Overview
Interleukin-28B (IL28B) is a gene located on the long arm of chromosome 19 and encodes interferon lambda-3 (IFN-λ3), a member of the type III interferon family. Along with IL28A and IL29, which encode IFN-λ2 and IFN-λ1, respectively, IL28B plays an important role in the host antiviral immune response. Type III interferons share antiviral and immunomodulatory properties similar to type I interferons but act on a more limited range of cells due to restricted receptor expression.
IL28B genetic polymorphism has been shown to have a strong association with spontaneous clearance of hepatitis C virus (HCV) infection and with sustained virological response (SVR) in patients treated with pegylated interferon-α and ribavirin. Because of this association, IL28B genotyping became an important predictive biomarker in the management of chronic hepatitis C, particularly before the widespread use of direct-acting antivirals.
Structure and Biological Function
Interleukin-28 exists in two main isoforms, IL-28A and IL-28B. These cytokines function as part of the innate immune response against viral infections. IL28B induces an antiviral state within infected cells by activating interferon-stimulated genes.
Key antiviral mechanisms include induction of Mx proteins, activation of 2′,5′-oligoadenylate synthetase, and stimulation of ISGF3G (Interferon-Stimulated Gene Factor 3). Through these pathways, IL28B limits viral replication and enhances immune-mediated viral clearance. Its antiviral activity is particularly relevant in chronic viral infections such as hepatitis C.
Genetic Polymorphism and Key Variants
Several single nucleotide polymorphisms (SNPs) in the IL28B gene have been identified and studied extensively. The most clinically significant SNPs include rs12979860, rs8099917, rs12980275, and rs72486680.
Among these, the rs12979860 polymorphism is the most widely studied. Individuals with the CC genotype at rs12979860 have a significantly higher likelihood of achieving sustained virological response following interferon-based therapy compared to those with CT or TT genotypes. This favorable genotype is also associated with higher rates of spontaneous viral clearance in acute HCV infection.
Ethnic Distribution and Disease Association
The distribution of favorable IL28B alleles varies significantly among different ethnic groups. The favorable CC genotype at rs12979860 is most commonly observed in Asian populations, followed by Caucasians, and is least frequent in African-American populations. These genetic differences partly explain variations in treatment response rates observed across different ethnic groups in chronic hepatitis C.
IL28B polymorphism has the strongest predictive value in patients infected with HCV genotype 1 and genotype 4. Its impact is less pronounced in genotypes 2 and 3, where treatment response rates are generally higher regardless of IL28B genotype.
Clinical Indications
The primary clinical indication for IL28B polymorphism testing is the management of chronic hepatitis C infection. The test helps predict the likelihood of response to interferon-based antiviral therapy and provides prognostic information regarding spontaneous viral clearance.
Although the clinical utility of IL28B testing has decreased in the current era of highly effective direct-acting antivirals, it still offers valuable prognostic insights. In resource-limited settings or in selected clinical scenarios, IL28B genotype may support treatment planning and patient counseling.
Laboratory Methods
IL28B polymorphism is detected using molecular genetic techniques. Commonly used methods include polymerase chain reaction (PCR) followed by DNA sequencing, real-time PCR with allelic discrimination using TaqMan probes, and PCR-CTPP, a cost-effective multiplex PCR mini-assay.
The general workflow involves sample collection, DNA extraction, PCR amplification, probe hybridization, and result analysis. These techniques allow accurate identification of specific IL28B genotypes associated with treatment response.
Sample Collection and Handling
Blood samples for IL28B testing are collected in EDTA (lavender-capped) tubes. A minimum of 6.0 mL of blood is recommended, typically collected as two 3.0 mL samples.
Plasma should be separated as early as possible to preserve nucleic acid integrity. Samples must be stored and transported under appropriate conditions to prevent DNA degradation. Specimens should ideally reach the laboratory within 8 hours at ambient temperature.
In addition to blood, saliva is an accepted alternative sample. For saliva collection, the patient should avoid eating, drinking, smoking, or chewing gum for at least 30 minutes prior to collection. A saliva swab collection kit is used, and samples remain stable at ambient temperature for up to 30 days.
Clinical Applications
IL28B polymorphism testing has been widely used to guide decision-making in hepatitis C therapy, especially during the interferon era. The test predicts sustained virological response to interferon-based regimens and helps stratify patients based on likelihood of treatment success.
Certain IL28B variants have also been linked to differences in liver fibrosis, steatosis, and inflammation, although these associations may vary depending on HCV genotype. While its role has diminished with modern antiviral therapy, IL28B genotyping continues to provide useful prognostic information in selected cases.
Limitations
IL28B polymorphism testing does not directly detect viral infection or viral load and should not be used as a standalone diagnostic tool. Its predictive value is reduced in the era of direct-acting antivirals, where treatment success rates are high regardless of genotype.
Results must be interpreted in conjunction with clinical findings, viral genotype, liver disease stage, and other laboratory parameters. Genetic variability across populations also limits universal applicability.
