Marie-France Hivert1,2,3, Costas A Christophi4, Kathleen A Jablonski4, Sharon L Edelstein4, Steven E Kahn5, Sherita Hill Golden6, Samuel Dagogo-Jack7, Kieren J Mather8, José A Luchsinger9, A Enrique Caballero10, Elizabeth Barrett-Connor11, William C Knowler12, Jose C Florez2,13,14, William H Herman15. 1. Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, Massachusetts. 2. Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. 3. Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada. 4. The Biostatistics Center, George Washington University, Rockville, Maryland. 5. Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington. 6. Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism and Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland. 7. Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, The University of Tennessee Health Science Center, Memphis, Tennessee. 8. Indiana University School of Medicine, Indianapolis, Indiana. 9. Departments of Medicine and Epidemiology, Columbia University Medical Center, New York, New York. 10. Harvard Medical School, Boston, Massachusetts. 11. Department of Family Medicine and Public Health, UC San Diego, La Jolla, California. 12. Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona. 13. Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts. 14. Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, Massachusetts. 15. Departments of Internal Medicine and Epidemiology, University of Michigan, Ann Arbor, Michigan.
Abstract
Purpose: HbA1c levels are higher in blacks than non-Hispanic whites (NHWs). We investigated whether genetics could explain this difference in Diabetes Prevention Program (DPP) participants. Methods: We tested (i) genetic variants causing hemoglobinopathies, (ii) a genetic risk score (GRS) based on 60 variants associated with HbA1c from genome-wide association meta-analysis, and (iii) principal component (PC) factors that capture continental ancestry derived from genetic markers distributed across the genome. Results: Of 2658 eligible DPP participants, 537 (20%) self-identified as black and 1476 (56%) as NHW. Despite comparable fasting and 2-hour glucose levels, blacks had higher HbA1c (mean ± SD = 6.2 ± 0.6%) compared with NHWs (5.8 ± 0.4%; P < 0.001). In blacks, the genetic variant causing sickle cell trait was associated with higher HbA1c [β (SE) = +0.44 (0.08)%; P = 2.1 × 10-4]. The GRS was associated with HbA1c in both blacks and NHWs. Self-identified blacks were distributed along the first PC axis, as expected in mixed ancestry populations. The first PC explained 60% of the 0.4% difference in HbA1c between blacks and NHWs, whereas the sickle cell variant explained 16% and GRS explained 14%. Conclusions: A large proportion of HbA1c difference between blacks and NHWs was associated with the first PC factor, suggesting that unidentified genetic markers influence HbA1c in blacks in addition to nongenetic factors.
Purpose: HbA1c levels are higher in blacks than non-Hispanic whites (NHWs). We investigated whether genetics could explain this difference in Diabetes Prevention Program (DPP) participants. Methods: We tested (i) genetic variants causing hemoglobinopathies, (ii) a genetic risk score (GRS) based on 60 variants associated with HbA1c from genome-wide association meta-analysis, and (iii) principal component (PC) factors that capture continental ancestry derived from genetic markers distributed across the genome. Results: Of 2658 eligible DPPparticipants, 537 (20%) self-identified as black and 1476 (56%) as NHW. Despite comparable fasting and 2-hour glucose levels, blacks had higher HbA1c (mean ± SD = 6.2 ± 0.6%) compared with NHWs (5.8 ± 0.4%; P < 0.001). In blacks, the genetic variant causing sickle cell trait was associated with higher HbA1c [β (SE) = +0.44 (0.08)%; P = 2.1 × 10-4]. The GRS was associated with HbA1c in both blacks and NHWs. Self-identified blacks were distributed along the first PC axis, as expected in mixed ancestry populations. The first PC explained 60% of the 0.4% difference in HbA1c between blacks and NHWs, whereas the sickle cell variant explained 16% and GRS explained 14%. Conclusions: A large proportion of HbA1c difference between blacks and NHWs was associated with the first PC factor, suggesting that unidentified genetic markers influence HbA1c in blacks in addition to nongenetic factors.
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