leos D, Polonsky W, Ruiz R, Smith J, Torio-Hurley J, Pi-Sunyer FX, Laferrere B, Lee JE, Hagamen S, Kelly-Dinham K, Allison DB, Agharanya N, Aronoff NJ, Baldo M, Crandall JP, Foo ST, Luchsinger JA, Pal C, Parkes K, Pena MB, Roman J, Rooney ES, Van Wye GEH, Viscovich KA, Prince MJ, Marrero DG, Mather KJ, de Groot M, Kelly SM, Jackson MA, McAtee G, Putenney P, Ackermann RT, Cantrell CM, Dotson YF, Fineberg ES, Fultz M, Guare JC, Hadden A, Ignaut JM, Kirkman MS, O'Kelly Phillips E, Pinner KL, Porter BD, Roach PJ, Rowland ND, Wheeler ML, Ratner RE, Aroda V, Magee M, Youssef G, Shapiro S, Andon N, Bavido-Arrage C, Boggs G, Bronsord M, Brown E, Burkott HL, Cheatham WW, Cola S, Evans C, Gibbs P, Kellum T, Leon L, Lagarda M, Levatan C, Lindsay M, Nair AK, Park J, Passaro M, Silverman A, Uwaifo G, Wells-Thayer D, Wiggins R, Saad MF, Watson K, Budget M, Jinagouda S, Botrous M, Sosa A, Tadros S, Akbar K, Conzues C, Magpuri P, Ngo K, Rassam A, Waters D, Xapthalamous K, Santiago JV, Dagogo-Jack S, White NH, Brown AL, Santiago A, Das S, Khare-Ranade P, Stich T, Fisher E, Hurt E, Jones J, Jones T, Kerr M, McCowan S, Ryder L, Wernimont C, Saudek CD, Golden SH, Bradley V, Sullivan E, Whittington T, Abbas C, Allen A, Brancati FL, Cappelli S, Clark JM, Charleston JB, Freel J, Horak K, Greene A, Jiggetts D, Johnson D, Joseph H, Kalyani R, Loman K, Mathioudakis N, Maruthur N, Mosley H, Reusing J, Rubin RR, Samuels A, Shields T, Stephens S, Stewart KJ, Thomas L, Utsey E, Williamson P, Schade DS, Adams KS, Johannes C, Hemphill C, Hyde P, Canady JL, Atler LF, Boyle PJ, Burge MR, Chai L, Colleran K, Fondino A, Gonzales Y, Hernandez-McGinnis DA, Katz P, King C, Middendorf J, Rassam A, Rubinchik S, Senter W, Waters D, Shamoon H, Crandall J, Brown JO, Trandafirescu G, Powell D, Adorno E, Cox L, Duffy H, Engel S, Friedler A, Goldstein A, Howard-Century CJ, Lukin J, Kloiber S, Longchamp N, Martinez H, Pompi D, Scheindlin J, Tomuta N, Violino E, Walker EA, Wylie-Rosett J, Zimmerman E, Zonszein J, Wing RR, Orchard T, Venditti E, Koenning G, Kramer MK, Smith M, Jeffries S, Weinzierl V, Barr S, Benchoff C, Boraz M, Clifford L, Culyba R, Frazier M, Gilligan R, Guimond S, Harrier S, Harris L, Kriska A, Manjoo Q, Mullen M, Noel A, Otto A, Pettigrew J, Rockette-Wagner B, Rubinstein D, Semler L, Smith CF, Williams KV, Wilson T, Arakaki RF, Mau MK, Latimer RW, Isonaga MK, Baker-Ladao NK, Beddow R, Bermudez NE, Dias L, Inouye J, Melish JS, Mikami K, Mohideen P, Odom SK, Perry RU, Yamamoto RE, Knowler WC, Hanson RL, Shah V, Hoskin MA, Percy CA, Cooeyate N, Natewa C, Dodge C, Enote A, Anderson H, Acton KJ, Andre VL, Barber R, Begay S, Bennett PH, Benson MB, Bird EC, Broussard BA, Bucca BC, Chavez M, Cook S, Curtis J, Dacawyma T, Doughty MS, Duncan R, Edgerton C, Ghahate JM, Glass J, Glass M, Gohdes D, Grant W, Horse E, Ingraham LE, Jackson M, Jay P, Kaskalla RS, Kavena K, Kessler D, Kobus KM, Krakoff J, Kurland J, Manus C, McCabe C, Michaels S, Morgan T, Nashboo Y, Nelson JA, Poirier S, Polczynski E, Piromalli C, Reidy M, Roumain J, Rowse D, Roy RJ, Sangster S, Sewenemewa J, Smart M, Spencer C, Tonemah D, Williams R, Wilson C, Yazzie M, Bain R, Fowler S, Larsen MD, Jablonski K, Temprosa M, Brenneman T, Edelstein SL, Abebe S, Bamdad J, Barkalow M, Bethepu J, Bezabeh T, Bowers A, Butler N, Callaghan J, Carter CE, Christophi C, Dwyer GM, Foulkes M, Gao Y, Gooding R, Gottlieb A, Grimes KL, Grover-Fairchild N, Haffner L, Hoffman H, Jones S, Jones TL, Katz R, Kolinjivadi P, Lachin JM, Ma Y, Mucik P, Orlosky R, Pan Q, Reamer S, Rochon J, Sapozhnikova A, Sherif H, Stimpson C, Tjaden AH, Walker-Murray F, Venditti EM, Kriska AM, Semler L, Weinzierl V, Marcovina S, Aldrich FA, Harting J, Albers J, Strylewicz G, Killeen A, Gabrielson D, Eastman R, Fradkin J, Garfield S, Lee C, Gregg E, Zhang P, O'Leary D, Evans G, Budoff M, Dailing C, Stamm E, Schwartz A, Navy C, Palermo L, Rautaharju P, Prineas RJ, Soliman EZ, Alexander T, Campbell C, Hall S, Li Y, Mills M, Pemberton N, Rautaharju F, Zhang Z, Hu J, Hensley S, Keasler L, Taylor T, Danis R, Davis M, Hubbard L, Blodi B, Endres R, Elsas D, Johnson S, Myers D, Barrett N, Baumhauer H, Benz W, Cohn H, Corkery E, Dohm K, Domalpally A, Gama V, Goulding A, Ewen A, Hurtenbach C, Lawrence D, McDaniel K, Pak J, Reimers J, Shaw R, Swift M, Vargo P, Watson S, Luchsinger JA, Manly J, Mayer-Davis E, Moran RR, Ganiats T, David K, Sarkin AJ, Groessl E, Katzir N, Chong H, Herman WH, Brändle M, Brown MB, Florez JC, Altshuler D, Billings LK, Chen L, Harden M, Hanson RL, Knowler WC, Pollin TI, Shuldiner AR, Jablonski K, Franks PW, Hivert MF, Li JH, Perry JA, Srinivasan S, Mercader JM, Todd JN
Keywords	Genetics, Genome-wide association study, Glipizide, Incretin, Metformin, Multi-ancestry, Pathophysiology, Pharmacogenetics, Sulfonylurea, Type 2 diabetes
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