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Genetics and hepatitis C: It’s good to be ‘CC’

Cleveland Clinic Journal of Medicine. 2015 February;82(2):97-104 | 10.3949/ccjm.82a.14004
February 1, 2015|Cleveland Clinic Journal of Medicine
Jose Mari Parungao, MD;Ibrahim A. Hanouneh, MD;Binu John, MD;Naim Alkhouri, MD;Nizar N. Zein, MD, FAASLD
Author and Disclosure Information

Jose Mari Parungao, MD
Department of Gastroenterology, Providence Hospital and Medical Centers, Southfield, MI

Ibrahim A. Hanouneh, MD
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Binu John, MD
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Naim Alkhouri, MD
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic

Nizar N. Zein, MD, FAASLD
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic; Associate Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Nizar N. Zein, MD, FAASLD, Department of Gastroenterology and Hepatology, A100, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: zeinn@ccf.org

ABSTRACTThe interleukin-28B (IL28B) gene contains a single-nucleotide polymorphism at location rs12979860 that affects both the natural history of hepatitis C virus infection and the patient’s response to treatment, particularly interferon-based regimens with or without protease inhibitors.

KEY POINTS

  • In IL28B, the rs12979860 location can be occupied by either cytosine (C) or thymine (T). The CC genotype is more favorable than the CT or TT genotype.
  • Testing for the IL28B polymorphism is currently available and allows for better outcomes through proper selection of treatment, particularly with interferon-based treatment.
  • Although newer therapies have shifted toward regimens that do not use interferon, the IL28B polymorphism remains clinically significant, especially in light of the potentially prohibitive costs of the newer regimens, and for patients in whom these treatments are contraindicated.

BIOLOGIC ASSOCIATION: IL28B POLYMORPHISM AND HEPATITIS C

The interferon lambda family consists of three cytokines:

  • Interleukin 29 (interferon lambda 1)
  • Interleukin 28A (interferon lambda 2)
  • Interleukin 28B (interferon  lambda 3).
Figure 2. Schematic of the interferon pathway in patients with hepatitis C virus infection. IFN = interferon; IL = interleukin; ISGF3 = interferon-stimulated gene factor 3; ISRE = interferon-stimulated response element; JAK 1 = Janus kinase 1; STAT = signal transducer and activator of transcription; TYK2 = tyrosine kinase 2

Production of these three molecules can be triggered by viral infection, and they induce antiviral activity through both innate and adaptive immune pathways. They signal through the IL10R-IL28R receptor complex.20–22 This receptor activates the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway, which regulates a large number of interferon-stimulated genes, primarily through the interferon-stimulated response element (Figure 2).

A 2013 study found that interferon-stimulated gene expression levels in patients with normal livers were highest in those with the CC genotype, intermediate with CT, and lowest with TT. Interestingly, this pattern was reversed in those with hepatitis C virus infection, indicating a relationship between the IL28B genotype and gene expression before infection.23

The mechanism underlying the association between the IL28B polymorphism and response to hepatitis C treatment is not well understood. The unfavorable TT genotype seems to lead to continuous activation of a subset of interferon-stimulated genes in the presence of intracellular hepatitis C viral RNA. But this level of expression is not sufficient to eliminate the virus from the cells. Instead, it might lead to up-regulation of interferon-inhibitory molecules that suppress JAK-STAT signaling, thereby reducing sensitivity to interferon signaling. Therefore, the hepatocyte not only cannot clear the virus by itself, but also cannot induce strong interferon-stimulated gene expression when interferon is given during therapy.20–22

The recently identified ss469425590 polymorphism, which is located in close proximity to rs12979860 in the IL28B gene, is particularly interesting, as it suggests a possible molecular mechanism. The delta G frameshift variant creates a novel gene called IFNL4, which is transiently activated in response to hepatitis C virus infection.24IFNL4 stimulates STAT1 and STAT2 phosphorylation and induces the expression of interferon-stimulated genes. Increased interferon-stimulated gene expression has been shown to be associated with decreased response to pegylated interferon-ribavirin treatment. These observations suggest that the ss469425590 delta G allele is responsible for the increased activation of interferon-stimulated genes and the lower sustained virologic response rate observed in patients who receive pegylated interferon-ribavirin treatment. It is possible that the activation of interferon-stimulated genes in patients with the ss469425590 delta G/delta G genotype reduces interferon-stimulated gene responsiveness to interferon alpha, which normally activates interferon-stimulated genes and inhibits hepatitis C progression.24

IL28B POLYMORPHISM AND ACUTE HEPATITIS C VIRUS INFECTION

Figure 3. IL28B rs12979860 polymorphism and the natural history of chronic hepatitis C virus infection.

From 70% to 80% of acute hepatitis C virus infections persist and become chronic, while 20% to 30% spontaneously resolve. Epidemiologic, viral, and host factors have been associated with the differences in viral clearance or persistence, and studies have found that a strong host immune response against the virus favors viral clearance. Thus, variation in the genes involved in the immune response may contribute to one’s ability to clear the virus. Consistent with these observations, recent studies have shown that the polymorphism in the IL28 gene region encoding interferon lambda 3 strongly predicts spontaneous resolution of acute hepatitis C virus infection. People who have the IL28B CC genotype are three times more likely to spontaneously clear the virus than those with the CT or TT genotype (Figure 3).24

IL28B POLYMORPHISM AND THE NATURAL HISTORY OF HEPATITIS C

In people in whom hepatitis C virus infection persists, up to 20% develop progressive liver fibrosis and eventually cirrhosis over 10 to 20 years.19,25,26 The speed at which fibrosis develops in these patients is variable and unpredictable.25 The relationship between IL28B polymorphisms and hepatic fibrosis in patients with chronic hepatitis C virus infection has not been clearly established, although a study indicated that in patients with a known date of infection, the IL28B genotype is not associated with progression of hepatic fibrosis.27 Obstacles in this field of study are that it is difficult to determine accurately when the patient contracted the virus, and that serial liver biopsies are needed to investigate the progression of hepatic fibrosis.

Patients with chronic hepatitis C virus infection are also at higher risk of hepatocellular carcinoma compared with the general population.28 An analysis of explanted livers of patients with hepatitis C found that the prevalence of hepatocellular carcinoma in those with the unfavorable TT genotype was significantly higher than with the other genotypes.29 Similarly, an earlier study demonstrated that patients with hepatitis C-associated hepatocellular carcinoma carried the T allele more frequently.30 As with other aspects of IL28B associations with hepatitis C, these findings indicate that the C allele confers a certain degree of protection.

An important implication of these relationships is that they may eventually help identify patients at greater risk, who therefore need earlier intervention.

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