Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations

Danielle E. Haslam, Gina M. Peloso, Melanie Guirette, Fumiaki Imamura, Traci M. Bartz, Achilleas N. Pitsillides, Carol A. Wang, Ruifang Li-Gao, Jason M. Westra, Niina Pitkänen, Kristin L. Young, Mariaelisa Graff, Alexis C. Wood, Kim V.E. Braun, Jian'an Luan, Mika Kähönen, Jessica C. Kiefte-De Jong, Mohsen Ghanbari, Nathan Tintle, Rozenn N. LemaitreDennis O. Mook-Kanamori, Kari North, Mika Helminen, Yasmin Mossavar-Rahmani, Linda Snetselaar, Lisa W. Martin, Jorma S. Viikari, Wendy H. Oddy, Craig E. Pennell, Frits R. Rosendall, M. Arfan Ikram, Andre G. Uitterlinden, Bruce M. Psaty, Dariush Mozaffarian, Jerome I. Rotter, Kent D. Taylor, Terho Lehtimäki, Olli T. Raitakari, Kara A. Livingston, Trudy Voortman, Nita G. Forouhi, Nick J. Wareham, Renée De Mutsert, Steven S. Rich, Jo Ann E. Manson, Samia Mora, Paul M. Ridker, Jordi Merino, James B. Meigs, Hassan S. Dashti, Daniel I. Chasman, Alice H. Lichtenstein, Caren E. Smith, Josée Dupuis, Mark A. Herman, Nicola M. McKeown

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Abstract

Background: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia. Methods: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake. Results: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; P<0.0001), but not significantly among the lowest SSB consumers (P=0.81; PDiff<0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (β, 0.06 [95% CI, 0.02-0.09] ln-mg/dL per allele, P=0.001) but not the lowest SSB consumers (P=0.84; PDiff=0.0005). Conclusions: Our results identified genetic variants in the CHREBP locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.

Original languageEnglish
Article numberE003288
JournalCirculation: Genomic and Precision Medicine
Volume14
Issue number4
DOIs
Publication statusPublished - 1 Aug 2021

Bibliographical note

Funding Information:
This work is supported by National Institutes of Health (NIH) 5T32HL069772-15 and NIH 2T32CA009001-39 (Haslam), American Heart Association 16CSA28590003 (Haslam, McKeown, and Herman), NIH R01 DK100425 (Herman), R01 DK121710 (McKeown, Herman, Smith, and Dupuis), K08 HL112845 (Smith), USDA ARS agreement No. 58-1950-4-003 (McKeown) and 588-1950-9-001 (Lichtenstein). Infrastructure for the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium is supported in part by the National Heart, Lung, and Blood Institute grant HL105756. Please see Table I in the Data Supplement for funding sources associated with investigators and infrastructure of individual CHARGE cohorts.

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