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Association between the APOA2 promoter polymorphism and body weight in Mediterranean and Asian populations: replication of a gene–saturated fat interaction

Abstract

Objective:

The APOA2 gene has been associated with obesity and insulin resistance (IR) in animal and human studies with controversial results. We have reported an APOA2–saturated fat interaction determining body mass index (BMI) and obesity in American populations. This work aims to extend our findings to European and Asian populations.

Methods:

Cross-sectional study in 4602 subjects from two independent populations: a high-cardiovascular risk Mediterranean population (n=907 men and women; aged 67±6 years) and a multiethnic Asian population (n=2506 Chinese, n=605 Malays and n=494 Asian Indians; aged 39±12 years) participating in a Singapore National Health Survey. Anthropometric, clinical, biochemical, lifestyle and dietary variables were determined. Homeostasis model assessment of insulin resistance was used in Asians. We analyzed gene–diet interactions between the APOA2 −265T>C polymorphism and saturated fat intake (22 g per day) on anthropometric measures and IR.

Results:

Frequency of CC (homozygous for the minor allele) subjects differed among populations (1–15%). We confirmed a recessive effect of the APOA2 polymorphism and replicated the APOA2–saturated fat interaction on body weight. In Mediterranean individuals, the CC genotype was associated with a 6.8% greater BMI in those consuming a high (P=0.018), but not a low (P=0.316) saturated fat diet. Likewise, the CC genotype was significantly associated with higher obesity prevalence in Chinese and Asian Indians only, with a high-saturated fat intake (P=0.036). We also found a significant APOA2–saturated fat interaction in determining IR in Chinese and Asian Indians (P=0.026).

Conclusion:

The influence of the APOA2 −265T>C polymorphism on body-weight-related measures was modulated by saturated fat in Mediterranean and Asian populations.

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References

  1. Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B et al. The human obesity gene map: the 2005 update. Obesity (Silver Spring) 2006; 14: 529–644.

    Article  Google Scholar 

  2. Walley AJ, Asher JE, Froguel P . The genetic contribution to non-syndromic human obesity. Nat Rev Genet 2009; 10: 431–442.

    Article  CAS  Google Scholar 

  3. Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 2009; 41: 18–24.

    Article  CAS  Google Scholar 

  4. Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009; 41: 25–34.

    Article  CAS  Google Scholar 

  5. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316: 889–894.

    Article  CAS  Google Scholar 

  6. Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007; 39: 724–726.

    Article  CAS  Google Scholar 

  7. Bouchard C . Gene-environment interactions in the etiology of obesity: defining the fundamentals. Obesity (Silver Spring) 2008; 16: S5–S10.

    Article  CAS  Google Scholar 

  8. Andreasen CH, Stender-Petersen KL, Mogensen MS, Torekov SS, Wegner L . Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes 2008; 57: 95–101.

    Article  CAS  Google Scholar 

  9. Rampersaud E, Mitchell BD, Pollin TI, Fu M, Shen H, O’Connell JR et al. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch Intern Med 2008; 168: 1791–1797.

    Article  Google Scholar 

  10. Vimaleswaran KS, Li S, Zhao JH, Luan J, Bingham SA, Khaw KT et al. Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene. Am J Clin Nutr 2009; 90: 425–428.

    Article  CAS  Google Scholar 

  11. Corella D, Peloso G, Arnett DK, Demissie S, Cupples LA, Tucker K et al. APOA2, dietary fat, and body mass index replication of a gene-diet interaction in 3 independent populations. Arch Internal Med 2009; 169: 1897–1906.

    Article  CAS  Google Scholar 

  12. Castellani LW, Goto AM, Lusis AJ . Studies with apolipoprotein A-II transgenic mice indicate a role for HDLs in adiposity and insulin resistance. Diabetes 2001; 50: 643–651.

    Article  CAS  Google Scholar 

  13. Castellani LW, Gargalovic P, Febbraio M, Charugundla S, Jien ML, Lusis AJ . Mechanisms mediating insulin resistance in transgenic mice overexpressing mouse apolipoprotein A-II. J Lipid Res 2004; 45: 2377–2387.

    Article  CAS  Google Scholar 

  14. Suto J . Quantitative trait locus analysis of plasma cholesterol levels and body weight by controlling the effects of the Apoa2 allele in mice. J Vet Med Sci. 2007; 69: 385–392.

    Article  CAS  Google Scholar 

  15. Castellani LW, Nguyen CN, Charugundla S, Weinstein MM, Doan CX, Blaner WS et al. Apolipoprotein AII is a regulator of very low density lipoprotein metabolism and insulin resistance. J Biol Chem 2008; 283: 11633–11644.

    Article  CAS  Google Scholar 

  16. Elbein SC, Hoffman MD, Teng K, Leppert MF, Hasstedt SJ . A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians. Diabetes 1999; 48: 1175–1182.

    Article  CAS  Google Scholar 

  17. Vionnet N, Hani EH, Dupont S, Gallina S, Francke S, Dotte S et al. Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24. Am J Hum Genet 2000; 67: 1470–1480.

    Article  CAS  Google Scholar 

  18. Xiang K, Wang Y, Zheng T, Jia W, Li J, Chen L et al. Genome-wide search for type 2 diabetes/impaired glucose homeostasis susceptibility genes in the Chinese: significant linkage to chromosome 6q21-q23 and chromosome 1q21-q24. Diabetes 2004; 53: 228–234.

    Article  CAS  Google Scholar 

  19. van ‘t Hooft FM, Ruotolo G, Boquist S, de Faire U, Eggertsen G, Hamsten A . Human evidence that the apolipoprotein A-II gene is implicated in visceral fat accumulation and metabolism of triglyceride-rich lipoproteins. Circulation 2001; 104: 1223–1228.

    Article  Google Scholar 

  20. Takada D, Emi M, Ezura Y, Nobe Y, Kawamura K, Iino Y . Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred. J Hum Genet 2002; 47: 656–664.

    Article  CAS  Google Scholar 

  21. Corella D, Arnett DK, Tsai MY, Kabagambe EK, Peacock JM, Hixson JE et al. The −256T>C polymorphism in the apolipoprotein A-II gene promoter is associated with body mass index and food intake in the genetics of lipid lowering drugs and diet network study. Clin Chem 2007; 53: 1144–1152.

    Article  CAS  Google Scholar 

  22. Lara-Castro C, Hunter GR, Lovejoy JC, Gower BA, Fernandez JR . Apolipoprotein A-II polymorphism and visceral adiposity in African-American and white women. Obesity 2005; 13: 507–512.

    Article  CAS  Google Scholar 

  23. Duesing K, Charpentier G, Marre M, Tichet J, Hercberg S, Balkau B et al. Evaluating the association of common APOA2 variants with type 2 diabetes. BMC Med Genet 2009; 10: 13.

    Article  Google Scholar 

  24. Estruch R, Martínez-González MA, Corella D, Salas-Salvadó J, Ruiz-Gutiérrez V, Covas MI et al. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med 2006; 145: 1–11.

    Article  Google Scholar 

  25. Cutter J, Tan BY, Chew SK . Levels of cardiovascular disease risk factors in Singapore following a national intervention programme. Bull World Health Organ 2001; 79: 908–915.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Deurenberg-Yap M, Chew SK, Lin VF, Tan BY, van Staveren WA, Deurenberg P . Relationships between indices of obesity and its co-morbidities in multi-ethnic Singapore. Int J Obes Relat Metab Disord 2001; 25: 1554–1562.

    Article  CAS  Google Scholar 

  27. Deurenberg P, Deurenberg-Yap M, Guricci S . Asians are different from Caucasians and from each other in their body mass index/body fat per cent relationship. Obes Rev 2002; 3: 141–146.

    Article  CAS  Google Scholar 

  28. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

    Article  CAS  Google Scholar 

  29. Alberti KG, Zimmet PZ . Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1. Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15: 539–553.

    Article  CAS  Google Scholar 

  30. Elosua R, Garcia M, Aguilar A, Molina L, Covas MI, Marrugat J . Validation of the Minnesota Leisure Time Physical Activity Questionnaire In Spanish Women. Investigators of the MARATDON Group. Med Sci Sports Exerc 2000; 32: 1431–1437.

    Article  CAS  Google Scholar 

  31. Martin-Moreno JM, Boyle P, Gorgojo L, Maisonneuve P, Fernandez-Rodriguez JC, Salvini S et al. Development and validation of a food frequency questionnaire in Spain. Int J Epidemiol 1993; 22: 512–519.

    Article  CAS  Google Scholar 

  32. Deurenberg-Yap M, Li T, Tan WL, Tan WL, van Staveren WA, Chew SK et al. Can dietary factors explain differences in serum cholesterol profiles among different ethnic groups (Chinese, Malays and Indians) in Singapore? Asia Pac J Clin Nutr 2001; 10: 39–45.

    Article  CAS  Google Scholar 

  33. Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E et al. STrengthening the REporting of Genetic Association studies (STREGA): an extension of the STROBE Statement. Ann Intern Med 2009; 150: 206–215.

    Article  Google Scholar 

  34. Martín-Campos JM, Escolà-Gil JC, Ribas V, Blanco-Vaca F . Apolipoprotein A-II, genetic variation on chromosome 1q21-q24, and disease susceptibility. Curr Opin Lipidol 2004; 15: 247–253.

    Article  Google Scholar 

  35. Weng W, Breslow JL . Dramatically decreased high density lipoprotein cholesterol, increased remnant clearance, and insulin hypersensitivity in apolipoprotein A-II knockout mice suggest a complex role for apolipoprotein A-II in atherosclerosis susceptibility. Proc Nat Acad Sci USA 1996; 93: 14788–14794.

    Article  CAS  Google Scholar 

  36. Sauvaget D, Chauffeton V, Dugué-Pujol S, Kalopissis AD, Guillet-Deniau I, Foufelle F et al. In vitro transcriptional induction of the human apolipoprotein A-II gene by glucose. Diabetes 2004; 53: 672–678.

    Article  CAS  Google Scholar 

  37. Escolà-Gil JC, Blanco-Vaca F, Julve J . Overexpression of human apolipoprotein A-II in transgenic mice does not increase their susceptibility to insulin resistance and obesity. Diabetologia 2002; 45: 600–601.

    Article  Google Scholar 

  38. Blanco-Vaca F, Escolà-Gil JC, Martín-Campos JM, Julve J . Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein. J Lipid Res 2001; 42: 1727–1739.

    CAS  PubMed  Google Scholar 

  39. Escola-Gil JC, Marzal-Casacuberta A, Julve-Gil J, Ishida BY, Ordonez-Llanos J, Chan L et al. Human apolipoprotein A-II is a pro-atherogenic molecule when it is expressed in transgenic mice at a level similar to that in humans: evidence of a potentially relevant species-specific interaction with diet. J Lipid Res 1998; 39: 457–462.

    CAS  PubMed  Google Scholar 

  40. Culnan DM, Cooney RN, Stanley B, Lynch CJ . Apolipoprotein A-IV, a putative satiety/antiatherogenic factor, rises after gastric bypass. Obesity (Silver Spring) 2009; 17: 46–52.

    Article  CAS  Google Scholar 

  41. Xiao J, Zhang F, Wiltshire S, Hung J, Jennens M, Beilby JP et al. The apolipoprotein AII rs5082 variant is associated with reduced risk of coronary artery disease in an Australian male population. Atherosclerosis 2008; 199: 333–339.

    Article  CAS  Google Scholar 

  42. Hasstedt SJ, Chu WS, Das SK, Wang H, Elbein SC . Type 2 diabetes susceptibility genes on chromosome 1q21–24. Ann Hum Genet 2008; 72: 163–169.

    Article  CAS  Google Scholar 

  43. Elbein SC, Chu W, Ren Q, Wang H, Hemphill C, Hasstedt SJ et al. Evaluation of apolipoprotein A-II as a positional candidate gene for familial Type II diabetes, altered lipid concentrations, and insulin resistance. Diabetologia 2002; 45: 1026–1033.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by National Heart, Lung, and Blood Institute grants U 01 HL72524 and HL-54776, National Institute of Diabetes and Digestive and Kidney Diseases, grant number DK075030 and by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research Service and grant from the Ministerio de Ciencia e Innovación (PR2008-268 and PR2009-392), the Generalitat Valenciana (GVACOMP2010-181, BEST10-211 and BEST10-032), the Centro Nacional de Investigaciones Cardiovasculares (CNIC06) and the Instituto de Salud Carlos III (CIBER CB06/03/0035, RD07/0067/0006, PI0890002 and PI070954), Spain.

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Correspondence to J M Ordovas.

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Corella, D., Tai, E., Sorlí, J. et al. Association between the APOA2 promoter polymorphism and body weight in Mediterranean and Asian populations: replication of a gene–saturated fat interaction. Int J Obes 35, 666–675 (2011). https://doi.org/10.1038/ijo.2010.187

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