{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:42:54Z","timestamp":1785163374706,"version":"3.55.0"},"reference-count":43,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T00:00:00Z","timestamp":1676419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,5,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Few studies have demonstrated reproducible gene\u2013diet 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\u2013glycemia 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], \u22120.013% HbA1c\/250 kcal substitution). In GDI meta-analyses, a common African ancestry\u2013enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate\u2013HbA1c association among major allele homozygotes only. Simulations revealed that &amp;gt;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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>We aimed to identify genetic modifiers of the dietary macronutrient\u2013glycemia 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\u2013enriched 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\u2013macronutrient interactions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db22-0851","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T17:00:36Z","timestamp":1676480436000},"page":"653-665","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":19,"title":["Investigating Gene\u2013Diet Interactions Impacting the Association Between Macronutrient Intake and Glycemic Traits"],"prefix":"10.2337","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7619-1868","authenticated-orcid":false,"given":"Kenneth E.","family":"Westerman","sequence":"first","affiliation":[{"name":"1Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA"},{"name":"2Department of Medicine, Harvard Medical School, Boston, MA"},{"name":"3Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura E.","family":"Walker","sequence":"additional","affiliation":[{"name":"4Department of Medicine, Section of Preventive Medicine, Boston University School of Medicine, Boston, MA"},{"name":"5Department of Health Sciences, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila M.","family":"Gaynor","sequence":"additional","affiliation":[{"name":"6Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Wessel","sequence":"additional","affiliation":[{"name":"7Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, IN"},{"name":"8Department of Medicine, Indiana University School of Medicine, Indianapolis, IN"},{"name":"9Diabetes Translational Research Center, Indiana University, Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"DiCorpo","sequence":"additional","affiliation":[{"name":"10Department of Biostatistics, Boston University School of Public Health, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiantao","family":"Ma","sequence":"additional","affiliation":[{"name":"11Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvaro","family":"Alonso","sequence":"additional","affiliation":[{"name":"12Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella","family":"Aslibekyan","sequence":"additional","affiliation":[{"name":"13University of Alabama at Birmingham, Birmingham, AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail S.","family":"Baldridge","sequence":"additional","affiliation":[{"name":"14Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain G.","family":"Bertoni","sequence":"additional","affiliation":[{"name":"15Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary L.","family":"Biggs","sequence":"additional","affiliation":[{"name":"16Department of Biostatistics, University of Washington, Seattle, WA"},{"name":"17Cardiovascular Health Research Unit, University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Brody","sequence":"additional","affiliation":[{"name":"17Cardiovascular Health Research Unit, University of Washington, Seattle, WA"},{"name":"18Department of Medicine, University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yii-Der Ida","family":"Chen","sequence":"additional","affiliation":[{"name":"19The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose\u00e9","family":"Dupuis","sequence":"additional","affiliation":[{"name":"10Department of Biostatistics, Boston University School of Public Health, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark O.","family":"Goodarzi","sequence":"additional","affiliation":[{"name":"20Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqing","family":"Guo","sequence":"additional","affiliation":[{"name":"19The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie R.","family":"Hasbani","sequence":"additional","affiliation":[{"name":"21Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Heath","sequence":"additional","affiliation":[{"name":"21Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertha","family":"Hidalgo","sequence":"additional","affiliation":[{"name":"22School of Public Health, University of Alabama at Birmingham, Birmingham, AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marguerite R.","family":"Irvin","sequence":"additional","affiliation":[{"name":"23Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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