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

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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.

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Abbreviations

ALB:

Serum albumin

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

BMI:

Body mass index

CAP:

Controlled attenuation parameter

FER:

Ferritin

FPG:

Fasting plasma glucose

GGT:

Gamma-glutamyl transferase

HA:

Hyaluronic acid

HCC:

Hepatocellular carcinoma

HDL-C:

High-density lipoprotein

Hp:

Haptoglobin

L:

Lymphocyte

LDH:

Lactate dehydrogenase

LDL-C:

Low-density lipoprotein

LSM:

Liver stiffness measurement

N:

Neutrophils

NAFLD:

Nonalcoholic fatty liver disease

NAS:

Nonalcoholic fatty liver disease activity score

NASH:

Nonalcoholic steatohepatitis

N/L ratio:

Neutrophil/lymphocyte ratio

OR:

Odds ratio

PIIINP:

Type III procollagen amino terminal peptide

SI:

Serum iron

T2DM:

Type 2 diabetes mellitus

TC:

Total cholesterol

TE:

Transient elastography

TG:

Triglyceride

TIBC:

Total ferritin binding

TNF-α:

Tumor necrosis factor alpha

UA:

Uric acid

WBC:

White blood cell

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Acknowledgements

Funding

Sponsorship for this study, development of this manuscript, and article processing charges were funded by the National Natural Science Foundation (81700510, 81570524), the Natural Science Foundation of Zhejiang Province (LY15H070004, LQ15H070006), the Science and Technology Planning Project of Hangzhou City (20170533B43, 20172016A02), the Nature Science Foundation of Min hang District of Shanghai (2018MHZ089, 2018MHZ027), and the Key Project of The Fifth People's Hospital of Shanghai (2018wyzd04). All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Editorial Assistance

Our thanks go to Dr Zhenjie Zhuang for assistance in preparation of this manuscript.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Authorship Contributions

Shufei Zang and Junping Shi designed experiments; Jingxin Zhou, Huiping Sheng, and Ningning You carried out experiments (Hp genotyping), Jun Liu analyzed experimental results and helped revise the manuscript (statistical analysis). Jin Chen and Xiaoxiao Mi performed physical examination and Fibroscan tests, Wenjun Yang performed histopathologic analyses. Jingxin Zhou and Shufei zang wrote the manuscript.

Disclosures

All authors (Jingxin Zhou, Jun Liu, Huiping Sheng, Ningning You, Jin Chen, Xiaoxiao Mi, Wenjun Yang, Shufei Zang, and Junping Shi) declare that they have nothing to disclose.

Compliance with Ethics Guidelines

All procedures performed in studies involving human participants were in accordance with the Ethics Committee of Hangzhou Normal University Affiliated Hospital (ethics no. 2015-HS-001) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Data Availability

The data sets generated and analyzed during the current study are not publicly available because of information security, but are available from the corresponding author on reasonable request.

Author information

Author notes

  1. Jingxin Zhou, Jun Liu, and Huiping Sheng contributed equally to this work.

Authors and Affiliations

  1. Hangzhou Normal University, Hangzhou, Zhejiang, China

    Jingxin Zhou & Ningning You

  2. Department of Endocrinology, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, China

    Jun Liu & Shufei Zang

  3. Department of Infectious Diseases, General Hospital of NingXia Medical University, Yinchuan, Ningxia, China

    Huiping Sheng

  4. Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China

    Jin Chen

  5. Centre for Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China

    Xiaoxiao Mi & Shufei Zang

  6. Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China

    Wenjun Yang

  7. Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China

    Junping Shi

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  1. Jingxin Zhou
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Consortia

the Chinese NAFLD Clinical Research Network (CNAFLD CRN)

Corresponding authors

Correspondence to Shufei Zang or Junping Shi.

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Zhou, J., Liu, J., Sheng, H. et al. Haptoglobin 2-2 Genotype is Associated with More Advanced Disease in Subjects with Non-Alcoholic Steatohepatitis: A Retrospective Study. Adv Ther 36, 880–895 (2019). https://doi.org/10.1007/s12325-019-00902-z

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