Investigating gene-diet interactions impacting the association between macronutrient intake and glycemic traits

Kenneth E. Westerman, Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA.
Maura E. Walker, Department of Medicine, Section of Preventative Medicine, Boston University School of Medicine, Boston, MA.
Sheila M. Gaynor, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.
Jennifer Wesse, Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, IN.
Daniel DiCorpo, Department of Biostatistics, Boston University School of Public Health, Boston, MA.
Jiantao Ma, Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
Alvaro Alonso, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA.
Stella Aslibekyan, University of Alabama at Birmingham, Birmingham, AL.
Abigail S. Baldridge, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
Alain G. Bertoni, Department of Epidemiology & Prevention, Wake Forest School of Medicine, Winston-Salem, NC.
Mary L. Biggs, Department of Biostatistics, University of Washington, Seattle, WA.
Jennifer A. Brody, Cardiovascular Health Research Unit, University of Washington, Seattle, WA.
Yii-Der Ida Chen, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
Joseé Dupuis, Department of Biostatistics, Boston University School of Public Health, Boston, MA.
Mark O. Goodarzi, Department of Medicine, Division of Endocrinology Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA.
Xiuqing Guo, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
Natalie R. Hasbani, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
Adam Heath, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
Bertha Hidalgo, Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, AL.
Marguerite R. Irvin, Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.
W Craig Johnson, Department of Biostatistics, University of Washington, Seattle, WA.
Rita R. Kalyani, GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD.
Leslie Lange, Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO.
Rozenn N. Lemaitre, Cardiovascular Health Research Unit, University of Washington, Seattle, WA.
Ching-Ti Liu, Department of Biostatistics, Boston University School of Public Health, Boston, MA.
Simin Liu, Center for Global Cardiometabolic Health (CGCH), Boston, MA.
Jee-Young Moon, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.
Rami Nassir, Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia.
James S. Pankow, Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.
Mary Pettinger, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
Laura Raffield, Department of Genetics, University of North Carolina, Chapel Hill, NC.
Laura J. Rasmussen-Torvik, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.

Document Type

Journal Article

Publication Date

2-15-2023

Journal

Diabetes

DOI

10.2337/db22-0851

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 N=33,187 diabetes-free participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) 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 hemoglobin A1c [HbA1c], -0.013 %HbA1c per 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 over 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.

Department

Exercise and Nutrition Sciences

Link to Full Text

Share

COinS