Do IL28B Gene Variations Affect Liver Disease Progression in People with Hepatitis C?

		SUMMARY: Variations in the IL28B gene, which have been shown to predict spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapy, may also play a role in liver disease progression, according to a set of studies presented at the recent American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston. Some investigators found that the unfavorable rs12979860 T/T gene pattern was associated with worse liver fibrosis, but others did not observed this link.

By Liz Highleyman

In 2009 researchers first reported that specific variations in the human genetic code near the IL28B gene can help predict who will spontaneously clear acute HCV infection and who will respond well to interferon for chronic infection.

Single nucleotide polymorphisms, or SNPs, are substitutions of a single nucleotide building block at a specific position in a DNA chain. A number of SNPs -- most often 12979860 -- on chromosome 19 near the IL28B gene have been linked to hepatitis C outcomes. The IL28B gene encodes interferon lambda, or interleukin 28; interferons produced by the body are key to the immune response against HCV, and injected interferon therapy strengthens this natural response.

Each individual carries 2 copies of every gene, one from each parent. The IL28B rs12979860 SNP has 2 variations, or alleles, known as "C" and "T." Hepatitis C patients with the homozygous or matching C/C pattern (2 copies of the "C" allele) are most likely to spontaneously clear HCV and have the best treatment outcomes. People with the homozygous T/T pattern (2 "T" alleles) have the least favorable response, while those with the heterozygous or mixed C/T pattern (1 copy of each variation) fall in between. Other implicated IL28B SNPs have different specific letter combinations, but the principle is the same.

Numerous studies have shown that hepatitis C patients with the C/C pattern have higher rates of rapid and sustained virological response (SVR) to pegylated interferon plus ribavirin than those with the T/T pattern. But it is not yet clear whether IL28B variations can also predict liver disease severity. Several presentations at the Liver Meeting addressed this topic.

Liver Fibrosis Link

Davide Bitetto from the University of Udine in Italy and colleagues looked at the link between the IL28B rs12979860 SNP and fibrosis progression in 548 people with HCV infection and 428 healthy blood donor; just over half of the hepatitis C patients were men and the median age was 56 years.

Participants were categorized according to liver disease severity. A total of 349 had chronic hepatitis and had never received antiviral treatment; in this group, 235 had mild liver fibrosis (Ishak stage F2 or lower) and 114 had advanced fibrosis (stage F3-F4). In addition, there were 199 patients with liver cirrhosis, 51 of whom also had hepatocellular carcinoma (HCC).

Looking at rs12979860 SNP frequency among the hepatitis C patients, 32% had the protective C/C gene pattern, 54% had the C/T pattern, and 14% had the unfavorable T/T pattern. Among healthy control subjects, the corresponding proportions were 47%, 42%, and 11%.

The likelihood of having the T/T pattern rose as liver disease worsened. Only 9% of patients with mild chronic hepatitis carried the T/T pattern, rising to 17% of those with more advanced liver disease, and 24% of those with cirrhosis and HCC -- a statistically significant trend.

IL-28B rs12979860 polymorphism "appears to influence the natural history of chronic hepatitis C," the researchers concluded. "Carrying the T/T genotype favors the evolution of the disease until the development of HCC."

No Fibrosis Difference

In contrast, a smaller Spanish study failed to find a similar association. Jose Del Campo from Hospital de Valme in Seville and colleagues looked at 129 hepatitis C patients with HCV genotype 1 patients who were treated with pegylated interferon/ribavirin for 48 weeks.

The researchers saw no difference in SNP pattern distribution according to extent of liver disease. About one-third (30%) of patients with absent-to-mild (METAVIR stage F0-F1) fibrosis carried the protective C/C pattern, compared with 41% of those with moderate (F2) fibrosis, and 36% of those with advanced (F3-F4) liver disease -- not a significant difference.

IL28B pattern was also not associated with HCV RNA levels. People with the C/C pattern, however, had lower blood glucose levels on average than those with C/T or T/T (95 vs 103 mg/dL), a difference that just reached statistical significance.

These findings led the researchers to conclude that, "IL28B SNP is a major predictor of SVR associated with glucose metabolism but unrelated to fibrosis stage and viral load."
Additional studies presented at the conference also found a link between IL28B and glucose metabolism or insulin resistance, while others saw an association with low-density lipoprotein (LDL) cholesterol levels. The relationship between IL28B, metabolic abnormalities, and liver disease progression is not well understood, and is an area ripe for further research.

IDEAL Study

Alexander Thompson and fellow investigators with the IDEAL study presented findings from 2 analyses looking at IL28B polymorphisms and liver disease severity. The Phase 3b IDEAL trial compared pegylated interferon alfa-2a (Pegasys) vs pegylated interferon alfa-2b (PegIntron), both with weight-adjusted ribavirin, in more that 3000 previously untreated HCV genotype 1 patients.

The first AASLD analysis included 1329 participants, most with mild (stage F1) liver fibrosis at baseline, who received genotypic testing to determine their rs12979860 SNP pattern.

Here, too, the researchers saw no relationship between IL28B pattern and advanced (METAVIR stage F3-F4) fibrosis. This was true overall and also when patients were categorized by race/ethnicity (white, black, or Hispanic) -- done because blacks are less likely than whites to carry the protective C/C pattern and respond more poorly to interferon.

In the second analysis, however, the researchers did see a link between rs12979860 pattern and alanine aminotransferase (ALT) levels and necro-inflammatory activity. People with the protective C/C gene pattern had higher pre-treatment ALT and were more likely to have moderate-to-severe (METAVIR stage A2-A3) necro-inflammatory activity.

Numerous prior studies have shown that people with higher ALT and greater necro-inflammatory activity -- an indicator of active liver inflammation -- are more likely to achieve SVR. The IDEAL researchers suggested that this association might be explained by IL28B variations.

Another pair of studies presented at the conference showed that IL28B variations also may help predict outcomes after liver transplantation.

Investigator affiliations:

Bitetto study: Medical Sciences Clinical and Experimental, Medical Liver Transplant Unit, University of Udine, Udine, Italy; Department of Clinical and Experimental Medicine, University of East Piedmont Amedeo Avogadro, Novara, Italy.

Del Campo study: Hospital de Valme, CIBEREHD, Sevilla, Spain; Structural Genomics, Neocodex SL, Sevilla, Spain; Hospital General de Valencia, Valencia, Spain; Hospital Virgen Macarena, Sevilla, Spain; Hospital Virgen de la Victoria, CIBEREHD, Málaga, Spain; Hospital Clínico San Carlos, CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.

Thompson studies: Duke Clinical Research Institute, Duke University Medical Centre, Durham, NC; Center for Human Genome Variation, Duke University, Durham, NC; Johns Hopkins University School of Medicine, Baltimore, MD; Beth Israel Deaconess Medical Center, Boston, MA; Weill Cornell Medical College, New York, NY; Hospital General Universitario Valle de Hebron, Barcelona, Spain; Cedars-Sinai Medical Center, Los Angeles, CA; Alamo Medical Research, San Antonio, TX; Mt. Vernon Endoscopy Center, Alexandria, VA; Virginia Commonwealth University, Richmond, VA; Kelsey Research Foundation, Houston, TX; Louisiana State University, Shreveport, LA; School of Medicine, Indiana University, Indianapolis, IN; Kaiser Permanente, San Diego, CA; Armed Forces Insitute of Pathology, Washington, DC; Schering-Plough Corporation/Merck & Co., Inc., Whitehouse Station, NJ.

11/19/10

References

D Bitetto, C Fabris, E Fornasiere, and others. C>T polymorphism affects the evolution of chronic hepatitis C. 61st Annual Meeting of the American Association for the Study of Liver Diseases AASLD 2010). Boston, October 29-November 2, 2010. Abstract 230.

JA Del Campo, M Maraver Zamora, R. Ramirez-Lorca, and other. IL28B polymorphism predicts sustained virological response in hepatitis C but is not associated with fibrosis or viral load. 61st Annual Meeting of the American Association for the Study of Liver Diseases AASLD 2010). Boston, October 29-November 2, 2010. Abstract 892.

AJ Thompson, J Clark, J Fellay, and others. IL28B genotype is not associated with advanced hepatic fibrosis in chronic hepatitis C patients enrolled in the IDEAL study. 61st Annual Meeting of the American Association for the Study of Liver Diseases AASLD 2010). Boston, October 29-November 2, 2010. Abstract 229.

AJ Thompson, PJ Clark, M Zhu, and others. Genome wide-association study identifies IL28B polymorphism to be associated with baseline ALT and hepatic necro-inflammatory activity in chronic hepatitis C patients enrolled in the IDEAL study. 61st Annual Meeting of the American Association for the Study of Liver Diseases AASLD 2010). Boston, October 29-November 2, 2010. Abstract 1893.