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.

Authors:
Saima Afaq
Saima Afaq
Institute of Public health and Social Sciences, Khyber medical university Peshawar Pakistan
Dr
Peshawar, KPK | Pakistan
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 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

PLoS Med 2017 Sep 12;14(9):e1002383. Epub 2017 Sep 12.

Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, United States of America.

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 × 10-29); 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.

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.

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Source
http://dx.doi.org/10.1371/journal.pmed.1002383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595282PMC
September 2017
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