Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis

Wheeler, Eleanor, Leong, Aaron, Liu, Ching-Ti, Hivert, Marie-France, Strawbridge, Rona J., Podmore, Clara, Li, Man, Yao, Jie, Sim, Xueling, Hong, Jaeyoung, Chu, Audrey Y., Zhang, Weihua, Wang, Xu, Chen, Peng, Maruthur, Nisa M., Porneala, Bianca C., Sharp, Stephen J., Jia, Yucheng, Kabagambe, Edmond K., Chang, Li-Ching, Chen, Wei-Min, Elks, Cathy E., Evans, Daniel S., Fan, Qiao, Giulianini, Franco, Go, Min Jin, Hottenga, Jouke-Jan, Hu, Yao, Jackson, Anne U., Kanoni, Stavroula, Kim, Young Jin, Kleber, Marcus E., Ladenvall, Claes, Lecoeur, Cecile, Lim, Sing-Hui, Lu, Yingchang, Mahajan, Anubha, Marzi, Carola, Nalls, Mike A., Navarro, Pau, Nolte, Ilja M., Rose, Lynda M., Rybin, Denis V., Sanna, Serena, Shi, Yuan, Stram, Daniel O., Takeuchi, Fumihiko, Tan, Shu Pei, van der Most, Peter J., Van Vliet-Ostaptchouk, Jana V., Wong, Andrew, Yengo, Loic, Zhao, Wanting, Goel, Anuj, Martinez Larrad, Maria Teresa, Radke, Dörte, Salo, Perttu, Tanaka, Toshiko, van Iperen, Erik P. A., Abecasis, Goncalo, Afaq, Saima, Alizadeh, Behrooz Z., Bertoni, Alain G., Bonnefond, Amelie, Böttcher, Yvonne, Bottinger, Erwin P., Campbell, Harry, Carlson, Olga D., Chen, Chien-Hsiun, Cho, Yoon Shin, Garvey, W. Timothy, Gieger, Christian, Goodarzi, Mark O., Grallert, Harald, Hamsten, Anders, Hartman, Catharina A., Herder, Christian, Hsiung, Chao Agnes, Huang, Jie, Igase, Michiya, Isono, Masato, Katsuya, Tomohiro, Khor, Chiea-Chuen, Kiess, Wieland, Kohara, Katsuhiko, Kovacs, Peter, Lee, Juyoung, Lee, Wen-Jane, Lehne, Benjamin, Li, Huaixing, Liu, Jianjun, Lobbens, Stephane, Luan, Jian'an, Lyssenko, Valeriya, Meitinger, Thomas, Miki, Tetsuro, Miljkovic, Iva, Moon, Sanghoon, Mulas, Antonella, Müller, Gabriele, Müller-Nurasyid, Martina, Nagaraja, Ramaiah, Nauck, Matthias, Pankow, James S., Polasek, Ozren, Prokopenko, Inga, Ramos, Paula S., Rasmussen-Torvik, Laura, Rathmann, Wolfgang, Rich, Stephen S., Robertson, Neil R., Roden, Michael, Roussel, Ronan, Rudan, Igor, Scott, Robert A., Scott, William R., Sennblad, Bengt, Siscovick, David S., Strauch, Konstantin, Sun, Liang, Swertz, Morris, Tajuddin, Salman M., Taylor, Kent D., Teo, Yik-Ying, Tham, Yih Chung, Tönjes, Anke, Wareham, Nicholas J., Willemsen, Gonneke, Wilsgaard, Tom, Hingorani, Aroon D., Egan, Josephine, Ferrucci, Luigi, Hovingh, G. Kees, Jula, Antti, Kivimaki, Mika, Kumari, Meena, Njølstad, Inger, Palmer, Colin N. A., Serrano Ríos, Manuel, Stumvoll, Michael, Watkins, Hugh, Aung, Tin, Blüher, Matthias, Boehnke, Michael, Boomsma, Dorret I., Bornstein, Stefan R., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chen, Yduan-Tsong, Cheng, Ching-Yu, Cucca, Francesco, de Geus, Eco J. C., Deloukas, Panos, Evans, Michele K., Fornage, Myriam, Friedlander, Yechiel, Froguel, Philippe, Groop, Leif, Gross, Myron D., Harris, Tamara B., Hayward, Caroline, Heng, Chew-Kiat, Ingelsson, Erik, Kato, Norihiro, Kim, Bong-Jo, Koh, Woon-Puay, Kooner, Jaspal S., Körner, Antje, Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lin, Xu, Liu, Yongmei, Loos, Ruth J. F., Magnusson, Patrik K. E., März, Winfried, McCarthy, Mark I., Oldehinkel, Albertine J., Ong, Ken K., Pedersen, Nancy L., Pereira, Mark A., Peters, Annette, Ridker, Paul M., Sabanayagam, Charumathi, Sale, Michele, Saleheen, Danish, Saltevo, Juha, Schwarz, Peter E.H., Sheu, Wayne H. H., Snieder, Harold, Spector, Timothy D., Tabara, Yasuharu, Tuomilehto, Jaakko, van Dam, Rob M., Wilson, James G., Wilson, James F., Wolffenbuttel, Bruce H. R., Wong, Tien Yin, Wu, Jer-Yuarn, Yuan, Jian-Min, Zonderman, Alan B., Soranzo, Nicole, Guo, Xiuqing, Roberts, David J., Florez, Jose C., Sladek, Robert, Dupuis, Josée, Morris, Andrew P., Tai, E-Shyong, Selvin, Elizabeth, Rotter, Jerome I., Langenberg, Claudia, Barroso, Inês and Meigs, James B. (2017) Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. PLoS Medicine, 14 9: e1002383. doi:10.1371/journal.pmed.1002383


Author Wheeler, Eleanor
Leong, Aaron
Liu, Ching-Ti
Hivert, Marie-France
Strawbridge, Rona J.
Podmore, Clara
Li, Man
Yao, Jie
Sim, Xueling
Hong, Jaeyoung
Chu, Audrey Y.
Zhang, Weihua
Wang, Xu
Chen, Peng
Maruthur, Nisa M.
Porneala, Bianca C.
Sharp, Stephen J.
Jia, Yucheng
Kabagambe, Edmond K.
Chang, Li-Ching
Chen, Wei-Min
Elks, Cathy E.
Evans, Daniel S.
Fan, Qiao
Giulianini, Franco
Go, Min Jin
Hottenga, Jouke-Jan
Hu, Yao
Jackson, Anne U.
Kanoni, Stavroula
Kim, Young Jin
Kleber, Marcus E.
Ladenvall, Claes
Lecoeur, Cecile
Lim, Sing-Hui
Lu, Yingchang
Mahajan, Anubha
Marzi, Carola
Nalls, Mike A.
Navarro, Pau
Nolte, Ilja M.
Rose, Lynda M.
Rybin, Denis V.
Sanna, Serena
Shi, Yuan
Stram, Daniel O.
Takeuchi, Fumihiko
Tan, Shu Pei
van der Most, Peter J.
Van Vliet-Ostaptchouk, Jana V.
Wong, Andrew
Yengo, Loic
Zhao, Wanting
Goel, Anuj
Martinez Larrad, Maria Teresa
Radke, Dörte
Salo, Perttu
Tanaka, Toshiko
van Iperen, Erik P. A.
Abecasis, Goncalo
Afaq, Saima
Alizadeh, Behrooz Z.
Bertoni, Alain G.
Bonnefond, Amelie
Böttcher, Yvonne
Bottinger, Erwin P.
Campbell, Harry
Carlson, Olga D.
Chen, Chien-Hsiun
Cho, Yoon Shin
Garvey, W. Timothy
Gieger, Christian
Goodarzi, Mark O.
Grallert, Harald
Hamsten, Anders
Hartman, Catharina A.
Herder, Christian
Hsiung, Chao Agnes
Huang, Jie
Igase, Michiya
Isono, Masato
Katsuya, Tomohiro
Khor, Chiea-Chuen
Kiess, Wieland
Kohara, Katsuhiko
Kovacs, Peter
Lee, Juyoung
Lee, Wen-Jane
Lehne, Benjamin
Li, Huaixing
Liu, Jianjun
Lobbens, Stephane
Luan, Jian'an
Lyssenko, Valeriya
Meitinger, Thomas
Miki, Tetsuro
Miljkovic, Iva
Moon, Sanghoon
Mulas, Antonella
Müller, Gabriele
Müller-Nurasyid, Martina
Nagaraja, Ramaiah
Nauck, Matthias
Pankow, James S.
Polasek, Ozren
Prokopenko, Inga
Ramos, Paula S.
Rasmussen-Torvik, Laura
Rathmann, Wolfgang
Rich, Stephen S.
Robertson, Neil R.
Roden, Michael
Roussel, Ronan
Rudan, Igor
Scott, Robert A.
Scott, William R.
Sennblad, Bengt
Siscovick, David S.
Strauch, Konstantin
Sun, Liang
Swertz, Morris
Tajuddin, Salman M.
Taylor, Kent D.
Teo, Yik-Ying
Tham, Yih Chung
Tönjes, Anke
Wareham, Nicholas J.
Willemsen, Gonneke
Wilsgaard, Tom
Hingorani, Aroon D.
Egan, Josephine
Ferrucci, Luigi
Hovingh, G. Kees
Jula, Antti
Kivimaki, Mika
Kumari, Meena
Njølstad, Inger
Palmer, Colin N. A.
Serrano Ríos, Manuel
Stumvoll, Michael
Watkins, Hugh
Aung, Tin
Blüher, Matthias
Boehnke, Michael
Boomsma, Dorret I.
Bornstein, Stefan R.
Chambers, John C.
Chasman, Daniel I.
Chen, Yii-Der Ida
Chen, Yduan-Tsong
Cheng, Ching-Yu
Cucca, Francesco
de Geus, Eco J. C.
Deloukas, Panos
Evans, Michele K.
Fornage, Myriam
Friedlander, Yechiel
Froguel, Philippe
Groop, Leif
Gross, Myron D.
Harris, Tamara B.
Hayward, Caroline
Heng, Chew-Kiat
Ingelsson, Erik
Kato, Norihiro
Kim, Bong-Jo
Koh, Woon-Puay
Kooner, Jaspal S.
Körner, Antje
Kuh, Diana
Kuusisto, Johanna
Laakso, Markku
Lin, Xu
Liu, Yongmei
Loos, Ruth J. F.
Magnusson, Patrik K. E.
März, Winfried
McCarthy, Mark I.
Oldehinkel, Albertine J.
Ong, Ken K.
Pedersen, Nancy L.
Pereira, Mark A.
Peters, Annette
Ridker, Paul M.
Sabanayagam, Charumathi
Sale, Michele
Saleheen, Danish
Saltevo, Juha
Schwarz, Peter E.H.
Sheu, Wayne H. H.
Snieder, Harold
Spector, Timothy D.
Tabara, Yasuharu
Tuomilehto, Jaakko
van Dam, Rob M.
Wilson, James G.
Wilson, James F.
Wolffenbuttel, Bruce H. R.
Wong, Tien Yin
Wu, Jer-Yuarn
Yuan, Jian-Min
Zonderman, Alan B.
Soranzo, Nicole
Guo, Xiuqing
Roberts, David J.
Florez, Jose C.
Sladek, Robert
Dupuis, Josée
Morris, Andrew P.
Tai, E-Shyong
Selvin, Elizabeth
Rotter, Jerome I.
Langenberg, Claudia
Barroso, Inês
Meigs, James B.
Title Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis
Journal name PLoS Medicine   Check publisher's open access policy
ISSN 1549-1676
1549-1277
Publication date 2017-09-01
Sub-type Article (original research)
DOI 10.1371/journal.pmed.1002383
Open Access Status DOI
Volume 14
Issue 9
Start page e1002383
Publisher Public Library of Science
Language eng
Subject 2700 Medicine
Abstract Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. Methods & findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04–1.06, per HbA1c-raising allele, p = 3 × 10); whereas GS-E was not (OR = 1.00, 95% CI 0.99–1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66–0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38–0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55–0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 DK089174
UL1 TR000124
R01 HL105756
P30 DK063491
K24 DK106414
UL1 TR001881
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: Scopus Import
 
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Created: Fri, 03 Nov 2017, 16:48:48 EST