Host IL28B genetic variations

The genotype CC of IL28B SNP rs12979860 is significantly associated

Accepted Articlewith sustained virological response in chronic HCV Pakistani

patients1

Bushra KHUBAIB 1, Muhammad IDREES 1, Samia AFZAL, 1 Muhammad WASIM2

1. National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore,

Pakistan

2. Genome Center for Molecular based Diagnostics & Research, CL-25, Abdalian Cooperative

Housing Society Lahore, Pakistan

Correspondence to: Muhammad IDREES,

Division of Molecular virology, National Centre of Excellence in Molecular Biology, University of

the Punjab, Lahore, Pakistan. Email: idreeskhan@cemb.edu.pk

Tel: +92 423 5293141

Conflict of interest: None.

This article has been accepted for publication and undergone full peer review but has not been through the copyediting,
typesetting, pagination and proofreading process, which may lead to differences between this version and the Version
of Record. Please cite this article as doi: 10.1111/1751-2980.12238

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 Host IL28B genetic variations

Accepted Article
ABSTRACT

Objective: To evaluate the association of genetic variation in interleukin 28B (IL28B) and viral

influential factors with treatment outcome in chronic hepatitis C virus (HCV) Pakistani patients.

Study Design: We enrolled 200 patients who received interferon+ribavirin combination therapy

and viral loads were checked at 3rd, 6th and after 6 months of treatment completion. Genotyping of

SNP rs12979860 was done by RFLP method and direct sequence analysis.

Results: Total 111 (55.5%) patients successfully completed anti-viral therapy and follow-up period.

Of these 91 (81.98%) achieved sustained virologic response (SVR) and only 20(18.02%) did not

show SVR. More than 92% and 91% patients with HCV genotype 3a showed early virologic

response (EVR) and SVR respectively. SVR was significantly high in female patents (p=0.003).

The statistically higher C allele frequency (81.9%) was observed in patients with SVR as compared

to the C allele frequency (30%) in patients who failed to achieve SVR (p=0. 00001). The odds of

achieving SVR were 10.351 times greater for the CC genotype as compared to CT/TT genotype of

SNP rs12979860 (p=0. 006, OR 10.351, 95% CI: 1.925-55.653).

Conclusions: The CC genotype of SNP rs12979860 of IL28B is a strong independent predictive

factor for SVR in Chronic HCV infected Pakistani patients. Other positive predictors observed for

SVR are: female gender, HCV-3a genotype and early virologic response (EVR).

Keywords:

Interleukin, Sustain virological response, Early virological response, Single nucleotide

polymorphism

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Accepted Article
Background

Among viral hepatitis, hepatitis C virus (HCV) is the second leading cause of hepatitis with

approximately 3% carriers worldwide and 8-10 % carriers among Pakistani population (1).

Infection with Chronic HCV frequently leads to liver cirrhosis and hepatocellular carcinoma (2). In

the absence of any approved vaccine against HCV, the pegylated- interferon-alpha in combination

with Ribavirin is the current standard regimen (3) for majority of patients. The goal of this

treatment is viral elimination to achieve sustained viral response (SVR) which means to decrease

the viral titer to undetectable levels after treatment completion. The duration of this treatment varies

for HCV different genotypes. For instance, 24 weeks of treatment are required for HCV genotype 2

or 3 and 48 weeks of treatment are required for HCV genotype1 and/or 4. Moreover, the chance to

attain SVR in the case of genotypes 1 and 4 is relatively lower than for genotype 3 and 2 (4).

Beside the viral genotype, that plays an important role to make precise decisions concerning the

risk and benefit of treatment, other viral related factors that are also deciding the outcome of

standard treatment includes baseline viral load, rapid virologic response (RVR) and early virologic

response (EVR) (5, 6). In addition, several host related factors including gender, age at the time of

treatment, body mass index (BMI), degree of hepatic steatosis and fibrosis are also contributing in

predicting the treatment response (6, 7). Type III interferon is a family of three cytokines IL29,

IL28A and IL28B (also known as IFN-ë1, IFN-ë2 and IFN-ë3) that were induced by a viral

infection and have antiviral activities (8). Further, four autonomous genome-wide association

studies (GWAS) have identified the single nucleotide polymorphisms (SNPs) of interleukin-28B

gene (IL28B), located on chromosome 19q13, that are strongly associated with interferon treatment

response and spontaneous viral clearance in chronic HCV patients (9-12).

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 Host IL28B genetic variations

A significant association of SNP rs12979860 that is located 3-kb upstream of IL28B, has
Accepted Article
recently been reported with spontaneous clearance of HCV and interferon treatment response in

different populations of the world like Spanish, Swiss, German and Japanese (11-13). No such

association of IL28B with viral clearance and/or treatment response has been reported from

Pakistan. Therefore, the objective of this study was to find out the association (if any) between viral

influential factors and genetic variation of Host IL28B with the treatment outcome in chronic

hepatitis C infected patients of the Pakistani population.

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Accepted Article
Methodology

Patients

We recruited a prospective cohort of 200 patients from the Pakistani population with chronic

hepatitis C virus who visited Genome Center for Molecular based Diagnostics & Research, CL-25,

Abdalian Cooperative Housing Society Lahore, Pakistan. All the patients received combination

therapy with Roferon-A (Interferon alfa-2a; Hoffmann-La Roche Inc. Nutley, New Jersey) 3 million

IU three times per week and ribavirin (10mg/kg body weight/day) for 24 weeks (for patients with

HCV genotypes 3a) to 48 weeks (for patients with HCV genotypes 1a and/or 1b). The

inclusion/exclusion criterion, anti-viral therapy protocols/guidelines, patients monitoring during

treatment and treatment responsiveness terminologies were the same as described previously (14).

We excluded 89 patients from the investigation as they either did not complete the entire therapy

course or follow-up. A written consent for genetic testing was taken before the sample collected

while ethical approval was taken from the ethics committee of the Molecular Virology Division of

CEMB, University of the Punjab. Undetectable HCV RNA by Real time PCR (≤20 IU/ml) at the

completion of treatment was called SVR. EVR was undetectable HCV RNA (viral load <20 IU/ml)

at 12th week of treatment.

HCV Quantification/Viral load and Genotyping

RNA was extracted using the GF-1 Nucleic Acid Extraction Kits (Vivantis Technologies Sdn. Bhd)

according to manufacturer’s protocol. Then, RNA was subjected to quantify viral RNA by using

SmartCycler II Real-time PCR (Cepheid, Sunnyvale, Calif. USA) with HCV RNA quantification

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 Host IL28B genetic variations

kit (Sacace Biotechnologies Como Italy). HCV genotyping was performed as described previously
Accepted Article
(15, 16).

Isolation of Genomic DNA and Genotying of IL28B SNPs

Peripheral blood was taken in EDTA vacutainer and genomic DNA was extracted by using a

NucleoSpin® Blood kit (MACHEREY-NAGEL GmbH & Co. KG) following the manufacturer’s

protocol. For amplification of the genomic region encompassing the IL-28B SNP rs12979860

primers (5’-CTGCACAGTCTGGGATTCCT-’3) sense and (5’- GCGGAGTGCAATTCAACC-’3)

antisense were designed by using primer 3 software. For PCR amplification 25 ng of genomic

DNA, 10 pM of primers, 25 mM MgCl2, 2.5 mM dNTPs and 2 units of Taq DNA polymerase

(Fermantas/Thermo Scientific Pittsburgh PA, USA) was used in 20µl of reaction mix. Cycling

parameters were initial denaturation at 95 ºC for 2 minutes, then 35 cycles, at 94 ºC for 45 seconds

at 58 ºC for 45 seconds and at 72 ºC for 1 minute, then final extension at 72 ºC for 10 minutes.

After purification the amplified PCR product was sequenced using BigDye terminators (Applied

Biosystems, Weiterstadt, Germany) and electrophoresed on automated Genetic Analyzer (Applied

Biosystems; 3100 DNA Analyzer). In addition genotyping of SNP rs1297860 was also carried out

by PCR-RFLP method exactly following the previously reported protocol (17).

Statistical Analysis

Categorical data were expressed in frequencies, percentages and numbers while continuous data

was expressed as mean and standard deviation (SD). The significant association among qualitative

variables was scrutinized by calculating the p-value using chi square (X2) and Fisher’s Exact test, p-

value less than 0.05 considered significant results. Quantitative data were analyzed by using Mann

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 Host IL28B genetic variations

Whitney U test. In order to identify predictors of SVR, statistical Odd Ratio (OR) was derived by
Accepted Article
performing Logistic Regression Analysis (LRA). Data was analyzed by using SPSS version 20.

While Hardy-weingber Equilibrium (HWE) was tested by using online calculator

http://www.oege.org/software/hardy-weinberg.html.

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 Host IL28B genetic variations

Accepted Article
RESULTS:

Study enrolments and disposition

Figure 1 shows the study enrolments, disposition and whole results. Two hundards patients with

chronic HCV infection who fulfilled the study criteria were initially screened and enrolled for this

study. Eight-nine patients who didn’t comply with our designed protocol were excluded from the

study. Of the total 111 patients who were with good adherence and completed the whole anti-viral

theray course, 92 (82.88%) showed EVR. Of these EVR cases, 85 (92.4%) were positive for SVR

and only 7 (7.76%) were negative for SVR. On the other hand of the total 19 (17.12%) non-EVR

cases, 6 achieved SVR (31.58%), and 13 (68.42%) did not achieve SVR. The proportion of

achieving SVR ws significantly higher in patients with EVR than in patients with non-EVR (p=0.

000) (Table 1).

Association of host and viral Influential Factors of Chronic HCV Patients with SVR

Of the one hundred and eleven patients with the mean age of 38.16 ±9. 88 years, 91(81.98%)

subjects with a mean age 38.38±10.38 were successfully achieved SVR and 20 (18.02%) subjects

with the mean age of 37.15±7.31 were failed to response to therapy (i.e. non-SVR). Statically no

significant difference in distribution of age, BMI and baseline viral load was observed between

these groups. The rate of achieving SVR is significantly higher in females compared to males (p=0.

003) (Table 1). With regard to the HCV genotype, 75.68% patients were infected with genotype 3a

and 24.32% patients were infected with genotype other than 3a.The result is consistent with

previously reported results evidencing the prevalence of HCV genotype 3a among Pakistani

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 Host IL28B genetic variations

population. A statistically significant association of attaining SVR was observed in patients infected
Accepted Article
with HCV genotype 3a as compared to patients infected with genotype 1a and/or1b (p=0. 000).

Distribution of SNP rs12979860 Genotype in chronic HCV Patients with and without EVR:

Initially we assessed the presence of SNP rs12979860 genotype in EVR patients who were found

negative by real-time PCR at week 12th of treatment. Observed EVR was: 59 (64.13%) were with

CC, 27 (29.35%) were with CT and 6 (6.52%) were with TT genotypes. In Non-EVR The

distribution of CC, CT and TT genotypes were 5(26.32%), 6 (31.58%) and 8 (42.11%) respectively

(Figure 1). This SNP have the power to predict the EVR as confirmed by multivariate/logistic

regression analysis (Table-2).

Distribution of SNP rs12979860 Genotype and Allele in chronic HCV Patients with positive

and negative SVR:

The SNP rs12979860 genotype was in accordance with Hardy Weinberg Equilibrium (HWE). The

statistical distribution of SNP rs12979860 genotype among patients with SVR was as follows: 61

(67%) were CC, 27 (29.7%) were CT and 3 (3.0%) was TT. The distribution of SNP rs12979860

genotype is significantly different in patients with non SVR was as follows: 3 (15%) were CC, 6

(20%) were CT and 11 (55%) was TT (p=0. 00001). The statistically higher C allele frequency

(81.9%) was observed in patients with SVR as compared to the C allele frequency (30%) in patients

who failed to achieve SVR (p=0. 00001) (Table 3).

rs 12979860 CC genotype is more powerful predictors than HCV genotype:

We evaluated the predictive ability of rs12979860 genotype and other influential factors for SVR

by logistic regression analysis. When these factors were entered into this model, interestingly, we

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 Host IL28B genetic variations

found that the CC genotype of SNP rs12979860 and EVR both are powerful predictor of SVR as
Accepted Article
compared to gender and HCV genotype (Table 4). The odds of achieving SVR are 10.351 times

greater for the CC genotype as compared to CT/TT genotype of SNP rs12979860 (p=0. 006, OR

10.351, 95% CI: 1.925-55.653). The rate of achieving SVR was 19.636 times greater in patients

with EVR (p=0.000, OR 19.636, 95% CI: 3.755-102.675) as compared to patients with non-EVR.

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 Host IL28B genetic variations

DISCUSSION
Accepted Article
We scrutinized the viral and host influential factors of HCV infected patients and interferon

treatment outcome. Among viral influential factors, HCV genotype and EVR are significantly

associated with SVR to interferon therapy. We observed high prevalence of HCV genotype 3a

among the Pakistani population as previously reported by Idrees et al 2008 (18) and higher response

rate to interferon treatment was observed in patients infected with HCV genotype 3a (p= 0. 000).

Monitoring EVR at week 12 is a part of routine assessment of response rate of interferon therapy

and its presence was considered an important predictor of SVR (19). Yu et al, had reported that

RVR and EVR are independent predictive factors for the antiviral treatment response (20). We have

also found EVR as an independent positive predictive factor of SVR (p=0. 000).

We investigated the association of host influential factors with treatment outcome. The rate of SVR

was found significantly higher in females than males (p=0. 003), as 56.04% females achieved SVR

compared to 43.95% SVR in males. Eighty percent of non responders were males. Our results are in

accordance with the previous report by Idrees and Riazuddin where the rate of attaining SVR was

56.7% in females as compared to 47.6% males (14). Similarly, Yu et al, reported that females with

age >40 years had higher rates of SVR as compared to males of the same age range. However,

contrary to this observation of Yu and co-workers, no significant association of age and BMI with

SVR was observed (p>0.005) in this study.

The most intresting finding of our study/data is the observation that the SNP rs129079860 of IL28B

is closely associated with the treatment outcome of chronic HCV infected patients among Pakistani

population. In this study, the C allele frequency of rs12979860 is significantly high in chronic HCV

patients who attained SVR as compared to those who failed to respond to treatment. The

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 Host IL28B genetic variations

distribution of CC genotype is significantly higher in patients who successfully respond to

Accepted Article
treatment (SVR) as compared to non-SVR patients (p = 0 00001). Similar results have also been

repoted from other countries by several researchers (9, 10, 11).

Further we analyzed the predictive ability of CC genotype versus CT/TT genotype by performing

logistic regression analysis; we found the odds of achieving SVR are 10.351 times greater for the

CC genotype as compared to CT/TT genotype of SNP rs12979860 (p=0. 006, OR 10.351, 95% CI:

1.925-55.653). Our results are consistent with Genome Wide Association (GWA) study by Ge et al,

where they identified SNP rs12979860, residing 3kb upstream of IL28B gene and was found to be

strongly associated with interferon treatment outcome from European American, African American

and Hispanic populations and suggested that the patients with genotype CC showed ~2 fold

increased response rate as compared to those with genotype CT/TT (9).

In conclusion, our results suggested that along with previously reported predictors such as HCV

genotype 3a and EVR, SNP rs12979860 CC genotype has statistically strong association with

successful treatment outcome in chronic HCV infected Pakistani patients. Further research is

needed to find out how signal nucleotide polymorphism of IL28B effect the host immune system to

provide protection against HCV infection and the mechanism by which virus evade the host

immune system.

Acknowledgements

We thank to Higher Education Commission Pakistan for the financial support of this study. Thanks

to Dr. Zahida from Akhtar Mubarik complex, Lahore, Pakistan and Mr. Muhammad Murad Khan

from Genome Center for Molecular based Diagnostics & Research, CL-25, Abdalian Cooperative

Housing Society Lahore, Pakistan for their kind help in sample collection from HCV infected

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 Host IL28B genetic variations

patients. We are also very grateful to Miss Marium Ilyas, lecturer at College of Statistical and
Accepted Article
Actuarial Sciences, University of the Punjab, Quaid-e-Azam Campus, Lahore, Pakistan for her

cordial cooperation in data analysis.

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Accepted Article
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9. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in
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16. Ohno O, Mizokami M, Wu RR, Saleh MG, Ohba K, Orito E, et al. New hepatitis C virus
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Table 1: Association between host and viral Influential Factors and treatment outcome
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Characteristic Total
(N=111)
SVR
(N=91)
Non SVR
(N=20)
P Value

Gender
Male 56 40 (71.4%) 16 (28.6%) 0.003b
Female 55 51 (92.7%) 4 (7.2%)
BMI (mean ±SD) 24.14±5.04 24.2±5.34 23.83±3.47 0.957 a

Age (mean ±SD) 38.16±9.87 38.38±10.38 37.15±7.307 0.095 a

HCV Genotype
3a 84 77 (91.7%) 7 (8.3%) 0.000b
1a and/or 1b 27 14 (51.9%) 13 (48.1%)
Baseline Viral Load
(IU/ml) 0.805b
<400,000 69 57 (82.6%) 12 (17.4%)
>400,000 42 34 (81%) 8 (19%)
Responses to
treatment 0.000b
EVR 92 85 (92.4%) 7 (7.6%)
Non EVR 19 6 (31.6%) 13 (68.4%)
a
Calculated by Mann-Whitney U test,
b
Calculated from the X2 test,
f: Frequency,
N: Numbers,
SD: Standard diviation
BMI: body mass index
EVR: Early Viral Response
SVR: Sustained Viral Response

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Accepted Article
Table 2: Factors predicted EVR to Interferon therapy in chronic HCV infected Patients by

multivariate logistic regression analysis.

Variable p value Odd 95% C.I

Ratio Lower Upper

Age 0.172 NS 0.95 0.89 1.02

Gender 0.271 NS 1.17 0.58 6.62

BMI 0.980 NS 0.99 0.88 1.12

SNP rs12979860 0.023* 4.06 1.22 13.58

BVL 0.811 NS 1.157 0.35 3.82

HCV Genotype 0.058 NS 3.107 0.96 10.04

*Statistically significant
EVR: Early Viral Response
C.I: Confidence interval
HCV: Hepatitis C Virus
BVL: Baseline viral load
BMI: Body mass index
NS: Non-significant

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Accepted Article
Table 3: Genotype and Allele frequencies of SNP rs12979860 among HCV infected patients
given Interferon therapy with SVR and non-SVR

SVR Non-SVR P Value

SNP rs12979860
91 (%) 20 (%)

Allele

C 149 (81.9) 33 (30.0) 0.00001

T 12 (18.1) 28 (70.0)

GENOTYPE

CC 61 (67) 3 (15)

CT 27 (29.7) 6 (30) 0.00001

TT 3 (3.3) 11 (55)

SNP: Single nucleotide polymorphism

SVR: Sustained Viral Response

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Accepted Article
Table 4: Factors Predicted Sustain Virological Response to Interferon treatment in chronic
HCV infected Patients by logistic regression analysis.

95% C.I
Variables P Value Odd Ratio
Lower Upper

Gender 0.034* 5.549 1.136 27.111

HCV Genotype 0.026* 5.722 1.236 26.500

EVR 0.000* 19.636 3.755 102.675

rs12979860 0.006* 10.351 1.925 55.653

Age 0.638 NS 1.019 0.943 1.10

BVL 0.953 NS 1.048 0.218 5.041

BMI 0.951 NS 1.006 0.842 1.201

*Statistically significant
EVR: Early Viral Response
C.I: Confidence interval
HCV: Hepatitis C Virus
BVL: Baseline viral load
BMI: Body mass index
NS: Non-significant

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Accepted Article
Figure 1: Flow Diagram elucidating the study enrollments, disposition and comprehensive

results.

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