Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis

Research output: Contribution to journalArticle


Aims/hypothesis: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. Methods: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. Results: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10−3) and higher fasting insulin (0.030 ± 0.005 [loge pmol/l], p = 2.0 × 10−10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 loge pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant. Conclusions/interpretation: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis. Trial registration: Trials related to this study were registered at clinicaltrials.govas NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses’ Health Study).


  • Nicola M. McKeown
  • Hassan S. Dashti
  • Jiantao Ma
  • Danielle E. Haslam
  • Jessica C. Kiefte-de Jong
  • Caren E. Smith
  • Toshiko Tanaka
  • Mariaelisa Graff
  • Rozenn N. Lemaitre
  • Denis Rybin
  • Alexis C. Frazier-Wood
  • Dennis O. Mook-Kanamori
  • Yanping Li
  • Carol A. Wang
  • Elisabeth T.M. Leermakers
  • Vera Mikkilä
  • Kristin L. Young
  • Kenneth J. Mukamal
  • L. Adrienne Cupples
  • Tzu An Chen
  • Ruifang Li-Gao
  • Tao Huang
  • Wendy H. Oddy
  • Olli Raitakari
  • Kenneth Rice
  • James B. Meigs
  • Lyn M. Steffen
  • Frits R. Rosendaal
  • Albert Hofman
  • Mika Kähönen
  • Bruce M. Psaty
  • Andre G. Uitterlinden
  • Jorma Viikari
  • David S. Siscovick
  • Ilkka Seppälä
  • Kari E. North
  • Dariush Mozaffarian
  • Josée Dupuis
  • Stephen S. Rich
  • Renée de Mutsert
  • Lu Qi
  • Craig E. Pennell
  • Oscar H. Franco
  • Terho Lehtimäki
  • Mark A. Herman
External organisations
  • Massachusetts General Hospital
  • Broad Institute
  • Erasmus University Medical Center
  • Leiden University
  • National Institute on Aging, United States
  • University of North Carolina
  • University of Washington
  • Boston University
  • Baylor College of Medicine
  • Leiden University Medical Centre
  • Harvard University
  • University of Western Australia, Crawley
  • University of Turku
  • University of Helsinki
  • Beth Israel Deaconess Medical Center
  • Telethon Kids Institute
  • University of Tasmania
  • Turku University Hospital
  • Harvard Medical School
  • University of Minnesota system
  • Tampere University Hospital
  • New York Academy of Medicine
  • University of Tampere
  • Tufts University
  • University of Virginia
  • Duke University
  • National Heart Lung and Blood Institute
  • Kaiser Permanente Research Institute
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
  • Nutrition and Dietetics


  • Carbohydrate metabolism, Epidemiology, Genetics, Meta-analysis, Nutrition, Type 2 diabetes
Original languageEnglish
Pages (from-to)317-330
Issue number2
Early online date2017 Nov 2
Publication statusPublished - 2018 Feb
Publication categoryResearch

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