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Item Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program(Elsevier, 2019-09-26) Sarnowski, Chloé; Leong, Aaron; Raffield, Laura M.; Wu, Peitao; de Vries, Paul S.; DiCorpo, Daniel; Guo, Xiuqing; Xu, Huichun; Liu, Yongmei; Zheng, Xiuwen; Hu, Yao; Brody, Jennifer A.; Goodarzi, Mark O.; Hidalgo, Bertha A.; Highland, Heather M.; Jain, Deepti; Liu, Ching-Ti; Naik, Rakhi P.; O’Connell, Jeffrey R.; Perry, James A.; Porneala, Bianca C.; Selvin, Elizabeth; Wessel, Jennifer; Psaty, Bruce M.; Curran, Joanne E.; Peralta, Juan M.; Blangero, John; Kooperberg, Charles; Mathias, Rasika; Johnson, Andrew D.; Reiner, Alexander P.; Mitchell, Braxton D.; Cupples, L. Adrienne; Vasan, Ramachandran S.; Correa, Adolfo; Morrison, Alanna C.; Boerwinkle, Eric; Rotter, Jerome I.; Rich, Stephen S.; Manning, Alisa K.; Dupuis, Josée; Meigs, James B.; TOPMed Diabetes Working Group; TOPMed Hematology Working Group; TOPMed Hemostasis Working Group; National Heart, Lung, and Blood Institute TOPMed Consortium; Epidemiology, School of Public HealthHemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (−0.88% in hemizygous males, −0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; −0.98% in hemizygous males, −0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.Item Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility(Nature Publishing Group, 2015-01-29) Wessel, Jennifer; Chu, Audrey Y.; Willems, Sara M.; Wang, Shuai; Yaghootkar, Hanieh; Brody, Jennifer A.; Dauriz, Marco; Hivert, Marie-France; Raghavan, Sridharan; Lipovich, Leonard; Hidalgo, Bertha; Fox, Keolu; Huffman, Jennifer E.; An, Ping; Lu, Yingchang; Rasmussen-Torvik, Laura J.; Grarup, Niels; Ehm, Margaret G.; Li, Li; Baldridge, Abigail S.; Stančáková, Alena; Abrol, Ravinder; Besse, Céline; Boland, Anne; Bork-Jensen, Jette; Fornage, Myriam; Freitag, Daniel F.; Garcia, Melissa E.; Guo, Xiuqing; Hara, Kazuo; Isaacs, Aaron; Jakobsdottir, Johanna; Lange, Leslie A.; Layton, Jill C.; Li, Man; Hua Zhao, Jing; Meidtner, Karina; Morrison, Alanna C.; Nalls, Mike A.; Peters, Marjolein J.; Sabater-Lleal, Maria; Schurmann, Claudia; Silveira, Angela; Smith, Albert V.; Southam, Lorraine; Stoiber, Marcus H.; Strawbridge, Rona J.; Taylor, Kent D.; Varga, Tibor V.; Allin, Kristine H.; Amin, Najaf; Aponte, Jennifer L.; Aung, Tin; Barbieri, Caterina; Bihlmeyer, Nathan A.; Boehnke, Michael; Bombieri, Cristina; Bowden, Donald W.; Burns, Sean M.; Chen, Yuning; Chen, Yii-DerI; Cheng, Ching-Yu; Correa, Adolfo; Czajkowski, Jacek; Dehghan, Abbas; Ehret, Georg B.; Eiriksdottir, Gudny; Escher, Stefan A.; Farmaki, Aliki-Eleni; Frånberg, Mattias; Gambaro, Giovanni; Giulianini, Franco; Goddard, William A.; Goel, Anuj; Gottesman, Omri; Grove, Megan L.; Gustafsson, Stefan; Hai, Yang; Hallmans, Göran; Heo, Jiyoung; Hoffmann, Per; Ikram, Mohammad K.; Jensen, Richard A.; Jørgensen, Marit E.; Jørgensen, Torben; Karaleftheri, Maria; Khor, Chiea C.; Kirkpatrick, Andrea; Kraja, Aldi T.; Kuusisto, Johanna; Lange, Ethan M.; Lee, I. T.; Lee, Wen-Jane; Leong, Aaron; Liao, Jiemin; Liu, Chunyu; Liu, Yongmei; Lindgren, Cecilia M.; Linneberg, Allan; Malerba, Giovanni; Mamakou, Vasiliki; Marouli, Eirini; Maruthur, Nisa M.; Matchan, Angela; McKean-Cowdin, Roberta; McLeod, Olga; Metcalf, Ginger A.; Mohlke, Karen L.; Muzny, Donna M.; Ntalla, Ioanna; Palmer, Nicholette D.; Pasko, Dorota; Peter, Andreas; Rayner, Nigel W.; Renström, Frida; Rice, Ken; Sala, Cinzia F.; Sennblad, Bengt; Serafetinidis, Ioannis; Smith, Jennifer A.; Soranzo, Nicole; Speliotes, Elizabeth K.; Stahl, Eli A.; Stirrups, Kathleen; Tentolouris, Nikos; Thanopoulou, Anastasia; Torres, Mina; Traglia, Michela; Tsafantakis, Emmanouil; Javad, Sundas; Yanek, Lisa R.; Zengini, Eleni; Becker, Diane M.; Bis, Joshua C.; Brown, James B.; Adrienne Cupples, L.; Hansen, Torben; Ingelsson, Erik; Karter, Andrew J.; Lorenzo, Carlos; Mathias, Rasika A.; Norris, Jill M.; Peloso, Gina M.; Sheu, Wayne H.-H.; Toniolo, Daniela; Vaidya, Dhananjay; Varma, Rohit; Wagenknecht, Lynne E.; Boeing, Heiner; Bottinger, Erwin P.; Dedoussis, George; Deloukas, Panos; Ferrannini, Ele; Franco, Oscar H.; Franks, Paul W.; Gibbs, Richard A.; Gudnason, Vilmundur; Hamsten, Anders; Harris, Tamara B.; Hattersley, Andrew T.; Hayward, Caroline; Hofman, Albert; Jansson, Jan-Håkan; Langenberg, Claudia; Launer, Lenore J.; Levy, Daniel; Oostra, Ben A.; O'Donnell, Christopher J.; O'Rahilly, Stephen; Padmanabhan, Sandosh; Pankow, James S.; Polasek, Ozren; Province, Michael A.; Rich, Stephen S.; Ridker, Paul M.; Rudan, Igor; Schulze, Matthias B.; Smith, Blair H.; Uitterlinden, André G.; Walker, Mark; Watkins, Hugh; Wong, Tien Y.; Zeggini, Eleftheria; Laakso, Markku; Borecki, Ingrid B.; Chasman, Daniel I.; Pedersen, Oluf; Psaty, Bruce M.; Shyong Tai, E.; van Duijn, Cornelia M.; Wareham, Nicholas J.; Waterworth, Dawn M.; Boerwinkle, Eric; Linda Kao, W. H.; Florez, Jose C.; Loos, Ruth J. F.; Wilson, James G.; Frayling, Timothy M.; Siscovick, David S.; Dupuis, Josée; Rotter, Jerome I.; Meigs, James B.; Scott, Robert A.; Goodarzi, Mark O.; Department of Epidemiology, Richard M. Fairbanks School of Public HealthFasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.Item Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine(Springer Nature, 2023) Tobias, Deirdre K.; Merino, Jordi; Ahmad, Abrar; Aiken, Catherine; Benham, Jamie L.; Bodhini, Dhanasekaran; Clark, Amy L.; Colclough, Kevin; Corcoy, Rosa; Cromer, Sara J.; Duan, Daisy; Felton, Jamie L.; Francis, Ellen C.; Gillard, Pieter; Gingras, Véronique; Gaillard, Romy; Haider, Eram; Hughes, Alice; Ikle, Jennifer M.; Jacobsen, Laura M.; Kahkoska, Anna R.; Kettunen, Jarno L. T.; Kreienkamp, Raymond J.; Lim, Lee-Ling; Männistö, Jonna M. E.; Massey, Robert; Mclennan, Niamh-Maire; Miller, Rachel G.; Morieri, Mario Luca; Most, Jasper; Naylor, Rochelle N.; Ozkan, Bige; Patel, Kashyap Amratlal; Pilla, Scott J.; Prystupa, Katsiaryna; Raghavan, Sridharan; Rooney, Mary R.; Schön, Martin; Semnani-Azad, Zhila; Sevilla-Gonzalez, Magdalena; Svalastoga, Pernille; Takele, Wubet Worku; Tam, Claudia Ha-Ting; Thuesen, Anne Cathrine B.; Tosur, Mustafa; Wallace, Amelia S.; Wang, Caroline C.; Wong, Jessie J.; Yamamoto, Jennifer M.; Young, Katherine; Amouyal, Chloé; Andersen, Mette K.; Bonham, Maxine P.; Chen, Mingling; Cheng, Feifei; Chikowore, Tinashe; Chivers, Sian C.; Clemmensen, Christoffer; Dabelea, Dana; Dawed, Adem Y.; Deutsch, Aaron J.; Dickens, Laura T.; DiMeglio, Linda A.; Dudenhöffer-Pfeifer, Monika; Evans-Molina, Carmella; Fernández-Balsells, María Mercè; Fitipaldi, Hugo; Fitzpatrick, Stephanie L.; Gitelman, Stephen E.; Goodarzi, Mark O.; Grieger, Jessica A.; Guasch-Ferré, Marta; Habibi, Nahal; Hansen, Torben; Huang, Chuiguo; Harris-Kawano, Arianna; Ismail, Heba M.; Hoag, Benjamin; Johnson, Randi K.; Jones, Angus G.; Koivula, Robert W.; Leong, Aaron; Leung, Gloria K. W.; Libman, Ingrid M.; Liu, Kai; Long, S. Alice; Lowe, William L., Jr.; Morton, Robert W.; Motala, Ayesha A.; Onengut-Gumuscu, Suna; Pankow, James S.; Pathirana, Maleesa; Pazmino, Sofia; Perez, Dianna; Petrie, John R.; Powe, Camille E.; Quinteros, Alejandra; Jain, Rashmi; Ray, Debashree; Ried-Larsen, Mathias; Saeed, Zeb; Santhakumar, Vanessa; Kanbour, Sarah; Sarkar, Sudipa; Monaco, Gabriela S. F.; Scholtens, Denise M.; Selvin, Elizabeth; Sheu, Wayne Huey-Herng; Speake, Cate; Stanislawski, Maggie A.; Steenackers, Nele; Steck, Andrea K.; Stefan, Norbert; Støy, Julie; Taylor, Rachael; Tye, Sok Cin; Ukke, Gebresilasea Gendisha; Urazbayeva, Marzhan; Van der Schueren, Bart; Vatier, Camille; Wentworth, John M.; Hannah, Wesley; White, Sara L.; Yu, Gechang; Zhang, Yingchai; Zhou, Shao J.; Beltrand, Jacques; Polak, Michel; Aukrust, Ingvild; de Franco, Elisa; Flanagan, Sarah E.; Maloney, Kristin A.; McGovern, Andrew; Molnes, Janne; Nakabuye, Mariam; Njølstad, Pål Rasmus; Pomares-Millan, Hugo; Provenzano, Michele; Saint-Martin, Cécile; Zhang, Cuilin; Zhu, Yeyi; Auh, Sungyoung; de Souza, Russell; Fawcett, Andrea J.; Gruber, Chandra; Mekonnen, Eskedar Getie; Mixter, Emily; Sherifali, Diana; Eckel, Robert H.; Nolan, John J.; Philipson, Louis H.; Brown, Rebecca J.; Billings, Liana K.; Boyle, Kristen; Costacou, Tina; Dennis, John M.; Florez, Jose C.; Gloyn, Anna L.; Gomez, Maria F.; Gottlieb, Peter A.; Greeley, Siri Atma W.; Griffin, Kurt; Hattersley, Andrew T.; Hirsch, Irl B.; Hivert, Marie-France; Hood, Korey K.; Josefson, Jami L.; Kwak, Soo Heon; Laffel, Lori M.; Lim, Siew S.; Loos, Ruth J. F.; Ma, Ronald C. W.; Mathieu, Chantal; Mathioudakis, Nestoras; Meigs, James B.; Misra, Shivani; Mohan, Viswanathan; Murphy, Rinki; Oram, Richard; Owen, Katharine R.; Ozanne, Susan E.; Pearson, Ewan R.; Perng, Wei; Pollin, Toni I.; Pop-Busui, Rodica; Pratley, Richard E.; Redman, Leanne M.; Redondo, Maria J.; Reynolds, Rebecca M.; Semple, Robert K.; Sherr, Jennifer L.; Sims, Emily K.; Sweeting, Arianne; Tuomi, Tiinamaija; Udler, Miriam S.; Vesco, Kimberly K.; Vilsbøll, Tina; Wagner, Robert; Rich, Stephen S.; Franks, Paul W.; Pediatrics, School of MedicinePrecision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.