Investigating Gene–Diet Interactions Impacting the Association Between Macronutrient Intake and Glycemic Traits

Author:

Westerman Kenneth E.123ORCID,Walker Maura E.45,Gaynor Sheila M.6,Wessel Jennifer789,DiCorpo Daniel10,Ma Jiantao11,Alonso Alvaro12,Aslibekyan Stella13,Baldridge Abigail S.14,Bertoni Alain G.15,Biggs Mary L.1617,Brody Jennifer A.1718,Chen Yii-Der Ida19,Dupuis Joseé10,Goodarzi Mark O.20,Guo Xiuqing19,Hasbani Natalie R.21,Heath Adam21,Hidalgo Bertha22,Irvin Marguerite R.23,Johnson W. Craig16,Kalyani Rita R.24,Lange Leslie25,Lemaitre Rozenn N.1726,Liu Ching-Ti10272829,Liu Simin30,Moon Jee-Young31,Nassir Rami32,Pankow James S.33,Pettinger Mary34,Raffield Laura M.35,Rasmussen-Torvik Laura J.14,Selvin Elizabeth36,Senn Mackenzie K.37,Shadyab Aladdin H.38,Smith Albert V.39,Smith Nicholas L.404142,Steffen Lyn33,Talegakwar Sameera43,Taylor Kent D.19,de Vries Paul S.21,Wilson James G.44,Wood Alexis C.37,Yanek Lisa R.24,Yao Jie19,Zheng Yinan14,Boerwinkle Eric2145,Morrison Alanna C.21,Fornage Miriam21,Russell Tracy P.46,Psaty Bruce M.17184047,Levy Daniel2748,Heard-Costa Nancy L.2749,Ramachandran Vasan S.272829,Mathias Rasika A.24,Arnett Donna K.50,Kaplan Robert51,North Kari E.52,Correa Adolfo53,Carson April54,Rotter Jerome I.19,Rich Stephen S.55,Manson JoAnn E.2,Reiner Alexander P.40,Kooperberg Charles34,Florez Jose C.235657,Meigs James B.2358,Merino Jordi235657,Tobias Deirdre K.5960,Chen Han2161,Manning Alisa K.123

Affiliation:

1. 1Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA

2. 2Department of Medicine, Harvard Medical School, Boston, MA

3. 3Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA

4. 4Department of Medicine, Section of Preventive Medicine, Boston University School of Medicine, Boston, MA

5. 5Department of Health Sciences, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, MA

6. 6Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA

7. 7Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, IN

8. 8Department of Medicine, Indiana University School of Medicine, Indianapolis, IN

9. 9Diabetes Translational Research Center, Indiana University, Indianapolis, IN

10. 10Department of Biostatistics, Boston University School of Public Health, Boston, MA

11. 11Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA

12. 12Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA

13. 13University of Alabama at Birmingham, Birmingham, AL

14. 14Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL

15. 15Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC

16. 16Department of Biostatistics, University of Washington, Seattle, WA

17. 17Cardiovascular Health Research Unit, University of Washington, Seattle, WA

18. 18Department of Medicine, University of Washington, Seattle, WA

19. 19The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA

20. 20Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA

21. 21Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX

22. 22School of Public Health, University of Alabama at Birmingham, Birmingham, AL

23. 23Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL

24. 24GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD

25. 25Department of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, CO

26. 26Department of Internal Medicine, University of Washington, Seattle, WA

27. 27National Heart, Lung, and Blood Institute and Boston University’s Framingham Heart Study, Framingham, MA

28. 28Evans Department of Medicine, Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, MA

29. 29Evans Department of Medicine, Whitaker Cardiovascular Institute and Cardiology Section, Boston University School of Medicine, Boston, MA

30. 30Center for Global Cardiometabolic Health, Boston, MA

31. 31Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY

32. 32Department of Pathology, School of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia

33. 33Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN

34. 34Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA

35. 35Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC

36. 36Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

37. 37USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX

38. 38Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA

39. 39Department of Biostatistics, University of Michigan, Ann Arbor, MI

40. 40Department of Epidemiology, University of Washington, Seattle, WA

41. 41Kaiser Permanente Washington Health Research Institute, Seattle, WA

42. 42Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, WA

43. 43Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, The George Washington University, Washington, DC

44. 44Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA

45. 45Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX

46. 46Department of Pathology and Laboratory Medicine, University of Vermont Larner College of Medicine, Burlington, VT

47. 47Department of Health Systems and Population Health, University of Washington, Seattle, WA

48. 48Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD

49. 49Department of Neurology, Boston University School of Medicine, Boston, MA

50. 50College of Public Health, University of Kentucky, Lexington, KY

51. 51Clinical Excellence Research Center, School of Medicine, Stanford University, Stanford, CA

52. 52Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC

53. 53Department of Population Health Science, University of Mississippi Medical Center, Jackson, MS

54. 54Department of Medicine, University of Mississippi Medical Center, Jackson, MS

55. 55Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA

56. 56Diabetes Unit, Massachusetts General Hospital, Boston, MA

57. 57Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA

58. 58Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA

59. 59Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

60. 60Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA

61. 61Center for Precision Health, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX

Abstract

Few studies have demonstrated reproducible gene–diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient–glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate had modestly lower glycemic trait values (e.g., for glycated hemoglobin [HbA1c], −0.013% HbA1c/250 kcal substitution). In GDI meta-analyses, a common African ancestry–enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate–HbA1c association among major allele homozygotes only. Simulations revealed that >150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error. These results generate hypotheses for further exploration of modifiable metabolic disease risk in additional cohorts with African ancestry. Article Highlights We aimed to identify genetic modifiers of the dietary macronutrient–glycemia relationship using whole-genome sequence data from 10 Trans-Omics for Precision Medicine program cohorts. Substitution models indicated a modest reduction in glycemia associated with an increase in dietary carbohydrate at the expense of fat. Genome-wide interaction analysis identified one African ancestry–enriched variant near the FRAS1 gene that may interact with macronutrient intake to influence hemoglobin A1c. Simulation-based power calculations accounting for measurement error suggested that substantially larger sample sizes may be necessary to discover further gene–macronutrient interactions.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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