Chemokine receptor 5 and primary biliary cirrhosis: a two-centre genetic association study.
BACKGROUND
Chemokines and their receptors are important mediators of leucocyte trafficking and are suggested to be critical for establishment of inflammatory autoimmune processes. CC chemokine receptor 5 (CCR5) is expressed preferentially by CD4+ T cells. We hypothesised that the CCR5delta(Delta)32 genotype, which impairs surface expression of CCR5 in heterozygotes and is linked to a functional polymorphism of CD45RA expressed on suppressor-inducer-like 'naive' CD4+ T cells, may modulate the inflammatory process in primary biliary cirrhosis (PBC).


METHODS
CCR5Delta32 polymorphism was determined by PCR in 226 Caucasian PBC patients and 197 racially matched controls from two geographical areas, Newcastle, UK and Padua, Italy. (UK: 144 PBC, 105 controls, Italy: 82 PBC, 92 controls).


RESULTS
When the two series were analysed separately, there were no significant differences in the genotype distribution comparing patients and controls (UK: wt/wt 72% vs 76%; wt/Delta32 28% vs 22%; Delta32/Delta32 0% vs 2%, P=0.24; Italy: wt/wt 72% vs 82%; wt/Delta32 27% vs 17%; Delta32/Delta32 0% vs 1%, P=0.14). However, when the data for the two series were pooled and reanalysed, we found an increase in the CCR5Delta32 mutation in PBC patients vs controls (28% vs 21%, OR=1.43, P=0.03), but there was no evidence that this Delta32 polymorphism is associated with less severe disease.


CONCLUSIONS
Although this two-centre genetic association study is large compared with others performed in PBC, taken separately, each geographically based cohort of patients and controls is underpowered to detect a small effect of this functional polymorphism. This emphasises the need for far larger case-control collections to address which polymorphic markers or haplotypes might modify the pathogenesis and clinical course of PBC. We propose that multi-centre collaboration on an international scale in 'orphan' complex liver diseases such as (PBC) is supported by the International Association for the Study of the Liver and promoted via their journal with development of a brief format for web-based publication of studies.
Baragiotta
A
A
Centre for Liver Research, School of Clinical Medical Sciences, The Medical School, University of Newcastle, Newcastle-upon-Tyne, UK.
Floreani
A
A
Agarwal
K
K
Venturi
C
C
Craggs
A
A
Jones
D E J
DE
Donaldson
P T
PT
Bassendine
M F
MF
D001483:Base Sequence; D016022:Case-Control Studies; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D007558:Italy; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008969:Molecular Sequence Data; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011336:Probability; D019713:Receptors, CCR5 / Q000235:genetics* / Q000378:metabolism; D012016:Reference Values; D012680:Sensitivity and Specificity; D006113:United Kingdom
D019713:Receptors, CCR5