Interactions Between Sugar-Sweetened Beverage Consumption and Genetic Variants in the CHREBP Locus on Risk of Dyslipidemia in Adults
Haslam, Danielle.
2019
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Background: High
sugar-sweetened beverage (SSB) consumption has been linked to a variety of
cardiometabolic disorders, including cardiovascular disease, type 2 diabetes, metabolic
syndrome, and non-alcoholic fatty liver disease. Dyslipidemia, a condition which is
traditionally characterized by high triglyceride (TG), high low-density lipoprotein
cholesterol (LDL-C) and/or low high-density ... read morelipoprotein cholesterol (HDL-C)
concentrations, is a common risk factor shared by these conditions. The effect of SSB
consumption on dyslipidemia is variable, and genetic susceptibility to dyslipidemia may
be modified by SSB consumption. Data from animal models have indicated that
carbohydrate-responsive element binding protein (CHREBP) expression is altered by sugar
consumption, while in observational studies, genetic variants within or near CHREBP
(also known as MLXIPL) have been associated with TG and HDL-C concentrations. This
evidence suggests that CHREBP is a promising candidate for population-based gene-SSB
interaction on TG and HDL-C concentrations. Aims: The aims of this study were to examine
the (1) association between SSB consumption and lipoprotein profiles, apolipoprotein
(apo), and lipoprotein particle size concentrations; (2) longitudinal association
between SSB, 100% fruit juice (FJ) and low-calorie sweetened beverage (LCSB) consumption
and 4-year changes in plasma lipoprotein concentrations and incident dyslipidemia; and
(3) interactions between SSB consumption and 1,606 selected single nucleotide
polymorphisms (SNPs) within or near CHREBP on HDL-C and TG concentrations. Methods: This
study utilized data from the Framingham Heart Study (FHS) (n=6,730) and Women's Genome
Health Study (WGHS) (n=21,794), as well as aggregated data from 11 cohorts who are part
of the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Nutrition
Working Group (n=63,599). Dietary intakes were estimated from food-frequency
questionnaires, and participants were grouped by category of beverage consumption (<1
serving/month, 1-4 serving/month, 1-2 serving/week, 3-7 serving/week, >1
serving/day). In Aim 1, linear regression models were applied to investigate the
association between SSB consumption and plasma cholesterol (LDL-C, HDL-C, non-HDL-C,
remnant-like particle [RLP]-C), TG (total TG, RLP-TG), and apolipoproteins (apo B, apo
A1, apo E, and apo C3) concentrations, and total cholesterol:HDL-C and apo B:apo A1
ratios among FHS and WGHS participants. Associations between SSB consumption and
lipoprotein particle sizes were also explored through measures of mean lipoprotein
particle size and lipoprotein particle size concentrations [triglyceride-rich
lipoprotein particles (TRL-P): very large, large, medium, small, and very small;
LDL-particles (LDL-P): large, medium, and small; HDL-particles (HDL-P): large, medium,
and small] in linear regression models. In Aim 2, mixed-effect linear regression models
were used to examine the association between SSB, FJ, and LCSB consumption and 4-year
changes in plasma lipid concentrations (LDL-C, HDL-C, TG, and non-HDL-C) and Cox
proportional hazard models were used to estimate hazard ratios (HR) for incident
dyslipidemia across categories of SSB, FJ and LCSB consumption among FHS participants.
In Aim 3, inverse-variance weighted fixed- and random-effect meta-analyses were used to
quantify the following cross-sectional associations using data from 11 CHARGE consortium
cohorts: 1) SSB consumption and HDL-C and TG concentrations; 2) selected SNPs (within or
near CHREBP) and HDL-C and TG concentrations; and 3) interactions between SSB
consumption and selected SNPs, and HDL-C and TG concentrations. Results: Aim 1: SSB
consumption was positively associated with LDL-C, apo B, TG, apo C3, RLP-TG, RLP-C and
non-HDL-cholesterol concentrations, and total:HDL cholesterol and apo B: apo A1 ratios,
and negatively associated with HDL-C and apoA1 concentrations (ptrend ranges from
<0.0001 to 0.008). After further adjustment for traditional lipoprotein measures
(LDL-C, HDL-C, or TG), high SSB consumers had smaller LDL-P and HDL-P size, lower
concentrations of large LDL-P and medium HDL-P, and higher concentrations of small
LDL-P, small HDL-P and large TRL-P (ptrend ranges from <0.0001 to 0.002). Aim 2:
Among FHS participants, participants in the highest category of SSB intake (>1
serving/day) had smaller mean 4-year changes in HDL-C [highest (>1 serving/day) vs.
lowest consumption category (<1 serving/month) (H vs. L): ± SE: -1.0
± 0.3 mg/dl, ptrend = 0.0001] and greater mean 4-year changes in TG (H vs. L:
± SE: 5.6 ± 2.1 mg/dl, ptrend = 0.0004), along with a higher
incidence of low HDL-C [H vs. L HR (95% CI): 1.98 (1.20-3.28); ptrend = 0.01)] and high
TG [HR (95% CI): 1.53 (1.01-2.31); p=0.05; ptrend = 0.004)] compared to those in the
lowest category of SSB intake (<1 serving/month). LCSB consumption was associated
with a higher incidence of high non-HDL-C [H vs. L HR (95% CI): 1.40 (1.17-1.69); ptrend
= 0.0002)]. No other significant associations between beverage consumption and lipids
were observed. Aim 3: In meta-analyses of CHARGE consortium cohorts, SSB consumption was
inversely associated with HDL-C and positively associated with TG concentrations (ptrend
<0.0001). We replicated previously observed GWAS associations between one SNP on
HDL-C and two distinct SNPs on TG concentrations (Bonferroni-corrected p<0.0001).
Additionally, we identified two distinct novel SNP associations with TG concentrations
(FZD9-rs42124 and VPS37D-rs10245965). One distinct SNP displayed a statistically
significant difference in effect by category of SSB consumption on HDL-C (TBL2-
rs71556729), and additional SNPs displayed a suggestive difference for both HDL-C and TG
concentrations. Conclusions: Higher consumption of SSB was adversely associated with
multiple measures of plasma lipoprotein concentrations that have been linked to higher
cardiometabolic risk, along with longitudinal changes in HDL-C and TG concentrations and
a higher risk of incident dyslipidemia. Overall, the results from these analyses
indicate that higher SSB consumption may contribute to the development of dyslipidemia.
Additionally, high SSB consumption may modify the association between genetic variants
within or near the CHREBP locus and HDL-C and TG concentrations, however, these
observations warrant further investigation. These data can assist in the development of
new hypotheses to investigate potential underlying mechanisms by which SSB consumption
and variation in the CHREBP locus may influence plasma lipoprotein
concentrations.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Nutritional Epidemiology.
Advisor: Nicola McKeown.
Committee: Alice Lichtenstein, Caren Smith, Josee Dupuis, and Mark Herman.
Keywords: Nutrition, Epidemiology, and Genetics.read less - ID:
- 6t053v695
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