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Genetic variants that associate with cirrhosis have pleiotropic effects on human traits
dc.contributor.authorChen, Vincent L.
dc.contributor.authorChen, Yanhua
dc.contributor.authorDu, Xiaomeng
dc.contributor.authorHandelman, Samuel K.
dc.contributor.authorSpeliotes, Elizabeth K.
dc.date.accessioned2020-02-05T15:05:42Z
dc.date.availableWITHHELD_13_MONTHS
dc.date.available2020-02-05T15:05:42Z
dc.date.issued2020-02
dc.identifier.citationChen, Vincent L.; Chen, Yanhua; Du, Xiaomeng; Handelman, Samuel K.; Speliotes, Elizabeth K. (2020). "Genetic variants that associate with cirrhosis have pleiotropic effects on human traits." Liver International 40(2): 405-415.
dc.identifier.issn1478-3223
dc.identifier.issn1478-3231
dc.identifier.urihttps://hdl.handle.net/2027.42/153621
dc.description.abstractBackground and AimsCirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver‐related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits.MethodsWe carried out a genome‐wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top‐associating loci for replication with cirrhosis in a hospital‐based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites.ResultsUnbiased genome‐wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase‐to‐platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits.ConclusionsWe identified eight loci that reproducibly associate with population‐based cirrhosis and define their diverse effects on human diseases and traits.See Editorial on Page 281
dc.publisherWiley Periodicals, Inc.
dc.subject.otherSNP
dc.subject.otherphenotype
dc.subject.othergenetics
dc.subject.otherfibrosis
dc.titleGenetic variants that associate with cirrhosis have pleiotropic effects on human traits
dc.typeArticle
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelInternal Medicine and Specialties
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/153621/1/liv14321_am.pdf
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/153621/2/liv14321.pdf
dc.identifier.doi10.1111/liv.14321
dc.identifier.sourceLiver International
dc.identifier.citedreferenceSpeliotes EK, Butler JL, Palmer CD, et al. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology. 2010; 52 ( 3 ): 904 ‐ 912.
dc.identifier.citedreferenceLi JZ, Huang Y, Karaman R, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest. 2012; 122 ( 11 ): 4130 ‐ 4144.
dc.identifier.citedreferenceWai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003; 38 ( 2 ): 518 ‐ 526.
dc.identifier.citedreferenceKim DS, Jackson AU, Li YK, et al. Novel association of TM6SF2 rs58542926 genotype with increased serum tyrosine levels and decreased apoB‐100 particles in Finns. J Lipid Res. 2017; 58 ( 7 ): 1471 ‐ 1481.
dc.identifier.citedreferenceHyysalo J, Gopalacharyulu P, Bian H, et al. Circulating triacylglycerol signatures in nonalcoholic fatty liver disease associated with the I148M variant in PNPLA3 and with obesity. Diabetes. 2014; 63: 312 ‐ 322.
dc.identifier.citedreferencePalmer CNA, Maglio C, Pirazzi C, et al. Paradoxical lower serum triglyceride levels and higher type 2 diabetes mellitus susceptibility in obese individuals with the PNPLA3 148M variant. PLoS ONE. 2012; 7 ( 6 ): e39362.
dc.identifier.citedreferencePilling LC, Tamosauskaite J, Jones G, et al. Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. BMJ. 2019; 364: k5222.
dc.identifier.citedreferenceElliott LT, Sharp K, Alfaro‐Almagro F, et al. Genome‐wide association studies of brain imaging phenotypes in UK Biobank. Nature. 2018; 562 ( 7726 ): 210 ‐ 216.
dc.identifier.citedreferenceTamosauskaite J, Atkins JL, Pilling LC, et al. Hereditary hemochromatosis associations with frailty, sarcopenia and chronic pain: evidence from 200,975 older UK biobank participants. J Gerontol A Biol Sci Med Sci. 2019; 74 ( 3 ): 337 ‐ 342.
dc.identifier.citedreferenceClark VC, Marek G, Liu C, et al. Clinical and histologic features of adults with alpha‐1 antitrypsin deficiency in a non‐cirrhotic cohort. J Hepatol. 2018; 69 ( 6 ): 1357 ‐ 1364.
dc.identifier.citedreferenceKim RG, Nguyen P, Bettencourt R, et al. Magnetic resonance elastography identifies fibrosis in adults with alpha‐1 antitrypsin deficiency liver disease: a prospective study. Aliment Pharmacol Ther. 2016; 44 ( 3 ): 287 ‐ 299.
dc.identifier.citedreferenceHamesch K, Mandorfer M, Pereira VM, et al. Liver fibrosis and metabolic alterations in adults with alpha‐1‐antitrypsin deficiency caused by the Pi*ZZ mutation. Gastroenterology. 2019; 157 ( 3 ): 705 – 719.e18.
dc.identifier.citedreferenceTanash HA, Piitulainen E. Liver disease in adults with severe alpha‐1‐antitrypsin deficiency. J Gastroenterol. 2019; 54 ( 6 ): 541 ‐ 548.
dc.identifier.citedreferenceEmdin CA, Haas M, Khera AV, et al. A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease. bioRxiv; 2019: 594523.
dc.identifier.citedreferenceMahdessian H, Taxiarchis A, Popov S, et al. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc Natl Acad Sci USA. 2014; 111 ( 24 ): 8913 ‐ 8918.
dc.identifier.citedreferenceTrauner M, Gulamhusein A, Hameed B, et al. The nonsteroidal FXR agonist cilofexor (GS‐9674) improves markers of cholestasis and liver injury in patients with PSC. Hepatology. 2019; 70: 788 ‐ 801.
dc.identifier.citedreferencePrivitera G, Spadaro L, Marchisello S, Fede G, Purrello F. Abnormalities of lipoprotein levels in liver cirrhosis: clinical relevance. Dig Dis Sci. 2018; 63 ( 1 ): 16 ‐ 26.
dc.identifier.citedreferenceTrepo E, Romeo S, Zucman‐Rossi J, Nahon P. PNPLA3 gene in liver diseases. J Hepatol. 2016; 65 ( 2 ): 399 ‐ 412.
dc.identifier.citedreferenceThabet K, Asimakopoulos A, Shojaei M, et al. MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. Nat Commun. 2016; 7: 12757.
dc.identifier.citedreferenceHolmen OL, Zhang HE, Fan Y, et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet. 2014; 46 ( 4 ): 345 ‐ 351.
dc.identifier.citedreferencePirola CJ, Sookoian S. The dual and opposite role of the TM6SF2‐rs58542926 variant in protecting against cardiovascular disease and conferring risk for nonalcoholic fatty liver: a meta‐analysis. Hepatology. 2015; 62 ( 6 ): 1742 ‐ 1756.
dc.identifier.citedreferenceNehra MS, Ma Y, Clark C, Amarasingham R, Rockey DC, Singal AG. Use of administrative claims data for identifying patients with cirrhosis. J Clin Gastroenterol. 2013; 47 ( 5 ): e50 ‐ e54.
dc.identifier.citedreferenceZhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol. 2014; 20 ( 23 ): 7312 ‐ 7324.
dc.identifier.citedreferenceMokdad AA, Lopez AD, Shahraz S, et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med. 2014; 12 ( 1 ): 145.
dc.identifier.citedreferenceMellinger JL, Shedden K, Winder GS, et al. The high burden of alcoholic cirrhosis in privately insured persons in the United States. Hepatology. 2018; 68 ( 3 ): 872 ‐ 882.
dc.identifier.citedreferenceWong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015; 148 ( 3 ): 547 ‐ 555.
dc.identifier.citedreferenceLoomba R, Schork N, Chen C‐H, et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology. 2015; 149 ( 7 ): 1784 ‐ 1793.
dc.identifier.citedreferenceYang J, Trépo E, Nahon P, et al. PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases. Int J Cancer. 2019; 144 ( 3 ): 533 ‐ 544.
dc.identifier.citedreferenceBuch S, Stickel F, Trépo E, et al. A genome‐wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol‐related cirrhosis. Nat Genet. 2015; 47 ( 12 ): 1443 ‐ 1448.
dc.identifier.citedreferenceHernaez R, McLean J, Lazo M, et al. Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound‐defined steatosis based on data from the third National Health and Nutrition Examination Survey. Clin Gastroenterol Hepatol. 2013; 11 ( 9 ): 1183 ‐ 1190.e1182.
dc.identifier.citedreferenceMa Y, Belyaeva OV, Brown PM, et al. HSD17B13 is a hepatic retinol dehydrogenase associated with histological features of non‐alcoholic fatty liver disease. Hepatology. 2019; 69 ( 4 ): 1504 ‐ 1519.
dc.identifier.citedreferenceSpeliotes EK, Yerges‐Armstrong LM, Wu J, et al. Genome‐wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011; 7 ( 3 ): e1001324.
dc.identifier.citedreferencePirola CJ, Garaycoechea M, Flichman D, et al. Splice variant rs72613567 prevents worst histologic outcomes in patients with nonalcoholic fatty liver disease. J Lipid Res. 2019; 60 ( 1 ): 176 ‐ 185.
dc.identifier.citedreferenceAbul‐Husn NS, Cheng X, Li AH, et al. A protein‐truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018; 378 ( 12 ): 1096 ‐ 1106.
dc.identifier.citedreferencePatin E, Kutalik Z, Guergnon J, et al. Genome‐wide association study identifies variants associated with progression of liver fibrosis from HCV infection. Gastroenterology. 2012; 143 ( 5 ): 1244 ‐ 1252.e12.
dc.identifier.citedreferenceRüeger S, Bochud P‐Y, Dufour J‐F, et al. Impact of common risk factors of fibrosis progression in chronic hepatitis C. Gut. 2015; 64 ( 10 ): 1605 ‐ 1615.
dc.identifier.citedreferenceStickel F, Buch S, Zoller H, et al. Evaluation of genome‐wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis. Hum Mol Genet. 2014; 23 ( 14 ): 3883 ‐ 3890.
dc.identifier.citedreferenceGreene CM, Marciniak SJ, Teckman J, et al. alpha1‐Antitrypsin deficiency. Nat Rev Dis Primers. 2016; 2: 16051.
dc.identifier.citedreferenceRadford‐Smith DE, Powell EE, Powell LW. Haemochromatosis: a clinical update for the practising physician. Intern Med J. 2018; 48 ( 5 ): 509 ‐ 516.
dc.identifier.citedreferenceCanela‐Xandri O, Rawlik K, Tenesa A. An atlas of genetic associations in UK Biobank. Nat Genet. 2018; 50: 1593 ‐ 1599.
dc.identifier.citedreferenceDey R, Schmidt EM, Abecasis GR, Lee S. A fast and accurate algorithm to test for binary phenotypes and its application to PheWAS. Am J Hum Genet. 2017; 101 ( 1 ): 37 ‐ 49.
dc.identifier.citedreferenceSudlow C, Gallacher J, Allen N, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015; 12 ( 3 ): e1001779.
dc.identifier.citedreferenceMaguire LH, Handelman SK, Du X, Chen Y, Pers TH, Speliotes EK. Genome‐wide association analyses identify 39 new susceptibility loci for diverticular disease. Nat Genet. 2018; 50 ( 10 ): 1359 ‐ 1365.
dc.identifier.citedreferenceZhou W, Nielsen JB, Fritsche LG, et al. Efficiently controlling for case‐control imbalance and sample relatedness in large‐scale genetic association studies. Nat Genet. 2018; 50 ( 9 ): 1335 ‐ 1341.
dc.identifier.citedreferenceJiang D‐K, Ma X‐P, Wu X, et al. Genetic variations in STAT4, C2, HLA‐DRB1 and HLA‐DQ associated with risk of hepatitis B virus‐related liver cirrhosis. Sci Rep. 2015; 5: 16278.
dc.identifier.citedreferenceAttallah AM, Omran D, Marie MS, et al. IL‐28B rs12979860 polymorphism affect the course of chronic hepatitis and the development of HCC in Egyptian patients with hepatitis C type 4. Br J Biomed Sci. 2018; 75 ( 4 ): 157 ‐ 162.
dc.identifier.citedreferenceBesheer T, Arafa M, El‐Maksoud MA, et al. Diagnosis of cirrhosis in patients with chronic hepatitis C genotype 4: Role of ABCB11 genotype polymorphism and plasma bile acid levels. Turk J Gastroenterol. 2018; 29 ( 3 ): 299 ‐ 307.
dc.identifier.citedreferenceMedrano LM, Rallón N, Berenguer J, et al. Relationship of TRIM5 and TRIM22 polymorphisms with liver disease and HCV clearance after antiviral therapy in HIV/HCV coinfected patients. J Transl Med. 2016; 14: 257.
dc.identifier.citedreferenceEzzikouri S, Elfihry R, Chihab H, et al. Effect of MBOAT7 variant on hepatitis B and C infections in Moroccan patients. Sci Rep. 2018; 8 ( 1 ): 12247.
dc.identifier.citedreferenceHuang L, Mo Z, Li S, Qin X. The association between PIN1 genetic polymorphisms and the risk of chronic hepatitis B and hepatitis B virus‐related liver cirrhosis: a case‐control study. Medicine (Baltimore). 2018; 97 ( 35 ): e12123.
dc.identifier.citedreferenceEl Sharkawy R, Thabet K, Lampertico P, et al. A STAT4 variant increases liver fibrosis risk in Caucasian patients with chronic hepatitis B. Aliment Pharmacol Ther. 2018; 48 ( 5 ): 564 ‐ 573.
dc.identifier.citedreferenceDai Z‐J, Liu X‐H, Wang M, et al. IL‐18 polymorphisms contribute to hepatitis B virus‐related cirrhosis and hepatocellular carcinoma susceptibility in Chinese population: a case‐control study. Oncotarget. 2017; 8 ( 46 ): 81350 ‐ 81360.
dc.identifier.citedreferenceZhang XQ, Hong XJ, Bai XJ. Susceptibility to active decompensated cirrhosis is associated with polymorphisms of intercellular adhesion molecule‐1 (ICAM‐1) in chronic HBV carriers. J Viral Hepatitis. 2008; 15 ( 3 ): 173 ‐ 178.
dc.identifier.citedreferenceMigita K, Maeda Y, Abiru S, et al. Polymorphisms of interleukin‐1beta in Japanese patients with hepatitis B virus infection. J Hepatol. 2007; 46 ( 3 ): 381 ‐ 386.
dc.identifier.citedreferenceSong Q‐L, He X‐X, Yang H, et al. Association of a TANK gene polymorphism with outcomes of hepatitis B virus infection in a Chinese Han population. Viral Immunol. 2012; 25 ( 1 ): 73 ‐ 78.
dc.identifier.citedreferenceKettunen J, Demirkan A, Würtz P, et al. Genome‐wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. Nat Commun. 2016; 7: 11122.
dc.identifier.citedreferenceThe CDC. A comprehensive 1000 Genomes–based genome‐wide association meta‐analysis of coronary artery disease. Nat Genet. 2015; 47: 1121.
dc.identifier.citedreferenceThe DGR, Meta‐analysis C. Large‐scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012; 44: 981.
dc.identifier.citedreferenceGlobal Lipids Genetics C, Willer CJ, Schmidt EM, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013; 45: 1274.
dc.identifier.citedreferenceShungin D, Winkler TW, Croteau‐Chonka DC, et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015; 518: 187.
dc.identifier.citedreferenceDupuis J, Langenberg C, Prokopenko I, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010; 42: 105.
dc.identifier.citedreferenceKilpeläinen TO, Carli JFM, Skowronski AA, et al. Genome‐wide meta‐analysis uncovers novel loci influencing circulating leptin levels. Nat Commun. 2016; 7: 10494.
dc.identifier.citedreferenceLu Y, Day FR, Gustafsson S, et al. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk. Nat Commun. 2016; 7: 10495.
dc.identifier.citedreferenceWatanabe K, Taskesen E, van Bochoven A, Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nat Commun. 2017; 8 ( 1 ): 1826.
dc.owningcollnameInterdisciplinary and Peer-Reviewed


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