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Chemical and Physical Biology Program

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

Wheeler E , Leong A , Liu CT , Hivert MF , Strawbridge RJ , Podmore C , Li M , Yao J , Sim X , Hong J , Chu AY , Zhang W , Wang X , Chen P , Maruthur NM , Porneala BC , Sharp SJ , Jia Y , Kabagambe EK , Chang LC , Chen WM , Elks CE , Evans DS , Fan Q , Giulianini F , Go MJ , Hottenga JJ , Hu Y , Jackson AU , Kanoni S , Kim YJ , Kleber ME , Ladenvall C , Lecoeur C , Lim SH , Lu Y , Mahajan A , Marzi C , Nalls MA , Navarro P , Nolte IM , Rose LM , Rybin DV , Sanna S , Shi Y , Stram DO , Takeuchi F , Tan SP , van der Most PJ , Van Vliet-Ostaptchouk JV , Wong A , Yengo L , Zhao W , Goel A , Martinez Larrad MT , Radke D , Salo P , Tanaka T , van Iperen EPA , Abecasis G , Afaq S , Alizadeh BZ , Bertoni AG , Bonnefond A , Böttcher Y , Bottinger EP , Campbell H , Carlson OD , Chen CH , Cho YS , Garvey WT , Gieger C , Goodarzi MO , Grallert H , Hamsten A , Hartman CA , Herder C , Hsiung CA , Huang J , Igase M , Isono M , Katsuya T , Khor CC , Kiess W , Kohara K , Kovacs P , Lee J , Lee WJ , Lehne B , Li H , Liu J , Lobbens S , Luan J , Lyssenko V , Meitinger T , Miki T , Miljkovic I , Moon S , Mulas A , Müller G , Müller-Nurasyid M , Nagaraja R , Nauck M , Pankow JS , Polasek O , Prokopenko I , Ramos PS , Rasmussen-Torvik L , Rathmann W , Rich SS , Robertson NR , Roden M , Roussel R , Rudan I , Scott RA , Scott WR , Sennblad B , Siscovick DS , Strauch K , Sun L , Swertz M , Tajuddin SM , Taylor KD , Teo YY , Tham YC , Tönjes A , Wareham NJ , Willemsen G , Wilsgaard T , Hingorani AD , , , , Egan J , Ferrucci L , Hovingh GK , Jula A , Kivimaki M , Kumari M , Njølstad I , Palmer CNA , Serrano Ríos M , Stumvoll M , Watkins H , Aung T , Blüher M , Boehnke M , Boomsma DI , Bornstein SR , Chambers JC , Chasman DI , Chen YI , Chen YT , Cheng CY , Cucca F , de Geus EJC , Deloukas P , Evans MK , Fornage M , Friedlander Y , Froguel P , Groop L , Gross MD , Harris TB , Hayward C , Heng CK , Ingelsson E , Kato N , Kim BJ , Koh WP , Kooner JS , Körner A , Kuh D , Kuusisto J , Laakso M , Lin X , Liu Y , Loos RJF , Magnusson PKE , März W , McCarthy MI , Oldehinkel AJ , Ong KK , Pedersen NL , Pereira MA , Peters A , Ridker PM , Sabanayagam C , Sale M , Saleheen D , Saltevo J , Schwarz PE , Sheu WHH , Snieder H , Spector TD , Tabara Y , Tuomilehto J , van Dam RM , Wilson JG , Wilson JF , Wolffenbuttel BHR , Wong TY , Wu JY , Yuan JM , Zonderman AB , Soranzo N , Guo X , Roberts DJ , Florez JC , Sladek R , Dupuis J , Morris AP , Tai ES , Selvin E , Rotter JI , Langenberg C , Barroso I , Meigs JB , . PLoS medicine. 2017 9 ; 14(9). e1002383

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.

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.