In the study of viral hepatitis, HIV/AIDS, cancer, and other illnesses, an increasing amount of attention in recent years has focused on individual genetic variations and how these affect disease pathogenesis and treatment.

Several studies presented at the recent Digestive Disease Week 2006 conference in Los Angeles looked at the influence of genetic variability on response to hepatitis C therapy, development of depression during treatment, and progression to hepatocellular carcinoma (HCC).

As previously reported, researchers found that polymorphisms (variations) in interferon-stimulated genes and genes involved in the interferon signaling pathway were associated with sustained response to interferon-based therapy. In addition, the human leukocyte antigen (HLA) alleles A*02, B*58, and DPB*1701 were independently associated with sustained response to pegylated interferon plus ribavirin; these variations may help explain the difference in response rates across different racial/ethnic groups.

Interferon-Induced Depression

M.R. Kraus and colleagues looked at the association between another genetic variation and the risk of developing depression during interferon-based therapy. Some types of depression are due to altered levels of the neurotransmitter serotonin; a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) is used to prevent or manage depression during hepatitis C treatment.

This study included 139 patients with chronic hepatitis C who were enrolled between 1997 and 2004 and treated with conventional or pegylated interferon, with or without ribavirin. Before and during therapy, the researchers assessed depression using the Hospital Anxiety and Depression Scale (HADS) and the DSM-IV criteria for major depression/major depressive disorder.

The researchers used DNA isolation extraction and polymerase chain reaction technology to determine whether or not subjects carried the C(-1019)G polymorphism of the 5-HT1A serotonin receptor gene.

Results

There was a significant association between the HT1A receptor polymorphism and the occurrence of interferon-induced depression during antiviral therapy.

Carriers of the "G" allele had both a higher incidence and greater severity of depressive symptoms.

Presence of the C(-1019)G polymorphism was associated with both maximum and mean increases in HADS depression scores during interferon therapy (P = 0.011 and P = 0.024, respectively).

Clinically relevant HADS depression scores (9 or higher) were also significantly associated with this polymorphism (P = 0.017).

Conclusion

The researchers concluded that allelic variation in expression of the 5-HT1A gene played a significant role in the development of interferon-induced depression during treatment of chronic hepatitis C. They suggested that this information might be used to develop models to predict interferon-induced depressive symptoms.

What is Hepatocellular Carcinoma? Most primary liver cancers are classified as hepatocellular carcinoma. Hepatocellular carcinoma is a malignant tumor composed of cells resembling hepatocytes ; however, the resemblance varies with the degree of differentiation . Hepatocellular carcinoma is commonly associated with cirrhosis

Development of Hepatocellular Carcinoma

N. Dharel and colleagues previously reported on several gene polymorphisms associated with development of HCC in people with chronic hepatitis C. Other researchers recently reported that a single nucleotide polymorphism (SNP) on the MDM2 gene, known as SNP309, was associated with accelerated tumor formation in patients with various hereditary and non-hereditary cancers; this SNP appears to down-regulate expression of the p53 tumor suppressor protein.

In the current study, the researchers sought to determine whether the SNP309 polymorphism is also linked to development of HCC in patients with hepatitis C. They performed polymerase chain reaction tests to determine the SNP309 alleles in 435 Japanese patients with chronic hepatitis C -- including 187 patients with HCC -- as well as 48 healthy volunteers.

Results

51% of the Japanese subjects carried the T/G allele of SNP309, 27% carried the G/G allele, and 22% had the T/T allele.

This differs from a previously reported distribution of 40%, 12%, and 48%, respectively, among Caucasians.

Among the subjects with hepatitis C, significantly more patients with HCC had the G/G genotype compared with non-HCC patients (33% vs 23%; odds ratio 2.28, 95% CI 1.30-3.98).

In a multivariate analysis, the following factors were independently associated with development of HCC:

- SNP309 polymorphism (G/G vs T/T) (odds ratio 2.27)
- age over 60 years (odds ratio 2.46)
- male gender (odds ratio 3.08)
- presence of cirrhosis (odds ratio 4.15)
- serum alpha-fetoprotein level > 20 mcg/L (odds ratio 4.87)
- serum albumin level < 3.2 g/dL (odds ratio 6.33).

Conclusion

The researchers concluded that the MDM2 promoter SNP309 is associated with development of HCC in Japanese patients with chronic hepatitis C. They added that the G/G allele could potentially serve as an important genetic marker for the risk of liver cancer in this population.

Together, these studies add to the evidence that genetic testing may become increasingly relevant in predicting and/or managing various aspects of hepatitis C and its treatment.

6/27/06

References

MR Kraus, O Al-Taie, A Schaefer, and others. Association between allelic variation in 5-HT1A receptor expression (C-[1019]G polymorphism) and interferon-induced depression in patients with chronic hepatitis C. Abstract 197. Digestive Disease Week 2006. May 20-25, 2006. Los Angeles, CA.

N Dharel, N Kato, R Muroyama, and others. MDM2 Promoter SNP309 is associated with hepatocellular carcinoma in Japanese patients with chronic hepatitis C. Abstract S1052. Digestive Disease Week 2006. May 20-25, 2006. Los Angeles, CA.