Lower copy numbers of the chemokine CCL3L1 gene in patients with chronic hepatitis C

Received 5 February 2009; received in revised form 2 August 2009; accepted 1 September 2009. published online 27 November 2009.

Background & Aims

Recently, variation of gene copy numbers was recognized as a novel type of common genetic diversity, but its impact on viral hepatitis is unknown. Here, we determine the influence of copy number variation on the susceptibility and disease severity in hepatitis C virus (HCV) infection, investigating copy number variants (CNVs) of the chemokine CCL3L1 gene, which encodes a potent CCR5 ligand.

Methods

CNVs were determined in 254 patients with chronic hepatitis C, 144 HCV/HIV co-infected patients, and 210 HCV negative controls, using quality-controlled real-time fluorescent dye-labeled quantitative PCR. Liver biopsies were obtained from HCV infected patients.

Results

Copy numbers of the CCL3L1 gene range from 0 to 12 (mean 2.7±1.4 copies). Patients with two or less copies are over-represented in the HCV infected cohort compared to HCV negative controls (odds ratio [OR] 1.54; p=0.02). CCL3L1 copies are shifted to lower numbers in HCV infected patients (means 2.6 vs. 2.9 in controls; p=0.011). HCV/HIV co-infected patients carry even lower CCL3L1 copy numbers compared to controls (means 2.2 vs. 2.9; p<0.001), with a higher proportion of patients possessing two or less copies (OR=3.42; p<0.001). No association was detected between CCL3L1 copy numbers and histological grades of inflammation or stages of fibrosis.

Conclusions

Lower CCL3L1 gene copy number compared to the population median is associated with chronic hepatitis C. Copy number variation of host genes represents a novel class of genetic diversity associated with viral hepatitis.

Abbreviations: BP, base pair, CCL3L1, CC-chemokine 3-like 1, CI, confidence interval, CNV, copy number variant, HBV, hepatitis B virus, HCV, hepatitis C virus, HIV, human immunodeficiency virus, OR, odds ratio, SNP, single nucleotide polymorphism

Keywords: Association study, Complex disease, Gene duplication, Gene variant, Hepatitis C virus, Polymorphism, Susceptibility factor

1 Department of Medicine II, Saarland University Hospital, Saarland University, Kirrberger Str. 1, 68421 Homburg, Germany

2 Department of Internal Medicine I, University Hospital Bonn, University of Bonn, Bonn, Germany

3 Department of Medicine III, University Hospital Aachen, Aachen University (RWTH), Germany

4 Department of Medicine I, University Hospital Regensburg, University of Regensburg, Germany

5 Institute of Clinical Chemistry and Pathobiochemistry and Central Laboratory, RWTH-University Hospital, Aachen, Germany

Corresponding author. Tel.: +49 684 11623202; fax: +49 6841 1623267.

† These authors contributed equally.

PII: S0168-8278(09)00725-9

doi:10.1016/j.jhep.2009.11.001

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