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Published in: Advances in Therapy 4/2019

01-04-2019 | Fatty Liver | Original Research

Haptoglobin 2-2 Genotype is Associated with More Advanced Disease in Subjects with Non-Alcoholic Steatohepatitis: A Retrospective Study

Authors: Jingxin Zhou, Jun Liu, Huiping Sheng, Ningning You, Jin Chen, Xiaoxiao Mi, Wenjun Yang, Shufei Zang, Junping Shi, the Chinese NAFLD Clinical Research Network (CNAFLD CRN)

Published in: Advances in Therapy | Issue 4/2019

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Abstract

Introduction

Haptoglobin (Hp) genotypes were reported as an independent risk factor for metabolic diseases. This study aimed to investigate the association between Hp gene polymorphism and the severity of nonalcoholic fatty liver disease (NAFLD).

Methods

A total of 441 subjects (NAFLD group, n = 272; healthy control, n = 169) were recruited, and their clinical biochemical parameters were measured in all subjects. Haptoglobin genotyping was performed using genomic DNA extracted from peripheral blood leukocytes. Among the NAFLD group, 107 patients underwent liver biopsy, and histology was evaluated by a pathologist on the basis of the CRN scoring system.

Results

NAFLD patients had much lower frequency of Hp 1-1 genotype and higher frequency of Hp 2-2 than healthy controls (0.4% vs 9.5%, 55.8% vs 47.9%, P < 0.001). NAFLD patients with Hp 2-2 genotype had much higher levels of body mass index (BMI), total cholesterol (TC), liver enzymes, ferritin, and controlled attenuation parameter (CAP) values than non-Hp 2-2 genotype (P < 0.05). In histology, patients with nonalcoholic steatohepatitis (NASH) had higher frequency of Hp 2-2 genotype than non-NASH patients (71.3% vs 22.2%, P < 0.001); patients with significant fibrosis had higher frequency of Hp 2-2 genotype (78.3% vs 54.8%, P < 0.05) than no/mild fibrosis patients. NAFLD patients with Hp 2-2 genotype had higher proportion with higher steatosis scores, lobular inflammation scores, ballooning scores, NAFLD activity scores (NAS), and fibrosis stages (P < 0.05 for all) than Hp 2-2 groups. Furthermore, Hp 2-2 genotype was independently associated with NASH (OR = 5.985, P < 0.05) and significant fibrosis (OR = 6.584, P < 0.05).

Conclusions

Hp 2-2 genotype is closely associated with the severity of NAFLD.
Literature
1.
go back to reference Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and aconsequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2014;2:901–10.CrossRefPubMed Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and aconsequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2014;2:901–10.CrossRefPubMed
2.
go back to reference Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–357. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–357.
3.
4.
go back to reference Wong 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;148:547–55.CrossRefPubMed Wong 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;148:547–55.CrossRefPubMed
5.
go back to reference Younossi ZM, Otgonsuren M, Henry L, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62(6):1723–30.CrossRefPubMed Younossi ZM, Otgonsuren M, Henry L, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62(6):1723–30.CrossRefPubMed
6.
go back to reference Xun YH, Fan JG, Zang GQ, et al. Suboptimal performance of simple noninvasive test for advanced fibrosis in Chinese patients with nonalcoholic fatty liver disease. J Dig Dis. 2012;13(11):588–95.CrossRefPubMed Xun YH, Fan JG, Zang GQ, et al. Suboptimal performance of simple noninvasive test for advanced fibrosis in Chinese patients with nonalcoholic fatty liver disease. J Dig Dis. 2012;13(11):588–95.CrossRefPubMed
7.
go back to reference Feng S, Rui-Dan Z, Jun-Ping S, et al. Impact of skin capsular distance on the performance of controlled attenuation parameter in patients with chronic liver disease. Liver Int. 2015;35:2392–400.CrossRef Feng S, Rui-Dan Z, Jun-Ping S, et al. Impact of skin capsular distance on the performance of controlled attenuation parameter in patients with chronic liver disease. Liver Int. 2015;35:2392–400.CrossRef
8.
go back to reference Osterreicher CH, Brenner DA. The genetics of nonalcoholic fatty liver disease. Ann Hepatol. 2007;6(2):83–8.CrossRefPubMed Osterreicher CH, Brenner DA. The genetics of nonalcoholic fatty liver disease. Ann Hepatol. 2007;6(2):83–8.CrossRefPubMed
9.
go back to reference Andersen CBF, Stødkilde K, Sæderup KL, et al. Haptoglobin. Antioxid Redox Signal. 2017;26(14):814–31.CrossRefPubMed Andersen CBF, Stødkilde K, Sæderup KL, et al. Haptoglobin. Antioxid Redox Signal. 2017;26(14):814–31.CrossRefPubMed
10.
go back to reference Blum S, Vardi M, Brown JB, et al. Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2–2 genotype. Pharmacogenomics. 2010;11(5):675–84.CrossRefPubMed Blum S, Vardi M, Brown JB, et al. Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2–2 genotype. Pharmacogenomics. 2010;11(5):675–84.CrossRefPubMed
11.
go back to reference Boettger LM, Salem RM, Handsaker RE, et al. Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels. Nat Genet. 2016;48(4):359. Boettger LM, Salem RM, Handsaker RE, et al. Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels. Nat Genet. 2016;48(4):359.
12.
go back to reference Suleiman M, Aronson D, Asleh R, et al. Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction. Diabetes. 2005;54(9):2802–6.CrossRefPubMed Suleiman M, Aronson D, Asleh R, et al. Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction. Diabetes. 2005;54(9):2802–6.CrossRefPubMed
13.
go back to reference Asleh R, Blum S, Kalet-Litman S, et al. Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2–2 genotype. Diabetes. 2008;57(10):2794–800.CrossRefPubMedPubMedCentral Asleh R, Blum S, Kalet-Litman S, et al. Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2–2 genotype. Diabetes. 2008;57(10):2794–800.CrossRefPubMedPubMedCentral
14.
go back to reference Levy AP, Hochberg I, Jablonski K, et al. Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes : the Strong Heart Study. J Am Coll Car. 2002;40(11):1984–90.CrossRef Levy AP, Hochberg I, Jablonski K, et al. Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes : the Strong Heart Study. J Am Coll Car. 2002;40(11):1984–90.CrossRef
15.
go back to reference Roguin A, Koch W, Kastrati A, et al. Haptoglobin genotype is predictive of major adverse cardiac events in the one-year period after PTCA in individuals with diabetes. Diabetes Care. 2003;26:2628–31.CrossRefPubMed Roguin A, Koch W, Kastrati A, et al. Haptoglobin genotype is predictive of major adverse cardiac events in the one-year period after PTCA in individuals with diabetes. Diabetes Care. 2003;26:2628–31.CrossRefPubMed
16.
go back to reference Milman U, Blum S, Shapira C, et al. Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective, double-blinded clinical trial. Art Thromb Vasc Biol. 2008;28(2):341–7.CrossRef Milman U, Blum S, Shapira C, et al. Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective, double-blinded clinical trial. Art Thromb Vasc Biol. 2008;28(2):341–7.CrossRef
17.
go back to reference Costacou T, Ferrell RE, Orchard TJ. Haptoglobin genotype: a determinant of cardiovascular complication risk in type 1 diabetes. Diabetes. 2008;57:1702–6.CrossRefPubMed Costacou T, Ferrell RE, Orchard TJ. Haptoglobin genotype: a determinant of cardiovascular complication risk in type 1 diabetes. Diabetes. 2008;57:1702–6.CrossRefPubMed
18.
go back to reference Nakagawa T, Muramoto Y, Hori M, et al. A preliminary investigation of the association between haptoglobin polymorphism, serum ferritin concentration and fatty liver disease. Clin Chim Acta. 2008;398(1):34–8.CrossRefPubMed Nakagawa T, Muramoto Y, Hori M, et al. A preliminary investigation of the association between haptoglobin polymorphism, serum ferritin concentration and fatty liver disease. Clin Chim Acta. 2008;398(1):34–8.CrossRefPubMed
20.
go back to reference Fan JG, Jia JD, Li YM, et al. Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010: (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166). J Dig Dis. 2011;12(1):45–50.CrossRefPubMed Fan JG, Jia JD, Li YM, et al. Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010: (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166). J Dig Dis. 2011;12(1):45–50.CrossRefPubMed
21.
go back to reference Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.CrossRefPubMed Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.CrossRefPubMed
22.
go back to reference Chalasani NP, Sanyal AJ, Kowdley KV, et al. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials. 2009;30(1):88–96.CrossRefPubMed Chalasani NP, Sanyal AJ, Kowdley KV, et al. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials. 2009;30(1):88–96.CrossRefPubMed
23.
go back to reference Koch W, Latz W, Eichinger M, et al. Genotyping of the common haptoglobin Hp 1/2polymorphism based on PCR. Clin Chem. 2002;48(9):1377–82.PubMed Koch W, Latz W, Eichinger M, et al. Genotyping of the common haptoglobin Hp 1/2polymorphism based on PCR. Clin Chem. 2002;48(9):1377–82.PubMed
24.
go back to reference Carter K, Worwood M. Haptoglobin: a review of the major allele frequencies worldwide and their association with diseases. Int J Lab Hematol. 2007;29(2):92–110.CrossRefPubMed Carter K, Worwood M. Haptoglobin: a review of the major allele frequencies worldwide and their association with diseases. Int J Lab Hematol. 2007;29(2):92–110.CrossRefPubMed
25.
26.
go back to reference Shiyun W, Jie W, Rong Z, et al. Mendelian randomization analysis to assess a causal efect of haptoglobin on macroangiopathy in Chinese type 2 diabetes patients. Cardiovasc Diabetol. 2018;16(1):14. Shiyun W, Jie W, Rong Z, et al. Mendelian randomization analysis to assess a causal efect of haptoglobin on macroangiopathy in Chinese type 2 diabetes patients. Cardiovasc Diabetol. 2018;16(1):14.
27.
go back to reference Xiaohong S, Liang S, Li W, et al. Haptoglobin 2-2 genotype Is associated with increased risk of type 2 diabetes mellitus in Northern Chinese. Genet Test Mol Biomarkers. 2012;16(6):563–8.CrossRef Xiaohong S, Liang S, Li W, et al. Haptoglobin 2-2 genotype Is associated with increased risk of type 2 diabetes mellitus in Northern Chinese. Genet Test Mol Biomarkers. 2012;16(6):563–8.CrossRef
28.
go back to reference Shufei Z, Jin C, Yu S, et al. Haptoglobin genotype and vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis in China: a multicenter, randomized, placebo-controlled trial design. Adv Ther. 2018;35:218–23.CrossRef Shufei Z, Jin C, Yu S, et al. Haptoglobin genotype and vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis in China: a multicenter, randomized, placebo-controlled trial design. Adv Ther. 2018;35:218–23.CrossRef
29.
30.
go back to reference Zethelius B, Berglund L, Sundström J, et al. Use of multiple biomarkers toimprove the prediction of death from cardiovascular causes. N Engl J Med 2008;358(20):2107–16.CrossRefPubMed Zethelius B, Berglund L, Sundström J, et al. Use of multiple biomarkers toimprove the prediction of death from cardiovascular causes. N Engl J Med 2008;358(20):2107–16.CrossRefPubMed
32.
go back to reference Boettger LM, Salem RM, Handsaker RE, et al. Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels. Nat Genet. 2016;48(4):359–66.CrossRefPubMedPubMedCentral Boettger LM, Salem RM, Handsaker RE, et al. Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels. Nat Genet. 2016;48(4):359–66.CrossRefPubMedPubMedCentral
33.
go back to reference Zheng NS, Bastarache LA, Bastarache JA, et al. A common deletion in the haptoglobin gene associated with blood cholesterol levels among Chinese women. J Hum Genet. 2017;62(10):911–4.CrossRefPubMedPubMedCentral Zheng NS, Bastarache LA, Bastarache JA, et al. A common deletion in the haptoglobin gene associated with blood cholesterol levels among Chinese women. J Hum Genet. 2017;62(10):911–4.CrossRefPubMedPubMedCentral
34.
go back to reference Salvatore A, Cigliano L, Carlucci A, et al. Haptoglobin binds apolipoprotein E and influences cholesterol esterification in the cerebrospinal fluid. J Neurochem. 2009;110(1):255–63.CrossRefPubMed Salvatore A, Cigliano L, Carlucci A, et al. Haptoglobin binds apolipoprotein E and influences cholesterol esterification in the cerebrospinal fluid. J Neurochem. 2009;110(1):255–63.CrossRefPubMed
Metadata
Title
Haptoglobin 2-2 Genotype is Associated with More Advanced Disease in Subjects with Non-Alcoholic Steatohepatitis: A Retrospective Study
Authors
Jingxin Zhou
Jun Liu
Huiping Sheng
Ningning You
Jin Chen
Xiaoxiao Mi
Wenjun Yang
Shufei Zang
Junping Shi
the Chinese NAFLD Clinical Research Network (CNAFLD CRN)
Publication date
01-04-2019
Publisher
Springer Healthcare
Keyword
Fatty Liver
Published in
Advances in Therapy / Issue 4/2019
Print ISSN: 0741-238X
Electronic ISSN: 1865-8652
DOI
https://doi.org/10.1007/s12325-019-00902-z

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