Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis.
Journal
Alimentary pharmacology & therapeutics
ISSN: 1365-2036
Titre abrégé: Aliment Pharmacol Ther
Pays: England
ID NLM: 8707234
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
14
08
2020
revised:
02
09
2020
accepted:
21
12
2020
pubmed:
11
2
2021
medline:
2
4
2021
entrez:
10
2
2021
Statut:
ppublish
Résumé
Cirrhosis develops in <10% of individuals homozygous for the C282Y variant in the homeostatic iron regulator (HFE) gene. Carriage of PCSK7:rs236918 is associated with an increased risk of cirrhosis in this population. To determine if genetic variants significantly associated with the risk of alcohol- and NAFLD-related cirrhosis also modulate the cirrhosis risk in C282Y homozygotes. Variants in PCSK7, PNPLA3, TM6SF2, MBOAT7 and HSD17B13 were genotyped in 1319 C282Y homozygotes, from six European countries, of whom 171 (13.0%) had cirrhosis. Genotypic and allelic associations with the risk for developing cirrhosis were assessed, adjusting for age and sex. Fixed effects meta-analyses of the adjusted summary data for each country were performed. Post hoc association testing was undertaken in the 131 (76.6%) cases and 299 (26.0%) controls with available liver histology. Significant associations were observed between PCSK7:rs236918 (OR = 1.52 [95% CI 1.06-2.19]; P = 0.022; I The risk of cirrhosis associated with carriage of PCSK7:rs236918 was confirmed in this much larger population of C282Y homozygotes. In addition, PNPLA3:rs738409 and TM6SF2:rs58542926 were established as significant additional risk factors. More detailed genetic testing of C282Y homozygotes would allow risk stratification and help guide future management.
Sections du résumé
BACKGROUND
Cirrhosis develops in <10% of individuals homozygous for the C282Y variant in the homeostatic iron regulator (HFE) gene. Carriage of PCSK7:rs236918 is associated with an increased risk of cirrhosis in this population.
AIM
To determine if genetic variants significantly associated with the risk of alcohol- and NAFLD-related cirrhosis also modulate the cirrhosis risk in C282Y homozygotes.
METHODS
Variants in PCSK7, PNPLA3, TM6SF2, MBOAT7 and HSD17B13 were genotyped in 1319 C282Y homozygotes, from six European countries, of whom 171 (13.0%) had cirrhosis. Genotypic and allelic associations with the risk for developing cirrhosis were assessed, adjusting for age and sex. Fixed effects meta-analyses of the adjusted summary data for each country were performed. Post hoc association testing was undertaken in the 131 (76.6%) cases and 299 (26.0%) controls with available liver histology.
RESULTS
Significant associations were observed between PCSK7:rs236918 (OR = 1.52 [95% CI 1.06-2.19]; P = 0.022; I
CONCLUSIONS
The risk of cirrhosis associated with carriage of PCSK7:rs236918 was confirmed in this much larger population of C282Y homozygotes. In addition, PNPLA3:rs738409 and TM6SF2:rs58542926 were established as significant additional risk factors. More detailed genetic testing of C282Y homozygotes would allow risk stratification and help guide future management.
Substances chimiques
Membrane Proteins
0
TM6SF2 protein, human
0
Lipase
EC 3.1.1.3
adiponutrin, human
EC 3.1.1.3
PCSK7 protein, human
EC 3.4.21.-
Subtilisins
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
830-843Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 John Wiley & Sons Ltd.
Références
Powell LW, Seckington RC, Deugnier Y. Haemochromatosis. Lancet. 2016;388:706-716.
Adams PC. Epidemiology and diagnostic testing for hemochromatosis and iron overload. Int J Lab Hematol. 2015;37(Suppl.1):25-30.
European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53:3-22.
Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358:221-230.
Byrnes V, Ryan E, Barrett S, Kenny P, Mayne P, Crowe J. Genetic hemochromatosis, a Celtic disease: is it now time for population screening? Genet Test. 2001;5:127-130.
Altes A, Ruiz A, Barceló MJ, et al. Prevalence of the C282Y, H63D, and S65C mutations of the HFE gene in 1,146 newborns from a region of Northern Spain. Genet Test. 2004;8:407-410.
Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2006;145:209-223.
Moirand R, Jouanolle A, Brissot P, Le Gall J, David V, Deugnier Y. Phenotypic expression of HFE mutations: a French study of 1110 unrelated iron-overloaded patients and relatives. Gastroenterology. 1999;2:372-377.
Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002;359:211-218.
Pilling LC, Tamosauskaite J, Jones G, et al. Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. BMJ. 2019;64:k5222.
Fargion S, Mandelli C, Piperno A, et al. Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis. Hepatology. 1992;15:655-659.
Fletcher LM, Dixon JL, Purdie DM, Powell LW, Crawford DHG. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis. Gastroenterology. 2002;122:281-289.
Scotet V, Mérour MC, Mercier AY, et al. Hereditary hemochromatosis: effect of excessive alcohol consumption on disease expression in patients homozygous for the C282Y mutation. Am J Epidemiol. 2003;158:129-134.
Wood MJ, Powell LW, Dixon JL, Ramm GA. Clinical cofactors and hepatic fibrosis in hereditary hemochromatosis: the role of diabetes mellitus. Hepatology. 2012;56:904-911.
Powell EE, Ali A, Clouston AD, et al. Steatosis is a cofactor in liver injury in hemochromatosis. Gastroenterology. 2005;129:1937-1943.
Adams LA, Angulo P, Abraham SC, Torgerson H, Brandhagen D. The effect of the metabolic syndrome, hepatic steatosis and steatohepatitis on liver fibrosis in hereditary hemochromatosis. Liver Int. 2006;26:298-304.
Tung BY, Emond MJ, Bronner MP, Raaka SD, Cotler SJ, Kowdley KV. Hepatitis C, iron status, and disease severity: relationship with HFE mutations. Gastroenterology. 2003;124:318-326.
Valenti L, Maggioni P, Piperno A, et al. Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis. World J Gastroenterol. 2012;18:2813-2820.
Buch 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;47:1443-1448.
Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461-1465.
Stickel 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;23:3883-3890.
Pelucchi S, Galimberti S, Greni F, et al. Proprotein convertase 7 rs236918 associated with liver fibrosis in Italian patients with HFE-related hemochromatosis. J Gastroenterol Hepatol. 2016;31:1342-1348.
Kozlitina J, Smagris E, Stender S, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46:352-356.
Krawczyk M, Rau M, Schattenburg JM, et al. Combined effects of the PNPLA3rs738409, TM6SF2rs58542926, and MBOAT7rs641738 variants on NAFLD severity: a multicenter biopsy-based study. J Lipid Res. 2017;58:247-255.
Dongiovanni P, Petta S, Maglio C, et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology. 2015;61:506-514.
Mancina RM, Dongiovanni P, Petta S, et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology. 2016;150:1219-1230.
Abul-Husn NS, Cheng X, Li AH, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018;378:1096-1106.
Stickel F, Lutz P, Buch S, et al. Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology. 2020;72:88-102.
The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology. 1994;20:15-20.
Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559-575.
Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7.
Viechtbauer W. Conducting met-analyses in R with the Meafor package. J Stat Softw. 2010;36:1-48.(https://www.jstatsoft.org/v36/i03/)
Mangiafico SS. Summary and Analysis of Extension Program Evaluation in R, version 1.18.1; 2016. rcompanion.org/documents/RHandbookProgramEvaluation.pdf
Witte JS, Visscher PM, Wray NR. The contribution of genetic variants to disease depends on the ruler. Nat Rev Genet. 2014;15:765-776.
Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT. Data quality control in genetic case-control association studies. Nat Protoc. 2010;5:1564-1573.
1000 Genomes Project Consortium, Auton A, Brooks LD, et al. A global reference for human genetic variation. Nature. 2015;526:68-74.
Grosse SD, Gurrin LC, Bertalli NA, Allen KJ. Clinical penetrance in hereditary hemochromatosis: estimates of the cumulative incidence of severe liver disease among HFE C282Y homozygotes. Genet Med. 2018;20:383-389.
Thabet 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.
About L, Abel F, Cobat A. HCV-associated liver fibrosis and HSD17B13. N Engl J Med. 2018;379:1875-1876.
Hollerer I, Bachmann A, Muckenthaler MU. Pathophysiological consequences and benefits of HFE mutations: 20 years of research. Haematologica. 2017;102:809-817.
Lin L, Nemeth E, Goodnough JB, Thapa DR, Gabayan V, Ganz T. Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site. Blood Cells Mol Dis. 2008;40:122-131.
Schranz M, Bakry R, Creus M, Bonn G, Vogel W, Zoller H. Activation and inactivation of the iron hormone hepcidin: biochemical characterization of prohepcidin cleavage and sequential degradation to N-terminally truncated hepcidin isoforms. Blood Cells Mol Dis. 2009;43:169-179.
Turpeinen H, Oksanen A, Kivinen V, et al. Proprotein convertase subtilisin/kexin type 7 (PCSK7) is essential for the zebrafish development and bioavailability of transforming growth factor β1a (TGFβ1a). J Biol Chem. 2013;288:36610-36623.
Dongiovanni P, Meroni M, Baselli G, et al. PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients. J Lipid Res. 2019;60:1144-1153.
He S, McPhaul C, Li JZ, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. 2010;285:6706-6715.
BasuRay S, Smagris E, Cohen JC, Hobbs H. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology. 2017;66:1111-1124.
Sookoian S, Castaño GO, Scian R, et al. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology. 2015;61:515-525.
Zamara E, Novo E, Marra F, et al. 4-Hydroxynonenal as a selective pro-fibrogenic stimulus for activated human hepatic stellate cells. J Hepatol. 2004;40:60-68.
Poli G, Biasi F, Leonarduzzi G. 4-Hydroxynonenal-protein adducts: a reliable biomarker of lipid oxidation in liver diseases. Mol Aspects Med. 2008;29:67-71.
Steinberg KK, Cogswell ME, Chang JC, et al. Prevalence of C282Y andH63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA. 2001;285:2216-2222.
de Tayrac M, Roth M-P, Jouanolle A-M, et al. Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis. J Hepatol. 2015;622:664-672.