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Human Genetics

, Volume 132, Issue 7, pp 783–792 | Cite as

Genome-wide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japan

  • Takuya Kitamoto
  • Aya Kitamoto
  • Masato Yoneda
  • Hideyuki Hyogo
  • Hidenori Ochi
  • Takahiro Nakamura
  • Hajime Teranishi
  • Seiho Mizusawa
  • Takato Ueno
  • Kazuaki Chayama
  • Atsushi Nakajima
  • Kazuwa Nakao
  • Akihiro Sekine
  • Kikuko Hotta
Original Investigation

Abstract

We examined the genetic background of nonalcoholic fatty liver disease (NAFLD) in the Japanese population, by performing a genome-wide association study (GWAS). For GWAS, 392 Japanese NAFLD subjects and 934 control individuals were analyzed. For replication studies, 172 NAFLD and 1,012 control subjects were monitored. After quality control, 261,540 single-nucleotide polymorphisms (SNPs) in autosomal chromosomes were analyzed using a trend test. Association analysis was also performed using multiple logistic regression analysis using genotypes, age, gender and body mass index (BMI) as independent variables. Multiple linear regression analyses were performed to evaluate allelic effect of significant SNPs on biochemical traits and histological parameters adjusted by age, gender, and BMI. Rs738409 in the PNPLA3 gene was most strongly associated with NAFLD after adjustment (P = 6.8 × 10−14, OR = 2.05). Rs2896019, and rs381062 in the PNPLA3 gene, rs738491, rs3761472, and rs2143571 in the SAMM50 gene, rs6006473, rs5764455, and rs6006611 in the PARVB gene had also significant P values (<2.0 × 10−10) and high odds ratios (1.84–2.02). These SNPs were found to be in the same linkage disequilibrium block and were associated with decreased serum triglycerides and increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in NAFLD patients. These SNPs were associated with steatosis grade and NAFLD activity score (NAS). Rs738409, rs2896019, rs738491, rs6006473, rs5764455, and rs6006611 were associated with fibrosis. Polymorphisms in the SAMM50 and PARVB genes in addition to those in the PNPLA3 gene were observed to be associated with the development and progression of NAFLD.

Keywords

Hyaluronic Acid NASH Nonalcoholic Fatty Liver Disease NAFLD Patient Simple Steatosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by a Grant-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan (21591186 to K. H, 23791027 to A. K., and 23701082 to T. K.).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

439_2013_1294_MOESM1_ESM.docx (1.4 mb)
Supplementary material 1 (DOCX 1419 kb)

References

  1. Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 18:1221–1231CrossRefGoogle Scholar
  2. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265CrossRefPubMedGoogle Scholar
  3. Basantani MK, Sitnick MT, Cai L, Brenner DS, Gardner NP, Li JZ, Schoiswohl G, Yang K, Kumari M, Gross RW, Zechner R, Kershaw EE (2011) Pnpla3/adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res 52:318–329CrossRefPubMedGoogle Scholar
  4. Brunt EM (2001) Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 21:3–16CrossRefPubMedGoogle Scholar
  5. Caldwell SH, Swerdlow RH, Khan EM, Iezzoni JC, Hespenheide EE, Parks JK, Parker WD Jr (1999) Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepato l 31:430–434CrossRefGoogle Scholar
  6. Chalasani N, Guo X, Loomba R, Goodarzi MO, Haritunians T, Kwon S, Cui J, Taylor KD, Wilson L, Cummings OW, Chen YD, Rotter JI, Nonalcoholic Steatohepatitis Clinical Research Network (2010) Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology 139:1567–1576CrossRefPubMedGoogle Scholar
  7. Chen W, Chang B, Li L, Chan L (2010) Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease. Hepatology 52:1134–1142CrossRefPubMedGoogle Scholar
  8. Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114:842–845CrossRefPubMedGoogle Scholar
  9. Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10:9–22CrossRefPubMedGoogle Scholar
  10. Farrell GC (2003) Non-alcoholic steatohepatitis: what is it, and why is it important in the Asia-Pacific region? J Gastroenterol Hepatol 18:124–138CrossRefPubMedGoogle Scholar
  11. Hotta K, Yoneda M, Hyogo H, Ochi H, Mizusawa S, Ueno T, Chayama K, Nakajima A, Nakao K, Sekine A (2010) Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease. BMC Med Genet 11:172CrossRefPubMedGoogle Scholar
  12. Johnstone CN, Mongroo PS, Rich AS, Schupp M, Bowser MJ, Delemos AS, Tobias JW, Liu Y, Hannigan GE, Rustgi AK (2008) Parvin-beta inhibits breast cancer tumorigenicity and promotes CDK9-mediated peroxisome proliferator-activated receptor gamma 1 phosphorylation. Mol Cell Biol 28:687–704CrossRefPubMedGoogle Scholar
  13. Kawaguchi T, Sumida Y, Umemura A, Matsuo K, Takahashi M, Takamura T, Yasui K, Saibara T, Hashimoto E, Kawanaka M, Watanabe S, Kawata S, Imai Y, Kokubo M, Shima T, Park H, Tanaka H, Tajima K, Yamada R, Matsuda F, Takeshi O, Japan Study Group of Nonalcoholic Fatty Liver Disease (2012) Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS One 7:e38322CrossRefPubMedGoogle Scholar
  14. Kimura M, Murakami T, Kizaka-Kondoh S, Itoh M, Yamamoto K, Hojo Y, Takano M, Kario K, Shimada K, Kobayashi E (2010) Functional molecular imaging of ILK-mediated Akt/PKB signaling cascades and the associated role of beta-parvin. J Cell Sci 123:747–755CrossRefPubMedGoogle Scholar
  15. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ, Nonalcoholic Steatohepatitis Clinical Research Network (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41:1313–1321CrossRefPubMedGoogle Scholar
  16. Kollerits B, Coassin S, Beckmann ND, Teumer A, Kiechl S, Döring A, Kavousi M, Hunt SC, Lamina C, Paulweber B, Kutalik Z, Nauck M, van Duijn CM, Heid IM, Willeit J, Brandstätter A, Adams TD, Mooser V, Aulchenko YS, Völzke H, Kronenberg F (2009) Genetic evidence for a role of adiponutrin in the metabolism of apolipoprotein B-containing lipoproteins. Hum Mol Genet 18:4669–4676CrossRefPubMedGoogle Scholar
  17. Krarup NT, Grarup N, Banasik K, Friedrichsen M, Færch K, Sandholt CH, Jørgensen T, Poulsen P, Witte DR, Vaag A, Sørensen T, Pedersen O, Hansen T (2012) The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation. PLoS ONE 7:e40376CrossRefPubMedGoogle Scholar
  18. Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, Castro-Perez J, Cohen JC, Hobbs HH (2012) Chronic overexpression of PNPLA3I148 M in mouse liver causes hepatic steatosis. J Clin Invest, in press. doi: 10.1172/JCI65179
  19. Ludwig J, Viggiano TR, McGill DB, Oh BJ (1980) Nonalcoholic steatohepatitis: Mayo clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55:434–438PubMedGoogle Scholar
  20. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N (2001) Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50:1844–1850CrossRefPubMedGoogle Scholar
  21. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ (1999) Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116:1413–1419CrossRefPubMedGoogle Scholar
  22. Nielsen DM, Ehm MG, Weir BS (1998) Detecting marker-disease association by testing for Hardy–Weinberg disequilibrium at a marker locus. Am J Hum Genet 63:1531–1540CrossRefPubMedGoogle Scholar
  23. Ohnishi Y, Tanaka T, Ozaki K, Yamada R, Suzuki H, Nakamura Y (2001) A high-throughput SNP typing system for genome-wide association studies. J Hum Genet 46:471–477CrossRefPubMedGoogle Scholar
  24. Ott C, Ross K, Straub S, Thiede B, Götz M, Goosmann C, Krischke M, Mueller MJ, Krohne G, Rudel T, Kozjak-Pavlovic V (2012) Sam50 functions in mitochondrial intermembrane space bridging and biogenesis of respiratory complexes. Mol Cell Biol 32:1173–1188CrossRefPubMedGoogle Scholar
  25. Palmer CN, Maglio C, Pirazzi C, Burza MA, Adiels M, Burch L, Donnelly LA, Colhoun H, Doney AS, Dillon JF, Pearson ER, McCarthy M, Hattersley AT, Frayling T, Morris AD, Peltonen M, Svensson PA, Jacobson P, Borén J, Sjöström L, Carlsson LM, Romeo S (2012) Paradoxical lower serum triglyceride levels and higher type 2 diabetes mellitus susceptibility in obese individuals with the PNPLA3 148 M variant. PLoS ONE 7:e39362CrossRefPubMedGoogle Scholar
  26. Patsenker E, Stickel F (2011) Role of integrins in fibrosing liver diseases. Am J Physiol Gastrointest Liver Physiol 301:G425–G434CrossRefPubMedGoogle Scholar
  27. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575CrossRefPubMedGoogle Scholar
  28. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH (2008) Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40:1461–1465CrossRefPubMedGoogle Scholar
  29. Sanyal AJ (2002) American Gastroenterological Association: AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 123:1705–1725CrossRefPubMedGoogle Scholar
  30. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN (2001) Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120:1183–1192CrossRefPubMedGoogle Scholar
  31. Sookoian S, Pirola CJ (2011) Meta-analysis of the influence of I148 M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 53:1883–1894CrossRefPubMedGoogle Scholar
  32. Speliotes EK, Butler JL, Palmer CD, Voight BF, GIANT Consortium; MIGen Consortium; NASH CRN, Hirschhorn JN (2010) PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 52:904–912Google Scholar
  33. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, Gudnason V, Eiriksdottir G, Garcia ME, Launer LJ, Nalls MA, Clark JM, Mitchell BD, Shuldiner AR, Butler JL, Tomas M, Hoffmann U, Hwang SJ, Massaro JM, O’Donnell CJ, Sahani DV, Salomaa V, Schadt EE, Schwartz SM, Siscovick DS; NASH CRN; GIANT Consortium; MAGIC Investigators, Voight BF, Carr JJ, Feitosa MF, Harris TB, Fox CS, Smith AV, Kao WH, Hirschhorn JN, Borecki IB; GOLD Consortium (2011) Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 7:e1001324Google Scholar
  34. Stefan N, Kantartzis K, Häring HU (2008) Causes and metabolic consequences of fatty liver. Endocr Rev 29:939–960CrossRefPubMedGoogle Scholar
  35. Teli MR, James OF, Burt AD, Bennett MK, Day CP (1995) The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 22:1714–1719CrossRefPubMedGoogle Scholar
  36. Wilfred de Alwis NM, Day CP (2008) Genes and nonalcoholic fatty liver disease. Curr Diab Rep 8:156–163CrossRefPubMedGoogle Scholar
  37. Yoneda M, Hotta K, Nozaki Y, Endo H, Uchiyama T, Mawatari H, Iida H, Kato S, Hosono K, Fujita K, Yoneda K, Takahashi H, Kirikoshi H, Kobayashi N, Inamori M, Abe Y, Kubota K, Saito S, Maeyama S, Wada K, Nakajima A (2008) Association between PPARGC1A polymorphisms and the occurrence of nonalcoholic fatty liver disease (NAFLD). BMC Gastroenterol 8:27–34CrossRefPubMedGoogle Scholar
  38. Yoneda M, Hotta K, Nozaki Y, Endo H, Uchiyama T, Mawatari H, Iida H, Kato S, Fujita K, Takahashi H, Kirikoshi H, Kobayashi N, Inamori M, Abe Y, Kubota K, Saito S, Maeyama S, Wada K, Nakajima A (2009a) Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int 29:1078–1085CrossRefPubMedGoogle Scholar
  39. Yoneda M, Hotta K, Nozaki Y, Endo H, Tomeno W, Watanabe S, Hosono K, Mawatari H, Iida H, Fujita K, Takahashi H, Kirikoshi H, Kobayashi N, Inamori M, Kubota K, Shimamura T, Saito S, Maeyama S, Wada K, Nakajima A (2009b) Influence of inducible nitric oxide synthase polymorphisms in Japanese patients with non-alcoholic fatty liver disease. Hepatol Res 39:963–971CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Takuya Kitamoto
    • 1
  • Aya Kitamoto
    • 1
  • Masato Yoneda
    • 2
  • Hideyuki Hyogo
    • 3
  • Hidenori Ochi
    • 3
  • Takahiro Nakamura
    • 4
  • Hajime Teranishi
    • 5
  • Seiho Mizusawa
    • 5
  • Takato Ueno
    • 6
  • Kazuaki Chayama
    • 3
  • Atsushi Nakajima
    • 2
  • Kazuwa Nakao
    • 1
    • 7
  • Akihiro Sekine
    • 1
  • Kikuko Hotta
    • 1
  1. 1.EBM Research CenterKyoto University Graduate School of MedicineKyotoJapan
  2. 2.Division of GastroenterologyYokohama City University Graduate School of MedicineYokohamaJapan
  3. 3.Division of Frontier Medical Science, Department of Medicine and Molecular SciencePrograms for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima UniversityHiroshimaJapan
  4. 4.Laboratory for MathematicsNational Defense Medical CollegeTokorozawaJapan
  5. 5.Center for Genomic Medicine, Unit of Genome InformaticsKyoto University Graduate School of MedicineKyotoJapan
  6. 6.Research Center for Innovative Cancer Therapy, Kurume UniversityKurumeJapan
  7. 7.Department of Medicine and Clinical ScienceKyoto University Graduate School of MedicineKyotoJapan

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