Abstract
OBJECTIVE: To investigate associations and gene–environment interactions of APOA-IV gene polymorphisms with obesity-related phenotypes in a Brazilian population.
METHODS: A total of 391 individuals (171 men and 220 women) were genotyped for Xbal, Thr347Ser and Gln360His polymorphisms by PCR-RFLP methods. Adjusted body mass index (BMI) and waist circumference (WC) were compared among genotypes/haplotypes by unpaired t-test or analysis of variance. Gene–environment interactions were tested by analysis of variance using a general linear model.
RESULTS: Analysis of the APOA-IV gene variants separately showed that X*2 and 347Ser alleles were associated with higher BMI (P=0.02 for both polymorphisms). Haplotype analysis confirmed this association. For these polymorphisms, the effect on BMI appeared to depend on smoking status (test for interaction, P=0.007 and 0.02, respectively), the Thr347Ser variant was associated with a BMI increase in smokers only (P=0.002). At the single-locus level no association was observed between 360His allele and BMI; however, haplotype analyses showed an association of this gene variant and higher BMI. A trend for association with WC (P=0.05) was observed in male carriers of the 360His allele. The effect of this polymorphism also depended on smoking status (test for interaction, P=0.018). Nonsmoker male carriers of the 360His allele had a larger waist circumference than homozygotes for the Gln allele (P=0.003).
CONCLUSION: Our data suggest that the APOA-IV gene polymorphisms investigated are associated with obesity-related traits. The effects of X*2 and 347Ser variants on BMI and the 360His variant on waist circumference depended on smoking status.
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References
Rankinen T, Pérusse L, Weisnagel SJ, Snyder EE, Chagnon YC, Bouchard C . The human obesity gene map: the 2001 update. Obes Res 2002; 10: 196–243.
Green PHR, Glickman RM, Riley JW, Quinet E . Human apolipoprotein A-IV—intestinal origin and distribution in plasma. J Clin Invest 1980; 65: 911–919.
Weinberg RB, Jordan MK . Effects of phospholipid on the structure of human apolipoprotein A-IV. J Biol Chem 1990; 265: 8081–8086.
Houppermans SB . L'apolipoprotéine A-IV humaine. Ann Biol Clin 1994; 52: 701–710.
Liu M, Shen L, Tso P . The role of enterostatin and apolipoprotein A-IV on the control of food intake. Neuropeptides 1999; 33: 425–433.
Tso P, Liu M, Kalogeris TJ . The role of apolipoprotein A-IV in food intake regulation. J Nutr 1999; 129: 1503–1506.
Tso P, Liu M, Kalogeris TJ, Thomson ABR . The role of apolipoprotein A-IV in the regulation of food intake. Annu Rev Nutr 2001; 21: 231–254.
Fujimoto K, Fukagawa K, Sakata T, Tso P . Increased apolipoprotein A-IV in rat mesenteric lymph after lipid meal acts as a physiological signal for satiation. Am J Physiol 1992; 262: 1002–1006.
Fujimoto K, Cardelli JA, Tso P . Suppression of food intake by apolipoprotein A-IV is mediated through the central nervous system in rats. J Clin Invest 1993; 91: 1830–1833.
Liu M, Doi T, Shen L, Woods SC, Seeley RJ, Zheng S, Jackman A, Tso P . Intestinal satiety protein apolipoprotein A-IV is synthesized and regulated in rat hypothalamus. Am J Physiol Regul Integr Comp Physiol 2001; 280: R1382–R1387.
Okumura T, Fukagawa K, Tso P, Taylor IL, Pappas TN . Intracisternal injection of apolipoprotein A-IV inhibits gastric secretion in pylorus-ligated conscious rats. Gastroenterology 1994; 107: 1861–1864.
Okumura T, Fukagawa K, Tso P, Taylor IL, Pappas TN . Mechanism of action of intracisternal apolipoprotein A-IV in inhibiting gastric acid secretion in rats. Gastroenterology 1995; 109: 1583–1588.
Kalogeris TJ, Qin X, Chey WY, Tso P . PYY stimulates synthesis and secretion of intestinal apolipoprotein AIV without affection mRNA expression. Gastrointest Liver Physiol 1998; 38: G668–G674.
Sonoyama K, Suzuki K, Kasai T . Peptide YY stimulate the expression of apolipoprotein A-IV gene in Caco-2 intestinal cells. Proc Soc Exp Biol Med 2000; 223: 270–275.
Morton NM, Emilsson V, Liu YL, Cawthorne MA . Leptin action in intestinal cells. J Biol Chem 1998; 273: 26194–26201.
Doi T, Liu M, Seeley RJ, Woods SC, Tso P . Effect of leptin on intestinal apolipoprotein AIV in response to lipid feeding. Am J Physiol Regul Integr Comp Physiol 2001; 281: R753–R759.
Elshourbagy NA, Walker DW, Paik YK, Boguski MS, Freeman M, Gordon JI, Taylor JM . Structure and expression of human apolipoprotein A-IV gene. J Biol Chem 1987; 262: 7973–7981.
Ehnoholm C, Tenkanen H, de Knijff P, Havekes L, Rosseneu M, Menzel H-J, Tiret L . Genetic polymorphism of apolipoprotein A-IV in five different regions of Europe. Relations to plasma lipoprotein and to history of myocardial: the EARS study. Atherosclerosis 1994; 107: 229–238.
Campos H, Lopez-Miranda J, Rodriguez C, Albajar M, Schaefer EJ, Ordovas JM . Urbanization elicits a more atherogenic lipoprotein profile in carriers of the apolipoprotein A-IV-2 allele than in A-IV-1 homozygotes. Arterioscler Thromb Vasc Biol 1997; 17: 1074–1081.
Kee F, Amouyel P, Fumeron F, Arveiler D, Camou JP, Evans A, Cambien F, Fruchart JC, Ducimetière P, Dallongeville J . Lack of association between genetic variations of apo A-I-C-III-A-IV gene cluster and myocardial infarction in a sample of European male: ECTIM study. Atherosclerosis 1999; 145: 187–195.
Groenendijk M, Cantor RM, de Bruin TWA, Dallinga-Thie G . The apoAI-CIII-AIV gene cluster. Atherosclerosis 2001; 157: 1–11.
Fisher RM, Burke H, Nicaud V, Ehnholm C, Humphries SE . Effect of variation in the apo A-IV gene on body mass index and fasting and postprandial lipids in the European Atherosclerosis Research Study II. J Lipid Res 1999; 40: 287–294.
Lefevre M, Lovejoy JC, DeFelice SM, Keener JW, Bray GA, Ryan DH, Hwang DH, Greenway FL . Common apolipoprotein A-IV variants are associated with differences in body mass index levels and percentage body fat. Int J Obes Relat Metab Disord 2000; 24: 945–953.
World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO consultation on obesity, Geneva, 3–5 June 1997. World Health Organization: Geneva; 1998.
Lean MEJ, Han TS, Morrison CE . Waist circumference as a measure for indicating need for weight management. BMJ 1995; 311: 158–161.
Pesce AJ, Kaplan LA . Methods in clinical chemistry. The C. V. Mosby Co.: St. Louis; 1987.
Friedewald NT, Levy RI, Fredrickson DS . Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use the preparative ultracentrifuge. Clin Chem 1972; 18: 499–502.
Lahiri DK, Nurnberger JI . A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991; 19: 5444.
Hixson JE, Powers PK . Restriction isotyping of human apolipoprotein A-IV: rapid typing of known isoforms and detection of a new isoform that deletes a conserved repeat. J Lipid Res 1991; 32: 1529–1535.
Zaiou M, Visvikis S, Gueguen R, Parra HJ, Fruchart JC, Siest G . DNA polymorphisms of human apolipoprotein A-IV gene: frequency and effects on lipid, lipoprotein and apolipoprotein levels in a French population. Clin Genet 1994; 46: 248–254.
Schneider S, Roessli D, Excoffier L . Arlequin ver. 2.000. A software for population genetics data analysis. University of Geneva: Geneva; 2000.
Lewontin RC . On measures of gametic disequilibrium. Genetics 1988; 120: 849–852.
Salzano FM, Freire-Maia N . Problems in human biology. A study of Brazilian populations. Wayne State University Press: Detroit; 1970.
Weinberg R . Apolipoprotein A-IV-2 allele: association of its worldwide distribution with adult persistence of lactase and speculation on its function and origin. Genet Epidemiol 1999; 17: 285–297.
Weinberg R . Apolipoprotein A-IV polymorphisms and diet–gene interactions. Curr Opin Lipidol 2002; 13: 125–134.
Stalenhoef AF, Aalto-Setala K, Armstrong VW, Benlian P, Dieplinger H, Humphries S, Steinmetz A . The 19th annual meeting of the European Lipoprotein Club. Arterioscler Thromb Vasc Biol 1997; 17: 2316–2325.
Troisi RJ, Heinold JW, Vokonas PS, Weiss ST . Cigarette smoking, dietary intake, and physical activity: effects on body fat distribution—the Normative Aging Study. Am J Clin Nutr 1991; 53: 1104–1111.
Han TS, Bijnen FCH, Lean MEJ, Seidell JC . Separate associations of waist and hip circumference with lifestyle factors. Int J Epidemiol 1998; 27: 422–430.
Visser M, Launer LJ, Deurenberg P, Deeg DJ . Past and current smoking in relation to body fat distribution in older men and women. J Gerontol A Biol Sci Med Sci 1999; 54: M293–M298.
Waterworth DM, Talmud PJ, Bujac SR, Fisher RM, Miller GJ, Humphries SE . Contribution of apolipoprotein C-III gene variants to determination of triglyceride levels and interaction with smoking in middle-aged men. Arterioscler Thromb Vasc Biol 2000; 20: 2663–2669.
Acknowledgements
Thanks are due to Ana Lúcia S Antunes and Maria Perpétua de O Pinto from the Clinical Analysis Laboratory of the Pharmacy College and to Gledison Gastaldo from the Biochemical Laboratory of the Clinical Hospital of Porto Alegre. We are also grateful to André Vargas, Fabiana M de Andrade, Marsel Arsand, Silvana de Almeida and Vanessa S Mattevi for help in sample collection. Financial support was provided by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil), Programa de Apoio a Núcleos de Excelência (PRONEX, Brazil) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Brazil).
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Fiegenbaum, M., Hutz, M. Further evidence for the association between obesity-related traits and the apolipoprotein A-IV gene. Int J Obes 27, 484–490 (2003). https://doi.org/10.1038/sj.ijo.0802256
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DOI: https://doi.org/10.1038/sj.ijo.0802256
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