CC-type chemokine receptor 5-Δ32 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, bacteria], viral, and toxic factors play a role in a genetically susceptible host. We hypothesized that CC-type chemokine receptor 5 (CCR5) would be ail 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-Delta 32) 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-Delta 32 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-Delta 32 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 (it = 17) carried CCR5-Delta 32. 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-Delta 32 variant may protect against PSC.