IL-28B Genetic Analysis And HBV Disease Association Studies With Small Number Study Subjects; Should We Rely On Results?

Muhammad Sohail Afzal

Muhammad Sohail Afzal, Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan

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Correspondence to: Muhammad Sohail Afzal, Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan.
Email: sohail.ncvi@gmail.com
Telephone: +92-321-5244808

Received: October 20, 2016
Revised: December 24, 2017
Accepted: December 25, 2017
Published online: December 26, 2017


Hepatitis B Virus (HBV) is one of the leading cause of cirrhosis and hepatocellular carcinoma worldwide. The virus has 10 different genotypes and has a specific geographic distribution for each genotype. Viral genotypes and certain mutations in the viral genome are associated with differential clinical features and therapeutic response. It is also evident that during HBV infection certain host genetic factors play major role in determining the outcome of infection and also impact the outcomes of antiviral therapy. IL28B plays an important role in the outcome of HBV infection and it could inhibit the viral replication. There are some functional genetic variants in IL28B gene which regulate the expression of IL28B. These genetic variants played significant role in predicting the antiviral therapy response and disease progression. There are several case control studies across the globe which are investigating the role of these functional variants on disease progression and antiviral therapy outcomes. In current study the available data on the genetic analysis of IL28B variants and their impact on HBV disease progression or antiviral therapy response is analyzed. The results showed that most of the studies including only small number of study participants hence the low sample number impact the power of statistical analysis. It is proposed that in future the case control studies must be conducted on large scale so statistical results can be justified and will be of help in clinical settings.

Key words: IL-28B; HBV; Ethnicity; Genetic analysis; Case-control studies

© 2017 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Afzal MS. IL-28B Genetic Analysis And HBV Disease Association Studies With Small Number Study Subjects; Should We Rely On Results? Journal of Gastroenterology and Hepatology Research 2017; 6(6): 2502-2504 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/2171

Dear Editor

The major recent breakthrough in genetics and hepatology is the role of variations found in the region of interleukin-28B (IL28B), the gene coding for the IL28B protein, also known as interferon (IFN)-λ3. The genetic variations in this region are highly predictive of pegylated INF alpha (Peg-IFN-α) and ribavirin (RBV) therapy response and viral clearance in different ethnic groups of chronic hepatitis C patients[1]. Recently there are growing numbers of studies on investigating the role of these genetic variations in different ethnic groups and Peg-IFN-α and RBV treatment response in hepatitis B patients.

A report published by Holmes et al (2013) showed that IL28B genotype (rs12979860) is not a useful predicting marker for treatment outcome in Asian chronic hepatitis B patients treated with pegylated interferon-α. The study includes very small number of patients as well control subjects. Conclusion of the study based on 52 patients and 32 controls from Asian ethnicity; study groups were further divided into 4 different groups on ethnic basis. The study includes 8, 14, 22, 8 patients of Cambodian, Chinese, Vietnam and other ethnic background respectively. Similarly the control group from Cambodian, Chinese, Vietnam and other ethnicity includes 7, 9, 11 and 5 individuals respectively. The Caucasian and African study groups includes 7, 1 patients and 2, 2 healthy control respectively[2]. The results showed that CC IL28B genotype was the major prevalent genotype and was present in 85% patients and 83.3% healthy individuals followed by CT genotype which was present in 15% patients and 13.9% controls. Genotype TT prevalence was 0% in cases and 2.8% in controls; the very low prevalence was may be due to very small number of investigated individuals. On the basis of these results authors concluded that IL-28B polymorphism (rs12979860) has no association with pegylated interferon therapy outcomes in HBV patients with Asian ethnic background.

The findings of other reports analyzing the role of IL-28B polymorphic variants on HBV infection susceptibility and therapy outcomes from different groups are conflicting but were based on comparatively larger number of patients and controls (Table 1)[3-18]. A recent report by Chen et al[6] investigated the IL-28B Gene polymorphism association and the Progress of Hepatitis B Infection in Han Chinese. Irrespective of results; the study includes 3 patients and a healthy group of 406, 406, 393 and 244 individuals respectively. A summary of all available studies in PubMed investigating the role of IL-28B polymorphism with respect to HBV infection is given in Table 1. The main problem of case control studies for genetic analysis of host genetic markers is the number of individuals being analyzed. The studies based on small number of samples like 1, 2, 7, 8 individuals may showed statistically false positive or false negative association. Therefore care should be taken while concluding such kind of studies. It is highly recommended that this kind of investigation must include larger study groups and should be done on larger scale.

Table 1 Summary of studies investigating IL-28B polymorphic variants association with HBV disease susceptibility, progression and Interferon ribavirin therapy response.
YearEthnicitySettingsConclusion/Association with IL-28 PolymorphismReference
Patients (n)Control (n)
2013Italian101-Good predictor of Interferon ribavirin therapy response3
2013Taiwanese115-Positive association with disease susceptibility4
2013Hong Kong203203Positive association with disease susceptibility5
2012Chinese Han1205244Positive association with disease progression6
2012Chinese140150No association with HBV recurrence in the liver transplant recipients or the donors.7
2012Han Chinese28347Positive association with disease susceptibility and chronicity8
2012Spanish4949No association with disease susceptibility9
2012Taiwanese133-No association with disease progression and chronicity10
2012Chinese512-Positive association with Interferon ribavirin therapy response11
2012Chinese651226No association with disease susceptibility12
2012Not differentiated205-Positive association with Interferon ribavirin therapy response13
2012Netherlands95-No association with HBeAg seroconversion or HBsAg clearance14
2011Chinese Han 406203Preventive effect on disease progression15
2011Taiwanese115-No association with HBeAg seroconversion16
2011Italian292344Positive correlation with viral infection17
2011Chinese342144No correlation with the outcome of HBV infection18


1. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009; 41: 1105-1109. [PMID: 19749757]; [DOI: 10.1038/ng.449]

2. Holmes JA, Nguyen T, Ratnam D, Heerasing NM, Tehan JV, Bonanzinga S, Dev A, Bell S, Pianko S, Chen R, Visvanathan K, Hammond R, Iser D, Rusli F, Sievert W, Desmond PV, Bowden DS, Thompson AJ. IL28B genotype is not useful for predicting treatment outcome in Asian chronic hepatitis B patients treated with pegylated interferon-a. Journal of Gastroenterology and Hepatology 2013; 28(5): 861-866. [PMID: 23301835]; [DOI: 10.1111/jgh.12110]

3. Lampertico P, Viganò M, Cheroni C, Facchetti F, Invernizzi F, Valveri V, Soffredini R, Abrignani S, De Francesco R, Colombo M. IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B. Hepatology 2013; 57(3): 890-896. [PMID: 22473858]; [DOI: 10.1002/hep.25749]

4. Lee IC, Lin CH, Huang YH, Huo TI, Su CW, Hou MC, Huang HC, Lee KC, Chan CC, Lin MW, Lin HC, Lee SD. IL28B Polymorphism Correlates with Active Hepatitis in Patients with HBeAg-Negative Chronic Hepatitis B. PLoS ONE 2013; 8(2): e58071. [PMID: 23469142]; [DOI: 10.1371/journal.pone.0058071]

5. Seto Wk, Wong DK, Kopaniszen M, Proitsi P, Sham P, Hung IF, Fung J, Lai C, Yuen M. HLA-DP and IL28B Polymorphisms: Influence of Host Genome on Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B. Clin Infect Dis 2013; 56(12): 1695-1703. [PMID: 23449268]; [DOI: 10.1093/cid/cit121]

6. Chen J, Wang L, Li Y, Cai B, Fu Y, Liao Y, Zhang J. Association Analysis between SNPs in IL-28B Gene and the Progress of Hepatitis B Infection in Han Chinese. PLoS ONE 2012, 7(12): e50787. [PMID: 23227209]; [DOI: 10.1371/journal.pone.0050787]

7. Li Y, Shi Y, Chen J, Cai B, Ying B, Wang L. Association of polymorphisms in interleukin-18 and interleukin-28B with hepatitis B recurrence after liver transplantation in Chinese Han population. Int J Immunogenet 2012; 39(4): 346-352. [PMID: 22325058]; [DOI: 10.1111/j.1744-313X.2012.01097.x]

8. Ren S, Lu J, Du X, Huang Y, Ma L, Huo H, Chen X, Wei L. Genetic variation in IL28B is associated with the development of hepatitis B-related hepatocellular carcinoma. Cancer Immunol Immunother 2012; 61(9): 1433-1439. [PMID: 22310928]; [DOI: 10.1007/s00262-012-1203-y]

9. Martín-Carbonero L, Rallón NI, Benito JM, Poveda E, González-Lahoz J, Soriano V. Short communication: Does interleukin-28B single nucleotide polymorphisms influence the natural history of hepatitis B? AIDS Res Hum Retroviruses. 2012; 28(10): 1262-1264. [PMID: 22324878]; [DOI: 10.1089/AID.2011.0365]

10. Lin CL, Tseng TC, Su TH, Liu CJ, Chen PJ, Lai MY, Chen DS, Kao JH. Host genetic variants and hepatitis B virologic features in HBeAg-negative hepatitis B carriers with long-term biochemical remission. Hepatology International 2012; 6(3): 598-605. [PMID: 21779934]; [DOI: 10.1007/s12072-011-9297-4]

11. Wu X, Xin Z, Zhu X, Pan L, Li Z, Li H, Liu Y. Evaluation of susceptibility locus for response to interferon-α based therapy in chronic hepatitis B patients in Chinese. Antiviral Res. 2012; 93(2): 297-300. [PMID: 22209781]; [DOI: 10.1016/j.antiviral.2011.12.009]

12. Peng LJ, Guo JS, Zhang Z, Shi H, Wang J, Wang JY. IL28B rs12979860 polymorphism does not influence outcomes of hepatitis B virus infection. Tissue Antigens 2012; 79(4): 302-305. [PMID: 22239156]; [DOI: 10.1111/j.1399-0039.2011.01835.x]

13. Sonneveld MJ, Wong VW, Woltman AM, Wong GL, Cakaloglu Y,Zeuzem S, Buster EH, Uitterlinden AG, Hansen BE, Chan HL, Janssen HL. Polymorphisms near IL28B and serological response to peginterferon in HBeAg-positive patients with chronic hepatitis B. Gastroenterology 2012; 142(3): 513-520. [PMID: 22108195]; [DOI: 10.1053/j.gastro.2011.11.025]

14. de Niet A, Takkenberg RB, Benayed R, Riley-Gillis B, Weegink CJ, Zaaijer HL, Koot M, Jansen PL, Beld MG, Lopatin U, Reesink HW. Genetic variation in IL28B and treatment outcome in HBeAg positive and -negative chronic hepatitis B patients treated with Peg interferon alfa-2a and adefovir. Scand J Gastroenterol 2012; 47(4): 475-481 [PMID: 22263608]; [DOI: 10.3109/00365521.2011.648952]

15. Li W, Jiang Y, Jin Q, Shi X, Jin J, Gao Y, Pan Y, Zhang H, Jiang J, Niu J. Expression and gene polymorphisms of interleukin 28B and hepatitis B virus infection in a Chinese Han population. Liver Int 2011; 31(8): 1118-1126. [PMID: 21745278]; [DOI: 10.1111/j.1478-3231.2011.02507.x]

16. Tseng TC, Yu ML, Liu CJ, Lin CL, Huang YW, Hsu CS, Liu CH, Kuo SF, Pan CJ, Yang SS, Su CW, Chen PJ, Chen DS, Kao JH. Effect of host and viral factors on hepatitis B e antigen-positive chronic hepatitis B patients receiving pegylated interferon-a-2a therapy. Antivir Ther 2011; 16(5): 629-637. [PMID: 21817184]; [DOI: 10.3851/IMP1841]

17. Fabris C, Falleti E, Cussigh A, Bitetto D, Fontanini E, Bignulin S, Cmet S, Fornasiere E, Fumolo E, Fangazio S, Cerutti A, Minisini R, Pirisi M, Toniutto P. IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis: role in the course of chronic viral hepatitis and the development of HCC. J Hepatol 2011; 54(4): 716-722. [PMID: 21146242]; [DOI: 10.1016/j.jhep.2010.07.019]

18. Jiao XL, Gao YT, Jing L, Liu T, Shi WX, Guo H, Yang B, DU Z. Studies on the relationship between polymorphism of IL-28B rs8099917 and the outcome of HBV infection. Zhonghua Liu Xing Bing Xue Za Zhi 2011; 32(11): 1143-1147. [PMID: 22336553]


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