TY - JOUR T1 - Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits. JF - Diabetes Care Y1 - 2015 A1 - Dashti, Hassan S A1 - Follis, Jack L A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Garaulet, Marta A1 - Gottlieb, Daniel J A1 - Hruby, Adela A1 - Jacques, Paul F A1 - Kiefte-de Jong, Jessica C A1 - Lamon-Fava, Stefania A1 - Scheer, Frank A J L A1 - Bartz, Traci M A1 - Kovanen, Leena A1 - Wojczynski, Mary K A1 - Frazier-Wood, Alexis C A1 - Ahluwalia, Tarunveer S A1 - Perälä, Mia-Maria A1 - Jonsson, Anna A1 - Muka, Taulant A1 - Kalafati, Ioanna P A1 - Mikkilä, Vera A1 - Ordovas, Jose M KW - Adult KW - Alleles KW - Blood Glucose KW - Circadian Rhythm Signaling Peptides and Proteins KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Diet, Fat-Restricted KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Gene-Environment Interaction KW - Humans KW - Insulin Resistance KW - Male KW - Middle Aged KW - Multicenter Studies as Topic KW - Observational Studies as Topic KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Sleep KW - Waist Circumference AB -

OBJECTIVE: Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations.

RESEARCH DESIGN AND METHODS: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

RESULTS: We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m(2) higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to <9 h).

CONCLUSIONS: Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet—specifically higher carbohydrate and lower fat composition—and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants.

VL - 38 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26084345?dopt=Abstract ER - TY - JOUR T1 - Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants. JF - Am J Clin Nutr Y1 - 2015 A1 - Dashti, Hassan S A1 - Follis, Jack L A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Cade, Brian E A1 - Gottlieb, Daniel J A1 - Hruby, Adela A1 - Jacques, Paul F A1 - Lamon-Fava, Stefania A1 - Richardson, Kris A1 - Saxena, Richa A1 - Scheer, Frank A J L A1 - Kovanen, Leena A1 - Bartz, Traci M A1 - Perälä, Mia-Maria A1 - Jonsson, Anna A1 - Frazier-Wood, Alexis C A1 - Kalafati, Ioanna-Panagiota A1 - Mikkilä, Vera A1 - Partonen, Timo A1 - Lemaitre, Rozenn N A1 - Lahti, Jari A1 - Hernandez, Dena G A1 - Toft, Ulla A1 - Johnson, W Craig A1 - Kanoni, Stavroula A1 - Raitakari, Olli T A1 - Perola, Markus A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Grarup, Niels A1 - Highland, Heather M A1 - Rallidis, Loukianos A1 - Kähönen, Mika A1 - Havulinna, Aki S A1 - Siscovick, David S A1 - Räikkönen, Katri A1 - Jørgensen, Torben A1 - Rotter, Jerome I A1 - Deloukas, Panos A1 - Viikari, Jorma S A A1 - Mozaffarian, Dariush A1 - Linneberg, Allan A1 - Seppälä, Ilkka A1 - Hansen, Torben A1 - Salomaa, Veikko A1 - Gharib, Sina A A1 - Eriksson, Johan G A1 - Bandinelli, Stefania A1 - Pedersen, Oluf A1 - Rich, Stephen S A1 - Dedoussis, George A1 - Lehtimäki, Terho A1 - Ordovas, Jose M KW - Adult KW - Body Mass Index KW - CLOCK Proteins KW - Cohort Studies KW - Cross-Sectional Studies KW - Diet KW - Dietary Proteins KW - Energy Intake KW - European Continental Ancestry Group KW - Fatty Acids, Unsaturated KW - Female KW - Gene-Environment Interaction KW - Genetic Predisposition to Disease KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Sleep KW - Young Adult AB -

BACKGROUND: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake.

OBJECTIVES: We examined associations between habitual sleep duration, body mass index (BMI), and macronutrient intake and assessed whether CLOCK variants modify these associations.

DESIGN: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations of sleep duration and BMI and macronutrient intake as percentages of total energy as well as interactions with CLOCK variants from 9 cohort studies including up to 14,906 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.

RESULTS: We observed a significant association between sleep duration and lower BMI (β ± SE = 0.16 ± 0.04, P < 0.0001) in the overall sample; however, associations between sleep duration and relative macronutrient intake were evident in age- and sex-stratified analyses only. We observed a significant association between sleep duration and lower saturated fatty acid intake in younger (aged 20-64 y) adults (men: 0.11 ± 0.06%, P = 0.03; women: 0.10 ± 0.05%, P = 0.04) and with lower carbohydrate (-0.31 ± 0.12%, P < 0.01), higher total fat (0.18 ± 0.09%, P = 0.05), and higher PUFA (0.05 ± 0.02%, P = 0.02) intakes in older (aged 65-80 y) women. In addition, the following 2 nominally significant interactions were observed: between sleep duration and rs12649507 on PUFA intake and between sleep duration and rs6858749 on protein intake.

CONCLUSIONS: Our results indicate that longer habitual sleep duration is associated with lower BMI and age- and sex-specific favorable dietary behaviors. Differences in the relative intake of specific macronutrients associated with short sleep duration could, at least in part, explain previously reported associations between short sleep duration and chronic metabolic abnormalities. In addition, the influence of obesity-associated CLOCK variants on the association between sleep duration and macronutrient intake suggests that longer habitual sleep duration could ameliorate the genetic predisposition to obesity via a favorable dietary profile.

VL - 101 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25527757?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts. JF - PLoS One Y1 - 2017 A1 - Mozaffarian, Dariush A1 - Dashti, Hassan S A1 - Wojczynski, Mary K A1 - Chu, Audrey Y A1 - Nettleton, Jennifer A A1 - Männistö, Satu A1 - Kristiansson, Kati A1 - Reedik, Mägi A1 - Lahti, Jari A1 - Houston, Denise K A1 - Cornelis, Marilyn C A1 - van Rooij, Frank J A A1 - Dimitriou, Maria A1 - Kanoni, Stavroula A1 - Mikkilä, Vera A1 - Steffen, Lyn M A1 - de Oliveira Otto, Marcia C A1 - Qi, Lu A1 - Psaty, Bruce A1 - Djoussé, Luc A1 - Rotter, Jerome I A1 - Harald, Kennet A1 - Perola, Markus A1 - Rissanen, Harri A1 - Jula, Antti A1 - Krista, Fischer A1 - Mihailov, Evelin A1 - Feitosa, Mary F A1 - Ngwa, Julius S A1 - Xue, Luting A1 - Jacques, Paul F A1 - Perälä, Mia-Maria A1 - Palotie, Aarno A1 - Liu, Yongmei A1 - Nalls, Nike A A1 - Ferrucci, Luigi A1 - Hernandez, Dena A1 - Manichaikul, Ani A1 - Tsai, Michael Y A1 - Kiefte-de Jong, Jessica C A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rallidis, Loukianos A1 - Ridker, Paul M A1 - Rose, Lynda M A1 - Buring, Julie E A1 - Lehtimäki, Terho A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Lemaitre, Rozenn A1 - Salomaa, Veikko A1 - Knekt, Paul A1 - Metspalu, Andres A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Eriksson, Johan G A1 - Kritchevsky, Stephen B A1 - Bandinelli, Stefania A1 - Siscovick, David A1 - Franco, Oscar H A1 - Deloukas, Panos A1 - Dedoussis, George A1 - Chasman, Daniel I A1 - Raitakari, Olli A1 - Tanaka, Toshiko KW - Adult KW - Aged KW - Cohort Studies KW - Docosahexaenoic Acids KW - Eicosapentaenoic Acid KW - Europe KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Seafood KW - United States AB -

BACKGROUND: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences.

OBJECTIVE: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption.

DESIGN: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts.

RESULTS: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA.

CONCLUSIONS: These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.

VL - 12 IS - 12 ER - TY - JOUR T1 - Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent. JF - Mol Nutr Food Res Y1 - 2017 A1 - Smith, Caren E A1 - Follis, Jack L A1 - Dashti, Hassan S A1 - Tanaka, Toshiko A1 - Graff, Mariaelisa A1 - Fretts, Amanda M A1 - Kilpeläinen, Tuomas O A1 - Wojczynski, Mary K A1 - Richardson, Kris A1 - Nalls, Mike A A1 - Schulz, Christina-Alexandra A1 - Liu, Yongmei A1 - Frazier-Wood, Alexis C A1 - van Eekelen, Esther A1 - Wang, Carol A1 - de Vries, Paul S A1 - Mikkilä, Vera A1 - Rohde, Rebecca A1 - Psaty, Bruce M A1 - Hansen, Torben A1 - Feitosa, Mary F A1 - Lai, Chao-Qiang A1 - Houston, Denise K A1 - Ferruci, Luigi A1 - Ericson, Ulrika A1 - Wang, Zhe A1 - de Mutsert, Renée A1 - Oddy, Wendy H A1 - de Jonge, Ester A L A1 - Seppälä, Ilkka A1 - Justice, Anne E A1 - Lemaitre, Rozenn N A1 - Sørensen, Thorkild I A A1 - Province, Michael A A1 - Parnell, Laurence D A1 - Garcia, Melissa E A1 - Bandinelli, Stefania A1 - Orho-Melander, Marju A1 - Rich, Stephen S A1 - Rosendaal, Frits R A1 - Pennell, Craig E A1 - Kiefte-de Jong, Jessica C A1 - Kähönen, Mika A1 - Young, Kristin L A1 - Pedersen, Oluf A1 - Aslibekyan, Stella A1 - Rotter, Jerome I A1 - Mook-Kanamori, Dennis O A1 - Zillikens, M Carola A1 - Raitakari, Olli T A1 - North, Kari E A1 - Overvad, Kim A1 - Arnett, Donna K A1 - Hofman, Albert A1 - Lehtimäki, Terho A1 - Tjønneland, Anne A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Franco, Oscar H A1 - German, J Bruce A1 - Siscovick, David S A1 - Cupples, L Adrienne A1 - Ordovas, Jose M AB -

SCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption.

METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3' of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure.

CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.

ER - TY - JOUR T1 - 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. JF - Diabetologia Y1 - 2018 A1 - McKeown, Nicola M A1 - Dashti, Hassan S A1 - Ma, Jiantao A1 - Haslam, Danielle E A1 - Kiefte-de Jong, Jessica C A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Graff, Mariaelisa A1 - Lemaitre, Rozenn N A1 - Rybin, Denis A1 - Sonestedt, Emily A1 - Frazier-Wood, Alexis C A1 - Mook-Kanamori, Dennis O A1 - Li, Yanping A1 - Wang, Carol A A1 - Leermakers, Elisabeth T M A1 - Mikkilä, Vera A1 - Young, Kristin L A1 - Mukamal, Kenneth J A1 - Cupples, L Adrienne A1 - Schulz, Christina-Alexandra A1 - Chen, Tzu-An A1 - Li-Gao, Ruifang A1 - Huang, Tao A1 - Oddy, Wendy H A1 - Raitakari, Olli A1 - Rice, Kenneth A1 - Meigs, James B A1 - Ericson, Ulrika A1 - Steffen, Lyn M A1 - Rosendaal, Frits R A1 - Hofman, Albert A1 - Kähönen, Mika A1 - Psaty, Bruce M A1 - Brunkwall, Louise A1 - Uitterlinden, André G A1 - Viikari, Jorma A1 - Siscovick, David S A1 - Seppälä, Ilkka A1 - North, Kari E A1 - Mozaffarian, Dariush A1 - Dupuis, Josée A1 - Orho-Melander, Marju A1 - Rich, Stephen S A1 - de Mutsert, Renée A1 - Qi, Lu A1 - Pennell, Craig E A1 - Franco, Oscar H A1 - Lehtimäki, Terho A1 - Herman, Mark A AB -

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 (β ± 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 β-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).

VL - 61 IS - 2 ER - TY - JOUR T1 - Genome-wide association study of breakfast skipping links clock regulation with food timing. JF - Am J Clin Nutr Y1 - 2019 A1 - Dashti, Hassan S A1 - Merino, Jordi A1 - Lane, Jacqueline M A1 - Song, Yanwei A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - McKeown, Nicola M A1 - Tucker, Chandler A1 - Sun, Dianjianyi A1 - Bartz, Traci M A1 - Li-Gao, Ruifang A1 - Nisa, Hoirun A1 - Reutrakul, Sirimon A1 - Lemaitre, Rozenn N A1 - Alshehri, Tahani M A1 - de Mutsert, Renée A1 - Bazzano, Lydia A1 - Qi, Lu A1 - Knutson, Kristen L A1 - Psaty, Bruce M A1 - Mook-Kanamori, Dennis O A1 - Perica, Vesna Boraska A1 - Neuhouser, Marian L A1 - Scheer, Frank A J L A1 - Rutter, Martin K A1 - Garaulet, Marta A1 - Saxena, Richa AB -

BACKGROUND: Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits.

OBJECTIVES: The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait.

METHODS: We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963).

RESULTS: In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095).

CONCLUSIONS: Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.

ER - TY - JOUR T1 - 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. JF - Circ Genom Precis Med Y1 - 2021 A1 - Haslam, Danielle E A1 - Peloso, Gina M A1 - Guirette, Melanie A1 - Imamura, Fumiaki A1 - Bartz, Traci M A1 - Pitsillides, Achilleas N A1 - Wang, Carol A A1 - Li-Gao, Ruifang A1 - Westra, Jason M A1 - Pitkänen, Niina A1 - Young, Kristin L A1 - Graff, Mariaelisa A1 - Wood, Alexis C A1 - Braun, Kim V E A1 - Luan, Jian'an A1 - Kähönen, Mika A1 - Kiefte-de Jong, Jessica C A1 - Ghanbari, Mohsen A1 - Tintle, Nathan A1 - Lemaitre, Rozenn N A1 - Mook-Kanamori, Dennis O A1 - North, Kari A1 - Helminen, Mika A1 - Mossavar-Rahmani, Yasmin A1 - Snetselaar, Linda A1 - Martin, Lisa W A1 - Viikari, Jorma S A1 - Oddy, Wendy H A1 - Pennell, Craig E A1 - Rosendall, Frits R A1 - Ikram, M Arfan A1 - Uitterlinden, André G A1 - Psaty, Bruce M A1 - Mozaffarian, Dariush A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Lehtimäki, Terho A1 - Raitakari, Olli T A1 - Livingston, Kara A A1 - Voortman, Trudy A1 - Forouhi, Nita G A1 - Wareham, Nick J A1 - de Mutsert, Renée A1 - Rich, Steven S A1 - Manson, JoAnn E A1 - Mora, Samia A1 - Ridker, Paul M A1 - Merino, Jordi A1 - Meigs, James B A1 - Dashti, Hassan S A1 - Chasman, Daniel I A1 - Lichtenstein, Alice H A1 - Smith, Caren E A1 - Dupuis, Josée A1 - Herman, Mark A A1 - McKeown, Nicola M AB -

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 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 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 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; <0.0001), but not significantly among the lowest SSB consumers (=0.81; <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, =0.001) but not the lowest SSB consumers (=0.84; =0.0005).

CONCLUSIONS: Our results identified genetic variants in the 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.

VL - 14 IS - 4 ER -