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

Authors: MCKEOWN, NICOLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; DASHTI, HASSAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MA, JIANTAO - National Heart, Lung And Blood Institute(NHLBI, NIH); HASLAM, DANIELLE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KIEFTE-DE JONG, JESSICA - Erasmus University; SMITH, CAREN - Massachusetts General Hospital; TANAKA, TOSHIKO - National Institute On Aging (NIA, NIH); GRAFF, MARIAELISA - University Of North Carolina; LEMAITRE, ROZENN - University Of Washington; RYBIN, DENIS - Boston University; SONESTEDT, EMILY - Lund University; FRAZIER-WOOD, ALEXIS - Baylor University; MOOK-KANAMORI, DENNIS - Leiden University; LI, YANPING - Harvard University; WANG, CAROL - University Of Western Australia; LEERMAKERS, ELISABETH - Erasmus University; MIKKILA, VERA - University Of Turku; YOUNG, KRISTIN - University Of North Carolina; MUKAMAL, KENNETH - Harvard University; CUPPLES, L - Boston University; SCHULZ, CHRISTINA - Lund University; CHEN, TZU-AN - Baylor University; LI-GAO, RUIFANG - Leiden University; HUANG, TAO - Harvard University; ODDY, WENDY - Telethon Kids Institute; RAITAKARI, OLLI - University Of Turku; RICE, KENNETH - University Of Washington; MEIGS, JAMES - Massachusetts General Hospital; ERICSON, ULRIKA - Lund University; STEFFEN, LYN - University Of Minnesota; ROSENDAAL, FRITS - Leiden University; HOFMAN, ALBERT - Erasmus University; KAHONEN, MIKA - University Of Tampere Medical School; PSATY, BRUCE - University Of Washington; BRUNKWALL, LOUISE - Lund University; UITTERLINDEN, ANDRE - Erasmus University; VIIKARI, JORMA - University Of Turku; SISCOVICK, DAVID - New York Academy Of Medicine; SEPPALA, ILKKA - University Of Tampere Medical School; NORTH, KARI - University Of North Carolina; MOZAFFARIAN, DARIUSH - Tufts University; DUPIUS, JOSEE - Boston University; ORHO-MELANDER, MARJU - Lund University; RICH, STEPHEN - University Of Virginia; DE MUTSERT, RENEE - Leiden University; QI, LU - Harvard University; PENNELL, CRAIG - University Of Western Australia; FRANCO, OSCAR - Erasmus University; LEHTIMAKI, TERHO - University Of Tampere Medical School; HERMAN, MARK - Duke University

Submitted to: Diabetologia
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/29/2017
Publication Date: 11/2/2017
Citation: McKeown, N.M., Dashti, H.S., Ma, J., Haslam, D., Kiefte-De Jong, J.C., Smith, C.E., Tanaka, T., Graff, M., Lemaitre, R.N., Rybin, D., Sonestedt, E., Frazier-Wood, A., Mook-Kanamori, D.O., Li, Y., Wang, C.A., Leermakers, E.T., Mikkila, V., Young, K.L., Mukamal, K.J., Cupples, L.A., Schulz, C.A., Chen, T., Li-Gao, R., Huang, T., Oddy, W.H., Raitakari, O., Rice, K., Meigs, J., Ericson, U., Steffen, L., Rosendaal, F.R., Hofman, A., Kahonen, M., Psaty, B.M., Brunkwall, L., Uitterlinden, A.G., Viikari, J., Siscovick, D.S., Seppala, I., North, K.E., Mozaffarian, D., Dupius, J., Orho-Melander, M., Rich, S.S., De Mutsert, R., Qi, L., Pennell, C.E., Franco, O.H., Lehtimaki, T., Herman, M. 2017. 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. Diabetologia. https://doi.org/10.1007/s00125-017-4475-0.
DOI: https://doi.org/10.1007/s00125-017-4475-0

Interpretive Summary: Evidence suggests that sugar-sweetened beverage (SSB) intake is associated with increased risk of metabolic syndrome and type 2 diabetes (T2D) and may contribute to weight gain in humans. Given that SSBs are a major part of some individuals' diets, the adverse consequences of excess intake may be important for public health. A few studies have linked SSB intake to increased fasting glucose and insulin levels, yet the influence of genetic variation on these associations is unknown. In this study, we were interested in looking at how dietary intake of SSBs, such as soda and fruit-flavored drinks, may be related to fasting glucose and insulin levels in 11 cohorts within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. We also considered the fact that everyone has a unique set of genes that may be related to how the SSBs are broken down in the body. To look at these effects, we chose to also look at a number of genes that have been shown to influence the breakdown of sugars in the liver (within the CHREBP-FGF21 pathway.) We looked at how variations in these genes could change the way consumption of SSBs is related to fasting glucose and insulin levels in different individuals. In this large meta-analysis of many observational studies, we observed that SSB intake was significantly associated with higher fasting glucose and insulin levels, even after adjustment for age, sex, energy intake, BMI, and other dietary covariates. Although a suggestive interaction with a genetic variant in the CHREBP-FGF21 pathway was observed in the discovery cohorts (6 cohorts,) this observation was not confirmed in the replication analysis (5 cohorts.)

Technical Abstract: Aims & Hypothesis: Sugar sweetened beverages 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 hypothesize that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to regulate glycemic traits, and in particular that risk allele single nucleotide polymorphisms (SNPs) may exacerbate positive associations between higher SSB intake and glycemic traits. Methods: Data from 11 cohorts (6 discovery and 5 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 (sodas, fruit punches, lemonades, or other fruit drinks) was derived from food frequency questionnaires (FFQs) and food diaries. In fixed-effects meta-analyses, we quantified 1) associations between SSBs and glycemic traits (fasting glucose (FG) and fasting insulin (FI)), and 2) interactions between SSBs and 18 independent SNPs related to the CHREBP-FGF21 pathway. Results: In our joint 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 FG [0.014 +/- 0.004 (mmol/L), P =1.5E-03] and higher FI [beta +/- SE = 0.031 +/- 0.008 (ln-pmol/L), P =8.0E-04]. No significant interactions on glycemic 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 beta-klotho (KLB) locus on FI (beta +/-SE = 0.030+/-0.011 ln-pmol/L, uncorrected P =0.006), results in the replication cohorts were non-significant. Conclusion: In this large meta-analysis, we observed that SSB intake was associated with higher FG and FI. 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. Further examination of the burden of common and rare variants in this pathway may be warranted.