Genetic variations of the chemokine scavenger receptor D6 are associated with liver inflammation in chronic hepatitis C.
Chronic hepatitis C (HCV) represents one of the most common chronic infections worldwide and is a major indication for liver transplantation. Liver inflammation is the main predictor of advanced fibrosis in HCV. Inflammatory cells are recruited to the liver by chemokines. Recently, a novel class of chemokine receptors has been characterized that lack signaling functions and are termed scavenger receptors. We determine here whether genetic variations of the scavenger receptor D6 contribute to the grade of liver inflammation in HCV. Four haplotype tagging single nucleotide polymorphisms (SNPs) were identified from HapMap that cover the genetic information of D6 (CCBP2). Among these SNPs, rs4683336 was associated with liver inflammation in qualitative (p = 0.003) and quantitative (p = 0.0086) genotype analysis. This association was confirmed in an independent cohort of HCV-infected patients (p = 0.006 for qualitative and p = 0.0046 for quantitative analysis, respectively). Furthermore, the haplotype that is tagged by marker rs4683336 was significantly correlated with liver inflammation when compared with the most common D6 haplotype (p = 0.014). The importance of genetic variations in D6 was supported through the demonstration of an association of D6 mRNA expression with histologic inflammation in liver biopsies and a considerable range of D6 mRNA expression in isolated human hepatocytes. In conclusion, we demonstrate that variations in a chemokine scavenging receptor are significantly correlated with clinical inflammatory phenotypes such as HCV infection.
Wiederholt
Tonio
T
Department of Dermatology, University Hospital Aachen, Aachen, Germany.
von Westernhagen
Michael
M
Zaldivar
Mirko Moreno
MM
Berres
Marie-Luise
ML
Schmitz
Petra
P
Hellerbrand
Claus
C
Müller
Tobias
T
Berg
Thomas
T
Trautwein
Christian
C
Wasmuth
Hermann E
HE
D000328:Adult; D015415:Biomarkers / Q000032:analysis; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis*; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology*; D051126:Scavenger Receptors, Class D / Q000235:genetics* / Q000276:immunology*; D000097628:Chemokine Receptor D6
D015415:Biomarkers; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D051126:Scavenger Receptors, Class D; C515708:ACKR2 protein, human; D000097628:Chemokine Receptor D6