CC-type chemokine receptor 5-Delta32 mutation protects against primary sclerosing cholangitis.
BACKGROUND
Primary sclerosing cholangitis (PSC) is commonly associated with inflammatory bowel disease (IBD) and characterized by fibrosing inflammatory destruction of biliary ducts. The pathogenesis of PSC remains unknown, but immunological, bacterial, viral, and toxic factors play a role in a genetically susceptible host. We hypothesized that CC-type chemokine receptor 5 (CCR5) would be an interesting candidate gene for susceptibility to PSC from its chromosomal location within the IBD susceptibility locus on 3p21, as well as from a functional perspective. We therefore investigated the role of the functional 32-bp deletion in this gene (CCR5-Delta32) with regard to susceptibility to PSC.


METHODS
A total of 110 patients with PSC, 56 with concomitant IBD (23 with Crohn's disease, 28 with ulcerative colitis, 5 with indeterminate colitis), were collected. All of the subjects were genotyped for CCR5-Delta32 with polymerase chain reaction amplification, followed by detection on ethidium bromide-stained agarose gel. Genotypes and allele frequencies were compared with a cohort of IBD patients without PSC (n = 400) and healthy control subjects (n = 362).


RESULTS
The frequency of the CCR5-Delta32 mutation in PSC (6.8%) was significantly lower compared with IBD (12.6%; P = 0.016) and healthy control subjects (12.2%, P = 0.026), suggesting a protective effect of this mutation on PSC. None of the PSC patients with severe disease necessitating liver transplantation (n = 17) carried CCR5-Delta32.


CONCLUSIONS
Because an intact CCR5 receptor is needed for internalization of specific pathogens and homing of memory T lymphocytes to the liver, we hypothesize that a deficient expression of this receptor resulting from the CCR5-Delta32 variant may protect against PSC.
Henckaerts
Liesbet
L
Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
Fevery
Johan
J
Van Steenbergen
Werner
W
Verslype
Chris
C
Yap
Paul
P
Nevens
Frederik
F
Roskams
Tania
T
Libbrecht
Louis
L
Rutgeerts
Paul
P
Vermeire
Séverine
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015209:Cholangitis, Sclerosing / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D019713:Receptors, CCR5 / Q000235:genetics*
D019713:Receptors, CCR5; D004247:DNA