Alcohol, Carbohydrate, and Calcium Intakes and Smoking Interactions with APOA5 rs662799 and rs2266788 were Associated with Elevated Plasma Triglyceride Concentrations in a Cross-Sectional Study of Korean Adults

Published:April 23, 2020DOI:



      Plasma triglyceride (TG) concentrations are markedly higher among Asians, which may be associated with the interaction of genetics and lifestyle factors.


      The purpose of this study was to investigate the genetic variants that have a strong association with plasma TG concentrations from genome-wide association study and to identify lifestyle interactions with the genetic variants that are associated with dyslipidemia in a cohort of Korean adults.


      Korean genome and epidemiology study utilized a cross-sectional design of Koreans to determine genetic variants and lifestyle factors, including nutrient intakes, in a retrospective hospital-based city cohort conducted by the Korean Center for Disease and Control during 2004-2013.


      Korean adults aged 40 to 77 years were participants (n=28,445).

      Main outcome measures

      The genetic variants that influence plasma TG concentrations were selected by genome-wide association study using an allele genetic model after adjusting for age, sex, area of residence, and body mass index. Lipid profiles and nutrient intakes from food frequency questionnaires were measured. The interactions between the single nucleotide polymorphisms and lifestyle factors were determined to influence plasma TG levels.


      Carrying the minor alleles of APOA5 rs662799 and rs2266788 had an association with higher plasma TG concentrations by 1.86- and 1.51-fold, respectively, compared with those with the major allele (P=8.89E-150 and P=4.75E-68, respectively). Sex had an interaction with these single nucleotide polymorphisms, with males having higher plasma TG concentrations. The single nucleotide polymorphisms had significant interactions with carbohydrate, fat, and calcium intakes; alcohol consumption; and smoking status that were associated with plasma TG concentrations. Carriers with the minor allele of each single nucleotide polymorphisms had higher plasma TG concentrations when consuming-low fat (<15%) and high carbohydrate (≥72%) diets than those with major alleles. Carriers of the minor alleles with low calcium intakes (<500 mg/day) experienced elevated plasma TG concentrations compared with carriers of the major alleles. Smokers and alcohol drinkers with either of the minor alleles of APOA5, rs662799 or rs2266788, had higher plasma TG concentrations than those with its major allele.


      These results indicated that carrying the minor alleles of APOA5 rs662799 and rs2266788, especially for men, was associated with elevated TG concentrations and suggested that Korean carriers of the minor alleles could be at increased risk of hypertriglyceridemia. Further research is needed to investigate the efficacy of modulating lifestyle factors to prevent dyslipidemia in people carrying the minor alleles of APOA5 rs662799 and rs2266788.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the Academy of Nutrition and Dietetics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Weir H.K.
        • Anderson R.N.
        • Coleman King S.M.
        • et al.
        Heart disease and cancer deaths— trends and projections in the United States, 1969-2020.
        Prev Chronic Dis. 2016; 13: E157
        • Kim E.H.
        • Lee J.B.
        • Kim S.H.
        • et al.
        Serum triglyceride levels and cardiovascular disease events in Koreans.
        Cardiology. 2015; 131: 228-235
        • Kajikawa M.
        • Maruhashi T.
        • Matsumoto T.
        • et al.
        Relationship between serum triglyceride levels and endothelial function in a large community-based study.
        Atherosclerosis. 2016; 249: 70-75
        • Nordestgaard B.G.
        • Varbo A.
        Triglycerides and cardiovascular disease.
        Lancet. 2014; 384: 626-635
        • Jain A.
        • Puri R.
        • Nair D.R.
        South Asians: Why are they at a higher risk for cardiovascular disease?.
        Curr Opin Cardiol. 2017; 32: 430-436
        • Park S.
        • Kim D.S.
        • Kang S.
        Carrying minor allele of FADS1 and haplotype of FADS1 and FADS2 increased the risk of metabolic syndrome and moderate but not low fat diets lowered the risk in two Korean cohorts.
        Eur J Nutr. 2019; 58: 831-842
        • Lin E.
        • Kuo P.H.
        • Liu Y.L.
        • Yang A.C.
        • Kao C.F.
        • Tsai S.J.
        Association and interaction of APOA5, BUD13, CETP, LIPA and health-related behavior with metabolic syndrome in a Taiwanese population.
        Sci Rep. 2016; 6: 36830
        • Park S.
        • Ahn J.
        • Lee B.K.
        Very-low-fat diets may be associated with increased risk of metabolic syndrome in the adult population.
        Clin Nutr. 2016; 35: 1159-1167
        • Sharma V.
        • Forte T.M.
        • Ryan R.O.
        Influence of apolipoprotein A-V on the metabolic fate of triacylglycerol.
        Curr Opin Lipidol. 2013; 24: 153-159
        • Grosskopf I.
        • Baroukh N.
        • Lee S.J.
        • et al.
        Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants.
        Arterioscler Thromb Vasc Biol. 2005; 25: 2573-2579
        • Walther T.C.
        • Farese Jr., R.V.
        Lipid droplets and cellular lipid metabolism.
        Annu Rev Biochem. 2012; 81: 687-714
        • Zubair N.
        • Graff M.
        • Luis Ambite J.
        • et al.
        Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci.
        Hum Mol Genet. 2016; 25: 5500-5512
        • Caussy C.
        • Charriere S.
        • Marcais C.
        • et al.
        An APOA5 3' UTR variant associated with plasma triglycerides triggers APOA5 downregulation by creating a functional miR-485-5p binding site.
        Am J Hum Genet. 2014; 94: 129-134
        • Jasim A.A.
        • Al-Bustan S.A.
        • Al-Kandari W.
        • Al-Serri A.
        • AlAskar H.
        Sequence analysis of APOA5 among the Kuwaiti population identifies association of rs2072560, rs2266788, and rs662799 With TG and VLDL levels.
        Front Genet. 2018; 9: 112
        • Kashyap S.
        • Kumar S.
        • Agarwal V.
        • Misra D.P.
        • Rai M.K.
        • Kapoor A.
        The association of polymorphic variants rs2267788, rs1333049 and rs2383207 with coronary artery disease, its severity and presentation in North Indian population.
        Gene. 2018; 648: 89-96
        • Li S.
        • Hu B.
        • Wang Y.
        • Wu D.
        • Jin L.
        • Wang X.
        Influences of APOA5 variants on plasma triglyceride levels in Uyghur population.
        PLoS One. 2014; 9e110258
        • Shou W.
        • Wang Y.
        • Xie F.
        • et al.
        A functional polymorphism affecting the APOA5 gene expression is causally associated with plasma triglyceride levels conferring coronary atherosclerosis risk in Han Chinese population.
        Biochim Biophys Acta. 2014; 1842: 2147-2154
        • Sumegi K.
        • Duga B.
        • Melegh B.I.
        • et al.
        Marked differences of haplotype tagging SNP distribution, linkage, and haplotype profile of APOA5 gene in Roma population samples.
        Pathol Oncol Res. 2017; 23: 853-861
        • Kim O.Y.
        • Moon J.
        • Jo G.
        • Kwak S.Y.
        • Kim J.Y.
        • Shin M.J.
        Apolipoprotein A5 3'-UTR variants and cardiometabolic traits in Koreans: Results from the Korean genome and epidemiology study and the Korea National Health and Nutrition Examination Survey.
        Nutr Res Pract. 2018; 12: 61-68
        • Kim Y.
        • Han B.G.
        Cohort profile: The Korean Genome and Epidemiology Study (KoGES) Consortium.
        Int J Epidemiol. 2017; 46: 1350
        • Kim M.
        • Kim M.
        • Yoo H.J.
        • et al.
        A promoter variant of the APOA5 gene increases atherogenic LDL levels and arterial stiffness in hypertriglyceridemic patients.
        PLoS One. 2017; 12e0186693
        • Park S.
        • Ham J.O.
        • Lee B.K.
        Effects of total vitamin A, vitamin C, and fruit intake on risk for metabolic syndrome in Korean women and men.
        Nutrition. 2015; 31: 111-118
        • Lim S.
        • Jang H.C.
        • Lee H.K.
        • Kimm K.C.
        • Park C.
        • Cho N.H.
        A rural-urban comparison of the characteristics of the metabolic syndrome by gender in Korea: The Korean Health and Genome Study (KHGS).
        J Endocrinol Invest. 2006; 29: 313-319
        • Schwarzfischer P.
        • Weber M.
        • Gruszfeld D.
        • et al.
        BMI and recommended levels of physical activity in school children.
        BMC Public Health. 2017; 17: 595
        • Song S.
        • Paik H.Y.
        • Park M.
        • Song Y.
        Dyslipidemia patterns are differentially associated with dietary factors.
        Clin Nutr. 2016; 35: 885-891
      1. Computer Aided Nutritional Analysis Program (Can-Pro) [computer program]. Version 5.0. Seoul, Korea: The Korea Nutrition Society; 2015.

        • Hong K.W.
        • Kim S.H.
        • Zhang X.
        • Park S.
        Interactions among the variants of insulin-related genes and nutrients increase the risk of type 2 diabetes.
        Nutr Res. 2018; 51: 82-92
      2. PLINK info [computer program]. Version 1.90b. The Center for Human Genetic Research, Boston, MA2014
      3. SCAN [database]. Chicago, IL: University of Chicago.

      4. Intake.
        in: Korean Dietary Referece Intakes. Ministry of Health & Welfare, Seoul, Korea2015
        • Woo H.W.
        • Lim Y.H.
        • Kim M.K.
        • et al.
        Prospective associations between total, animal, and vegetable calcium intake and metabolic syndrome in adults aged 40 years and older.
        Clin Nutr. 2019 October 23; ([Epub ahead of print])
      5. PLINK info [computer program]. Version 1.07. The Center for Human Genetic Research, Boston, MA2014
      6. SAS [computer program]. Version 9.4. SAS Institute, Cary, NC2013
      7. G∗Power [computer program]. Version 3.1. Heinrich Heine Universitat Dusseldorf, Dusseldorf, German2007
        • Zhou J.Y.
        • Song M.Y.
        • Park S.
        Carbohydrate and sodium intake and physical activity interact with genetic risk scores of four genetic variants mainly related to lipid metabolism to modulate metabolic syndrome risk in Korean middle-aged adults.
        Br J Nutr. 2019; 122: 919-927
        • Cha S.
        • Yu H.
        • Park A.Y.
        • Song K.H.
        Effects of apolipoprotein A5 haplotypes on the ratio of triglyceride to high-density lipoprotein cholesterol and the risk for metabolic syndrome in Koreans.
        Lipids Health Dis. 2014; 13: 45
        • Cui G.
        • Li Z.
        • Li R.
        • et al.
        A functional variant in APOA5/A4/C3/A1 gene cluster contributes to elevated triglycerides and severity of CAD by interfering with microRNA 3201 binding efficiency.
        J Am Coll Cardiol. 2014; 64: 267-277
        • Suarez-Sanchez F.
        • Klunder-Klunder M.
        • Valladares-Salgado A.
        • et al.
        APOA5 and APOA1 polymorphisms are associated with triglyceride levels in Mexican children.
        Pediatr Obes. 2017; 12: 330-336
        • Liu Z.K.
        • Hu M.
        • Baum L.
        • Thomas G.N.
        • Tomlinson B.
        Associations of polymorphisms in the apolipoprotein A1/C3/A4/A5 gene cluster with familial combined hyperlipidaemia in Hong Kong Chinese.
        Atherosclerosis. 2010; 208: 427-432
        • Shahid S.U.
        • Shabana N.A.
        • Cooper J.A.
        • Rehman A.
        • Humphries S.E.
        Common variants in the genes of triglyceride and HDL-C metabolism lack association with coronary artery disease in the Pakistani subjects.
        Lipids Health Dis. 2017; 16: 24
        • Shahid S.U.
        • Shabana
        • Cooper J.A.
        • et al.
        Genetic risk analysis of coronary artery disease in Pakistani subjects using a genetic risk score of 21 variants.
        Atherosclerosis. 2017; 258: 1-7
        • Ye H.
        • Zhou A.
        • Hong Q.
        • et al.
        Positive association between APOA5 rs662799 polymorphism and coronary heart disease: A case-control study and meta-analysis.
        PLoS One. 2015; 10e0135683
        • You Y.
        • Wu Y.H.
        • Zhang Y.
        • et al.
        Effects of polymorphisms in APOA5 on the plasma levels of triglycerides and risk of coronary heart disease in Jilin, northeast China: A case-control study.
        BMJ Open. 2018; 8e020016
        • Nicoll R.
        • Wiklund U.
        • Zhao Y.
        • et al.
        Gender and age effects on risk factor-based prediction of coronary artery calcium in symptomatic patients: A Euro-CCAD study.
        Atherosclerosis. 2016; 252: 32-39
        • Kris-Etherton P.M.
        • Taylor D.S.
        • Zhao G.
        Is there an optimal diet for the hypertriglyceridemic patient?.
        J Cardiovasc Risk. 2000; 7: 333-337
        • DiNicolantonio J.J.
        • O’Keefe J.H.
        Effects of dietary fats on blood lipids: A review of direct comparison trials.
        Open Heart. 2018; 5e000871
        • Park S.
        • Ahn J.
        • Kim N.S.
        • Lee B.K.
        High carbohydrate diets are positively associated with the risk of metabolic syndrome irrespective to fatty acid composition in women: The KNHANES 2007-2014.
        Int J Food Sci Nutr. 2017; 68: 479-487
        • Torres M.R.
        • Sanjuliani A.F.
        Does calcium intake affect cardiovascular risk factors and/or events?.
        Clinics. 2012; 67: 839-844
        • Kopin L.
        • Lowenstein C.
        Ann Intern Med. 2017; 167: Itc81-Itc96
        • Fernandez-Sola J.
        Cardiovascular risks and benefits of moderate and heavy alcohol consumption.
        Nat Rev Cardiol. 2015; 12: 576-587
        • Shi J.
        • Bai Y.
        • Qiu S.
        • et al.
        Classified status of smoking and quitting has different associations with dyslipidemia in residents in northeast China.
        Clin Chim Acta. 2018; 486: 209-213


      S. Park is a professor of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, ChungNam-Do, South Korea.


      S. Kang is a researcher, Obesity/Diabetes Research Center, Hoseo University, ChungNam-Do, South Korea.