Case Control Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 21, 2015; 21(39): 11141-11151
Published online Oct 21, 2015. doi: 10.3748/wjg.v21.i39.11141
Low-density lipoprotein receptor genetic polymorphism in chronic hepatitis C virus Egyptian patients affects treatment response
Mazen Naga, Mona Amin, Dina Algendy, Ahmed Elbadry, May Fawzi, Ayman Foda, Serag Esmat, Dina Sabry, Laila Rashed, Samia Gabal, Manal Kamal
Mazen Naga, Mona Amin, Dina Algendy, Ahmed Elbadry, May Fawzi, Ayman Foda, Serag Esmat, Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
Dina Sabry, Laila Rashed, Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
Samia Gabal, Department of Pathology, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
Manal Kamal, Department of Clinical and Chemical pathology, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
Author contributions: Naga M designed the study; Amin M, Algendy D, Elbadry A, Fawzi M, Foda A, Esmat S, Sabry D, Rashed L, Gabal S, Kamal M contributed to the drafting of the manuscript; Naga M, Amin M, Algendy D, Elbadry A, Fawzi M, Foda A, Esmat S revised the manuscript and contributed to patient selection; Amin M and Esmat S collected the data; Amin M, Algendy D, Elbadry A, Fawzi M, Foda A, Esmat S, Sabry D, Rashed L, Gabal S and Kamal M contributed to data analyses and interpretation under the supervision of Naga M; Amin M, Fawzi M and Algendy D performed the abdominal ultrasounds and liver biopsies; Esmat S, Elbadry A and Foda A performed the clinical examinations; Gabal S performed the histopathological analyses; Sabry D and Rashed L performed laboratory analyses; Kamal M performed statistical analyses; all authors approved the present version for publication.
Supported by the Science and Technology Development Fund, Ministry of Scientific Research Egypt, Project No. 1587; and Cairo University.
Institutional review board statement: The review board of the Department of Internal Medicine, Faculty of Medicine, Cairo University approved the study protocol, which was performed according to the Declaration of Helsinki.
Informed consent statement: All study participants provided informed written consent prior to study enrolment.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: The technical appendix, statistical code, and dataset are available from the corresponding author at monasleman@kasralainy.edu.eg. No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Mona Amin, Professor, Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 11562, Egypt. monasleman@hotmail.com
Telephone: +20-23-646394 Fax: +20-23-657104
Received: March 8, 2015
Peer-review started: March 11, 2015
First decision: April 24, 2015
Revised: May 25, 2015
Accepted: August 29, 2015
Article in press: August 29, 2015
Published online: October 21, 2015
Processing time: 225 Days and 3.8 Hours
Abstract

AIM: To correlate a genetic polymorphism of the low-density lipoprotein (LDL) receptor with antiviral responses in Egyptian chronic hepatitis C virus (HCV) patients.

METHODS: Our study included 657 HCV-infected patients with genotype 4 who received interferon-based combination therapy. Patients were divided into two groups based on their response to therapy: 356 were responders, and 301 were non-responders. Patients were compared to 160 healthy controls. All patients and controls underwent a thorough physical examination, measurement of body mass index (BMI) and the following laboratory tests: serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total bilirubin, direct bilirubin, prothrombin time, prothrombin concentration, INR, complete blood count, serum creatinine, fasting blood sugar, HCV antibody, and hepatitis B surface antigen. All HCV patients were further subjected to the following laboratory tests: HCV-RNA using quantitative polymerase chain reaction (PCR), antinuclear antibodies, thyroid-stimulating hormone, an LDL receptor (LDLR) genotype study of LDLR exon8c.1171G>A and exon10c.1413G>A using real-time PCR-based assays, abdominal ultrasonography, ultrasonographic-guided liver biopsy, and histopathological examination of liver biopsies. Correlations of LDL receptor polymorphisms with HAI, METAVIR score, presence of steatosis, and BMI were performed in all cases.

RESULTS: There were no statistically significant differences in response rates between the different types of interferon used or LDLR exon10c.1413G>A. However, there was a significant difference in the frequency of the LDL receptor exon8c.1171G>A genotype between cases (AA: 25.9%, GA: 22.2%, GG: 51.9%) and controls (AA: 3.8%, GA: 53.1% and GG: 43.1%) (P < 0.001). There was a statistically significant difference in the frequency of the LDLR exon 8C:1171 G>A polymorphism between responders (AA: 3.6%, GA: 15.2%, GG: 81.2%) and non-responders (AA: 52.2%, GA: 30.6%, GG: 17.2%) (P < 0.001). The G allele of LDL receptor exon8c.1171G>A predominated in cases and controls over the A allele, and a statistically significant association with response to interferon was observed. The frequency of the LDLR exon8c.1171G>A allele in non-responders was: A: 67.4% and G: 32.6 vs A: 11.2% and G: 88.8% in responders (P < 0.001). Therefore, carriers of the A allele exhibited a 16.4 times greater risk for non-response. There was a significant association between LDL receptors exon8 c.1171G>A and HAI (P < 0.011). There was a significant association between LDL receptors exon8c.1171G>A and BMI. The mean BMI level was highest in patients carrying the AA genotype (28.7 ± 4.7 kg/m2) followed by the GA genotype (28.1 ± 4.8 kg/m2). The lowest BMI was the GG genotype (26.6 ± 4.3 kg/m2) (P < 0.001). The only significant associations were found between LDL receptors exon8 c.1171G>A and METAVIR score or steatosis (P < 0.001).

CONCLUSION: LDL receptor gene polymorphisms play a role in the treatment response of HCV and the modulation of disease progression in Egyptians infected with chronic HCV.

Keywords: Hepatitis C virus, Genetic polymorphisms, Low-density lipoprotein receptor, Egypt, Hepatitis C virus response to treatment

Core tip: Two molecules may function as hepatitis C virus (HCV) receptors, namely the low density lipoprotein receptor (LDLR) and CD81. This work assessed the role of genetic polymorphisms of the LDLR in Egyptian chronic HCV patients and its correlation with antiviral responses to treatment with pegylated interferon /ribavirin therapy. The study demonstrated that LDLR gene polymorphisms play a role in the response to viral treatment. The G allele of LDLRs exon8c.1171G>A predominated in cases and controls over the A allele. Carriers of the A allele exhibited a 16.4 times greater risk for non-response.