Analysis of the CC chemokine receptor 5 (CCR5) delta-32 polymorphism in inflammatory bowel disease

Abstract

The inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) are complex multifactorial traits involving both environmental and genetic factors. Recent studies have shown the important role of pro-inflammatory cytokines and chemokines, including RANTES, in IBD. RANTES is the natural ligand for the CC-chemokine receptor 5 (CCR5). The chromosomal location of the CCR5 gene on 3p21 coincides with an IBD-susceptibility locus identified by genome-wide scanning. A 32-bp deletion (A32) in the CCR5 gene results in a nonfunctional receptor and is found with high frequency in Caucasians. In this study, we investigated the presence of the CCR5delta32 allele in a large cohort of IBD patients and in a healthy control population. Blood samples were obtained from 538 unselected IBD cases (433 unrelated IBD patients: 289 CD, 142 UC, 2 indeterminate colitis; 105 affected first-degree relatives) and 135 unaffected first-degree family members. Of the IBD patients, 36% had familial IBD with at least two members being affected. There were no significant differences in the CCR5delta32 mutation frequency between IBD patients and healthy controls, nor between CD and UC patients. There was no correlation between the CCR5delta32 genotype and the age at IBD-diagnosis, the frequency of surgical intervention, or disease localization. Only the association between CCR5delta32 homozygosity and the presence of anal lesions in CD patients was statistically significant (P=0.007). Analysis by the transmission/disequilibrium test showed no significant transmission distortion to the probands or their clinically silent siblings. Based on these results, it is unlikely that the CCR5delta32 allele is an important marker for predisposition to IBD.

Polymorphisms in CCL2&CCL5 chemokines/chemokine receptors genes and their association with diseases

“…However, it is unlikely that the CCR5Δ32 allele is an important marker for predisposition to IBD 74,75 .…”

CCR5-Δ32 mutation is strongly associated with primary sclerosing cholangitis

“…One study found a significant association between CCR5-D32 homozygosity and perianal CD. 29 There were no associations with disease susceptibility or other clinical features of IBD, and none of these studies included PSC patients. [30][31][32][33][34] PSC patients have been included in two studies appearing in abstract form only.…”

CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis

“…The CCR5 gene has also been associated with both diseases [5,6], Significant associations have been demonstrated between both a functional CARD15 SNP (2104T, haplotype 4) and a synonymous CARD15 SNP (1761G, haplotype 1), and severe pulmonary sarcoidosis phenotypes. An association between the CCR5 HHC haplotype and chest radiographic stage IV disease has been established.…”

“…There are associations between phenotypic variability and human leukocyte antigen class II alleles in both sarcoidosis (DQB1*0201 with Lofgren's syndrome and erythema nodosum [1]; DQB1*0602 with severe pulmonary disease [1,2]) and Crohn's disease (DRB1*07 with ileal involvement [3]; DRB1*0103 with extraintestinal manifestations [4]). Furthermore, the HHC haplotype of the C-C chemokine receptor (CCR)5 gene (which promotes T-cell recruitment and activation) is a marker for parenchymal involvement [5] but not for sarcoidosis overall, whereas the 32 bp deletion (D32) polymorphism of CCR5 is associated with the subgroup of Crohn's patients with perianal disease [6].…”