title: 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.
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.
authors.affiliation: EBM Research Center, Kyoto University Graduate School of Medicine, Yoshida-Konoecho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kitamoto
authors.forename: Aya
authors.initials: A
authors.lastname: Kitamoto
authors.forename: Masato
authors.initials: M
authors.lastname: Yoneda
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hyogo
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ochi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hajime
authors.initials: H
authors.lastname: Teranishi
authors.forename: Seiho
authors.initials: S
authors.lastname: Mizusawa
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sekine
authors.forename: Kikuko
authors.initials: K
authors.lastname: Hotta
mesh_terms: D000185:Actinin / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood / Q000235:genetics; D044466:Asian People; D001219:Aspartate Aminotransferases / Q000097:blood / Q000235:genetics; D005234:Fatty Liver / Q000097:blood / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005355:Fibrosis; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D014280:Triglycerides / Q000097:blood / Q000235:genetics; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D000185:Actinin; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D008049:Lipase; D008565:Membrane Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D014280:Triglycerides; C486591:PARVB protein, human; C522815:SAMM50 protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
references.citation: Hum Mol Genet. 2009 Dec 1;18(23):4669-76
references.pmid: 19729411
references.citation: Gastroenterology. 2010 Nov;139(5):1567-76, 1576.e1-6
references.pmid: 20708005
references.citation: Mayo Clin Proc. 1980 Jul;55(7):434-8
references.pmid: 7382552
references.citation: PLoS Genet. 2011 Mar;7(3):e1001324
references.pmid: 21423719
references.citation: N Engl J Med. 2002 Apr 18;346(16):1221-31
references.pmid: 11961152
references.citation: PLoS One. 2012;7(7):e40376
references.pmid: 22792295
references.citation: J Gastroenterol Hepatol. 2003 Feb;18(2):124-38
references.pmid: 12542595
references.citation: Mol Cell Biol. 2012 Mar;32(6):1173-88
references.pmid: 22252321
references.citation: J Hum Genet. 2001;46(8):471-7
references.pmid: 11501945
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: PLoS One. 2012;7(6):e38322
references.pmid: 22719876
references.citation: J Hepatol. 1999 Sep;31(3):430-4
references.pmid: 10488700
references.citation: Semin Liver Dis. 2001;21(1):3-16
references.pmid: 11296695
references.citation: Hepatology. 2011 Jun;53(6):1883-94
references.pmid: 21381068
references.citation: Endocr Rev. 2008 Dec;29(7):939-60
references.pmid: 18723451
references.citation: Gastroenterology. 2001 Apr;120(5):1183-92
references.pmid: 11266382
references.citation: Hepatology. 2005 Jun;41(6):1313-21
references.pmid: 15915461
references.citation: Mol Cell Biol. 2008 Jan;28(2):687-704
references.pmid: 17998334
references.citation: Gastroenterology. 2002 Nov;123(5):1705-25
references.pmid: 12404245
references.citation: Gastroenterology. 1998 Apr;114(4):842-5
references.pmid: 9547102
references.citation: Hepatology. 1995 Dec;22(6):1714-9
references.pmid: 7489979
references.citation: Diabetes. 2001 Aug;50(8):1844-50
references.pmid: 11473047
references.citation: PLoS One. 2012;7(6):e39362
references.pmid: 22724004
references.citation: Am J Hum Genet. 1998 Nov;63(5):1531-40
references.pmid: 9867708
references.citation: Curr Diab Rep. 2008 Apr;8(2):156-63
references.pmid: 18445359
references.citation: BMC Med Genet. 2010 Dec 22;11:172
references.pmid: 21176169
references.citation: Hepatol Res. 2009 Oct;39(10):963-71
references.pmid: 19624767
references.citation: Gastroenterology. 1999 Jun;116(6):1413-9
references.pmid: 10348825
references.citation: J Cell Sci. 2010 Mar 1;123(Pt 5):747-55
references.pmid: 20164304
references.citation: Nat Rev Cancer. 2010 Jan;10(1):9-22
references.pmid: 20029421
references.citation: Nat Genet. 2008 Dec;40(12):1461-5
references.pmid: 18820647
references.citation: J Lipid Res. 2011 Feb;52(2):318-29
references.pmid: 21068004
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Liver Int. 2009 Aug;29(7):1078-85
references.pmid: 19302184
references.citation: BMC Gastroenterol. 2008 Jun 27;8:27
references.pmid: 18588668
references.citation: J Clin Invest. 2012 Nov;122(11):4130-44
references.pmid: 23023705
references.citation: Hepatology. 2010 Sep;52(3):904-12
references.pmid: 20648472
references.citation: Hepatology. 2010 Sep;52(3):1134-42
references.pmid: 20648554
references.citation: Am J Physiol Gastrointest Liver Physiol. 2011 Sep;301(3):G425-34
references.pmid: 21659620