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Associations Between Genetic Variants near the CHREBP Locus and Lipoprotein Concentrations May Be Modified by Sugar-Sweetened Beverage Consumption

ABSTRACT: Abstract Objectives Carbohydrate responsive element binding protein (ChREBP) is a transcription factor that responds to sugar consumption. Consumption of sugar-sweetened beverages (SSB) and genetic variants at the CHREBP (also known as MLXIPL) locus have separately been linked to dyslipidemia. We hypothesized that SSB intake may modify the associations between CHREBP variants and HDL-C and TG concentrations. Methods We conducted a cross-sectional analysis of data from 11 Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium cohorts (N = 63,599). A total of 1606 single-nucleotide polymorphisms (SNPs) were selected within or near the CHREBP locus. SSB intake (sodas, fruit punches, lemonades, or other fruit drinks) was estimated from food-frequency questionnaires. Participants were grouped by five categories of SSB intake (ranging from < 1 serving/month to > 1 serving/day). Inverse-variance weighted fixed- and random-effect meta-analyses were used to quantify the following associations: 1) SSB consumption and HDL-C and TG concentrations; 2) selected SNPs and HDL-C and TG concentrations; and 3) interactions between SSB consumption and selected SNPs, and HDL-C and TG concentrations. Results were corrected for multiple testing to achieve a global p < 0.05. Results SSB intake was inversely associated with HDL-C and positively associated with TG concentrations (ptrend < 0.0001). We replicated previously observed GWAS associations between one distinct SNP on HDL-C (rs71556736) and two distinct SNPs (rs71556736 and rs13225660) on TG concentrations (Bonferroni-corrected P < 0.0001). Additionally, we identified two distinct novel SNP associations with TG concentrations (rs42124 and rs10245965). One distinct SNP displayed a statistically significant difference in effect size by category of SSB intake with HDL-C, where each additional minor allele at rs71556729 was significantly associated with HDL-C concentrations only among the highest SSB consumers [>1 serving/day: ? (SE) = 4.47 (1.10) mg/dl, P = 5.0E-05; pinteract = 0.0001]. Additional SNPs displayed a suggestive difference in effect size for both HDL-C and TG concentrations. Conclusions Our results indicate that high SSB consumption may modify the association between genetic variants within or near the CHREBP locus and HDL-C and TG concentrations. Funding Sources NIH, AHA, USDA-ARS.

SUBMITTER: Haslam D

PROVIDER: S-EPMC7257881 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Project description:Abstract Objectives A meta-analysis of 11 CHARGE cohorts (N = 63,599) suggested that genetic variants within or near the CHREBP locus may modify the associations between sugar sweetened beverage (SSB) consumption and high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations. The study objective was to replicate these findings in a large independent cohort. Methods Blood lipids and 24-hour recalls were available for 57,794 adults of European ancestry in the UK Biobank (2006-‘10). SSBs included “squash” and “fizzy” drinks derived from a single 24-hr recall. A total of 875 SNPs within or near the CHREBP locus were identified and included in this analysis. Associations between these SNPs and HDL-C and TG concentrations were quantified among participants who did not report SSB consumption (non-consumers, n = 45,866), reported ≥0.5 servings/day of SSB (consumers, n = 11,928), and a subset of consumers who reported ≥2 servings/day of SSB (high consumers, n = 3742). Interaction between SSB and selected SNPs on HDL-C and TG concentrations was evaluated by examining the difference in beta coefficients between strata. Results were considered statistically significant at a Bonferroni-corrected pinteract < 0.0001 (0.05/499 effective tests). Results A significant interaction between SSB consumption and TBL2-rs71556729 on HDL-C concentration previously observed in the meta-analysis was replicated in UK Biobank. However, we observed a stronger interaction for a SNP in high linkage disequilibrium (R2 = 0.93) FZD9-rs34821369 (MAF = 0.03, pinteract = 8.2E-05) with TBL2-rs71556729 (MAF = 0.03, pinteract = 0.0004). Among only SSB consumers, each additional minor G allele at FZD9-rs34821369 was associated with mean HDL-C concentrations 1.63 mg/dL (SE = 0.53, P = 0.002) higher than those with the major T allele. Conclusions Our results suggest that adults with the minor allele at FZD9-rs34821369 may be protected against SSB-induced low HDL-C concentrations. These results are consistent the findings from a prior meta-analysis of 11 cohorts. Funding Sources NIH, AHA, USDA-ARS. This research has been conducted using the UK Biobank Resource (Application Number 35,835).

Project description: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 (? ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10-3) and higher fasting insulin (0.030 ± 0.005 [log e 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 ?-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 log e 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.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses' Health Study).

Project description:BackgroundCeramides have been implicated in the pathogenesis of type 2 diabetes and cardiovascular disease. Limited data exist on how habitual dietary intake of foods that can alter hepatic lipid metabolism may influence circulating ceramide concentrations.ObjectivesWe investigated the cross-sectional association of cumulative sugar-sweetened beverage (SSB) consumption with concentrations of 3 circulating ceramides and ceramide ratios.MethodsWe examined participants from the Framingham Heart Study's Offspring Cohort who had 3 ceramides measured (n = 1561, mean age 66 y, 59% women). SSB consumption was measured 4 times over ∼14 y. Participants were categorized by cumulative SSB intake as nonconsumers (0 to <1 SSB serving/mo) and occasional (1 SSB serving/mo to <1 serving/wk), frequent (1 SSB serving/wk to <1 serving/d), and daily (≥1 SSB serving/d) consumers. Multivariable linear regression models were used to relate cumulative SSB consumption (independent variable) to blood concentrations of ceramides (C16:0, C22:0, and C24:0) and ceramide ratios (C22:0/C16:0 and C24:0/C16:0).ResultsIn adjusted models, more frequent cumulative SSB consumption was positively associated with concentrations of the C16:0 and C22:0 ceramides (Ptrend < 0.05). Compared with nonconsumers, daily consumers had 0.01 μg/mL (95% CI: 0.002, 0.017 µg/mL) and 0.06 µg/mL (95% CI: 0.018, 0.092 µg/mL) higher mean concentrations of the C16:0 and C22:0 ceramides, respectively. Results were consistent when modeling continuous cumulative SSB consumption per 1 serving/d. We observed effect modification by diabetes status in the relation between cumulative SSB consumption and concentrations of the C24:0 ceramide (Pinteraction = 0.014). In a stratified analysis, more frequent cumulative SSB consumption was positively associated with concentrations of the C24:0 ceramide only in individuals with prediabetes or diabetes (Ptrend = 0.001).ConclusionsOur study raises the possibility that higher concentrations of distinct ceramide species, previously associated with adverse metabolic health, may be one mechanism by which SSB consumption contributes to higher risk of cardiometabolic diseases.

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Associations Between Genetic Variants near the CHREBP Locus and Lipoprotein Concentrations May Be Modified by Sugar-Sweetened Beverage Consumption

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