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: β (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.