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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

Overview of attention for article published in PLOS Medicine, September 2017
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  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (97th percentile)
  • Good Attention Score compared to outputs of the same age and source (74th percentile)

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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
Published in
PLOS Medicine, September 2017
DOI 10.1371/journal.pmed.1002383
Pubmed ID
Authors

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

Abstract

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. 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 × 10-29); 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. 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.

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Geographical breakdown

Country Count As %
Unknown 507 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 82 16%
Student > Master 62 12%
Student > Ph. D. Student 52 10%
Student > Bachelor 43 8%
Student > Postgraduate 25 5%
Other 99 20%
Unknown 144 28%
Readers by discipline Count As %
Medicine and Dentistry 120 24%
Biochemistry, Genetics and Molecular Biology 59 12%
Agricultural and Biological Sciences 34 7%
Nursing and Health Professions 25 5%
Psychology 12 2%
Other 79 16%
Unknown 178 35%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 110. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 March 2021.
All research outputs
#379,963
of 25,382,440 outputs
Outputs from PLOS Medicine
#663
of 5,161 outputs
Outputs of similar age
#8,070
of 323,484 outputs
Outputs of similar age from PLOS Medicine
#13
of 50 outputs
Altmetric has tracked 25,382,440 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 98th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 5,161 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 77.7. This one has done well, scoring higher than 87% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 323,484 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 97% of its contemporaries.
We're also able to compare this research output to 50 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 74% of its contemporaries.