Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease
Masato Yoneda
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
*These authors contributed equally to this work
Search for more papers by this authorKikuko Hotta
Laboratory for Endocrinology and Metabolism, Center for Genomic Medicine, RIKEN, Tsurumi-ku, Yokohama, Japan
*These authors contributed equally to this work
Search for more papers by this authorYuichi Nozaki
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorHiroki Endo
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorTakashi Uchiyama
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorHironori Mawatari
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorHiroshi Iida
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorShingo Kato
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorKoji Fujita
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorHirokazu Takahashi
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorHiroyuki Kirikoshi
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorNoritoshi Kobayashi
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorMasahiko Inamori
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorYasunobu Abe
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorKensuke Kubota
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorSatoru Saito
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorShiro Maeyama
Kitakashiwa Rehabilitation Hospital, Kashiwa, Japan
Search for more papers by this authorKoichiro Wada
Department of Pharmacology, Osaka University, Graduate School of Dentistry, Suita, Osaka, Japan
Search for more papers by this authorAtsushi Nakajima
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorMasato Yoneda
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
*These authors contributed equally to this work
Search for more papers by this authorKikuko Hotta
Laboratory for Endocrinology and Metabolism, Center for Genomic Medicine, RIKEN, Tsurumi-ku, Yokohama, Japan
*These authors contributed equally to this work
Search for more papers by this authorYuichi Nozaki
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorHiroki Endo
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorTakashi Uchiyama
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorHironori Mawatari
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorHiroshi Iida
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorShingo Kato
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorKoji Fujita
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorHirokazu Takahashi
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorHiroyuki Kirikoshi
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorNoritoshi Kobayashi
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorMasahiko Inamori
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorYasunobu Abe
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorKensuke Kubota
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorSatoru Saito
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorShiro Maeyama
Kitakashiwa Rehabilitation Hospital, Kashiwa, Japan
Search for more papers by this authorKoichiro Wada
Department of Pharmacology, Osaka University, Graduate School of Dentistry, Suita, Osaka, Japan
Search for more papers by this authorAtsushi Nakajima
Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City University Hospital, Yokohama, Japan
Search for more papers by this authorAbstract
Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver injury in many countries. Genetic factors are important for the development of NAFLD, as well as environmental factors. Recently an angiotensin II type 1 receptor (AGTR1) has been recognized as important in the aetiology of fibrosis in the liver.
Objective: In this study we investigated the association between angiotensin II type 1 receptor gene polymorphism (ATGR1) and NAFLD.
Methods: One hundred and sixty-seven NAFLD patients [106 with nonalcoholic steatohepatitis (NASH) and 61 with simple steatosis] with a positive diagnosis by liver biopsy and 435 healthy control subjects were recruited in this study.
Results: We investigated 12 single nucleotide polymorphisms (SNPs) of the ATGR1 gene, among which rs3772622 showed the lowest P-value of allele frequency model (P=0.0000012) with an odds ratio (95% confidence interval) of 1.95 (1.49–2.55). Five SNPs (rs3772622, rs3772633, rs2276736, rs3772630 and rs3772627) were significantly associated with NAFLD, even when the most conservative Bonferroni's correction was applied. Linkage disequilibrium analysis revealed that SNP rs3772622 and another four SNPs (rs3772633, rs2276736, rs3772630 and rs3772627) were in the same block. We investigated the association between rs3772622 genotypes and the fibrosis index. The results of the analysis revealed an additive increase of the fibrosis index in the patients with the A allele of rs3772622.
Conclusions: This is the first report to demonstrate the genetic variations in ATGR1 that may influence the risk of NAFLD and liver fibrosis in NAFLD.
References
- 1 Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 18: 1221–31.
- 2 Farrell GC. Non-alcoholic steatohepatitis: what is it, and why is it important in the Asia-Pacific region? J Gastroenterol Hepatol 2003; 18: 124–38.
- 3 Ludwig J, Viggiano TR, McGill DB, et al. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 434–8.
- 4 Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: 1844–50.
- 5 Namikawa C, Shu-Ping Z, Vyselaar JR, et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol 2004; 40: 781–6.
- 6 Gambino R, Cassader M, Pagano G, et al. Polymorphism in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH? Hepatology 2007; 45: 1097–107.
- 7 Tokushige K, Takakura M, Tsuchiya-Matsushita N, et al. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol 2007; 46: 1104–10.
- 8 Merriman RB, Aouizerat BE, Bass NM. Genetic influences in nonalcoholic fatty liver disease. J Clin Gastroenterol 2006; 40: S30–3.
- 9 Tanabe A, Yanagiya T, Iida A, et al. Functional SNPs in the secretogranin III (SCG3) gene that forms secretory granules with appetite-related neuropeptides are associated with obesity. J Clin Endocrinol Metab 2007; 92: 1145–54.
- 10 Yanagiya T, Tanabe A, Iida A, et al. Association of single nucleotide polymorphisms in MTMR9 gene with obesity. Hum Mol Genet 2007; 16: 3017–26.
- 11 Yonada M, Hotta K, Nozaki Y, et al. Association between PPARGC1A polymorphisms and the occurrence of nonalcoholic fatty liver disease (NAFLD). BMC Gastroenterol 2008; 8: 27.
- 12 Crawford DC, Chobanian AV, Brecher P. Angiotensin II induces fibronectin expression associated with cardiac fibrosis in the rat. Circ Res 1994; 74: 727–39.
- 13 Sadoshima J, Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res 1993; 73: 413–23.
- 14 Wilke A, Funck R, Rupp H, et al. Effect of the renin–angiotensin–aldosterone system on the cardiac interstitium in heart failure. Basic Res Cardiol 1996; 91 (Suppl. 2): 79–84.
- 15 Lafayette RA, Mayer G, Park SK, et al. Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest 1992; 90: 766–71.
- 16 Rosenberg ME, Smith LJ, Correa-Rotter R, et al. The paradox of the renin–angiotensin system in chronic renal disease. Kidney Int 1994; 45: 403–10.
- 17 Wolthuis A, Boes A, Rodemann HP, et al. Vasoactive agents affect growth and protein synthesis of cultured rat mesangial cells. Kidney Int 1992; 41: 124–31.
- 18 Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993; 45: 205–51.
- 19 Togashi N, Ura N, Higashiura K, et al. The contribution of skeletal muscle tumor necrosis factor-alpha to insulin resistance and hypertension in fructose-fed rats. J Hypertens 2000; 18: 1605–10.
- 20 Bonnardeaux A, Davies E, Jeunemaitre X, et al. Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 1994; 24: 63–9.
- 21 Benetos A, Topouchian J, Ricard S, et al. Influence of angiotensin II type 1 receptor polymorphism on aortic stiffness in never-treated hypertensive patients. Hypertension 1995; 26: 44–7.
- 22 Fujita K, Yoneda M, Wada K, et al. Telmisartan, an angiotensin II type 1 receptor blocker, controls progress of nonalcoholic steatohepatitis in rats. Dig Dis Sci 2007; 52: 3455–64.
- 23 Hirose A, Ono M, Saibara T, et al. Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology 2007; 4: 1375–81.
- 24 Ibanez P, Solis N, Pizarro M, et al. Effect of losartan on early liver fibrosis development in a rat model of nonalcoholic steatohepatitis. J Gastroenterol Hepatol 2007; 22: 846–51.
- 25 Yokohama S, Yoneda M, Haneda M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 2004; 40: 1222–5.
- 26 Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 1705–25.
- 27 Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116: 1413–9.
- 28 Teli MR, James OF, Burt AD, et al. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22: 1714–9.
- 29 Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 2001; 21: 3–16.
- 30 Hirakawa M, Tanaka T, Hashimoto Y, et al. JSNP: a database of common gene variations in the Japanese population. Nucleic Acids Res 2002; 30: 158–62.
- 31 Ohnishi Y, Tanaka T, Ozaki K, et al. A high-throughput SNP typing system for genome-wide association studies. J Hum Genet 2001; 46: 471–7.
- 32 Nielsen DM, Ehm MG, Weir BS. Detecting marker-disease association by testing for Hardy–Weinberg disequilibrium at a marker locus. Am J Hum Genet 1998; 63: 1531–40.
- 33
Barrett JC,
Fry B,
Maller J, et al. Haploview: analysis and visualization of LD and haplotype maps.
Bioinformatics
2005; 21: 263–5.
10.1073/pnas.88.11.4675 Google Scholar
- 34 Kugelmas M, Hill DB, Vivian B, et al. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 2003; 38: 413–9.
- 35 Hasegawa T, Yoneda M, Nakamura K, et al. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001; 15: 1667–72.
- 36 Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003; 38: 1008–17.
- 37 Tilg H, Kaser A. Treatment strategies in nonalcoholic fatty liver disease. Nat Clin Pract Gastroenterol Hepatol 2005; 2: 148–55.
- 38 Yoshiji H, Kuriyama S, Yoshii J, et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 2001; 34: 745–50.
- 39 Benetos A, Cambien F, Gautier S, et al. Influence of the angiotensin II type 1 receptor gene polymorphism on the effects of perindopril and nitrendipine on arterial stiffness in hypertensive individuals. Hypertension 1996; 28: 1081–4.
Citing Literature
