Increase in CCR5 Delta32/Delta32 genotype in multiple sclerosis

Abstract

Chemokines and their receptors participate in the development of multiple sclerosis (MS) by guiding immune cells into the brain tissue. A CCR5 Delta32 deletion mutation abolishes functional CCR5 on the cell surface and may reduce cell entry into the lesion sites. To analyse the significance of this mutation in MS, we compared the frequencies of CCR5 genotype in peripheral blood mononuclear cells from 89 MS patients and 119 healthy controls. The CCR5 genotype was further compared with the CCR5 RNA and surface protein expression in 48 MS patients and their controls. In all MS patients, the Delta32/32 genotype was found with 6.7% frequency, whereas it was present only in 0.8% of the controls (6/89 vs 1/119, P = 0.01). Specifically, the Delta32/Delta32 genotype was increased (11.5%, P = 0.05) among primary progressive MS patients, whereas it was present only in 4.8% in other MS subtypes and only in 0.8% of the controls. The amount of CCR5 protein on CD4(+) cells analysed in 48 MS patients (nine primary progressive MS, 18 secondary progressive MS, 21 relapsing-remitting MS) and 13 controls decreased with genotype, being 8.9% in wt/wt, 7.7% in wt/Delta32 and 4.3% in Delta32/Delta32. CCR5 surface expression analysed on these 48 MS patients and 13 controls was significantly decreased in Delta32/Delta32 MS patients as compared with that in wt/wt genotype individuals (P = 0.004). The significantly increased number of Delta32/Delta32 individuals among our MS patients suggests that this genotype could contribute as a general risk factor for MS. However, neither the levels of RNA or surface protein correlated with MS subtype, neurological disability as expressed by expanded disability status scale, or disease progression index. Our results suggest that the lack of CCR5 does not protect from MS, but rather it may predispose to the chronic course of the disease. This would further imply that in view of the redundancy in the chemokine system, CCR5 ligands must be assumed to function through other closely related chemokine receptors.

Genetics of primary progressive multiple sclerosis

“…A Finnish study of 63 RR/SPMS, 26 PPMS, and 119 healthy controls found that the CCR5 d32 homozygous alleles were overrepresented in PPMS patients relative to controls (OR ¼ 15.4, p ¼ 0.018), although individuals homozygous for this were rare in either PPMS (3/23) patients or controls (1/118) and corrections for multiple comparisons were not implemented Furthermore, this study did not show an association between CCR5 expression (RNA or protein) and disease course (Pulkkinen et al, 2004).…”

CCR5-Δ32 genetic polymorphism associated with benign clinical course and magnetic resonance imaging findings in Brazilian patients with multiple sclerosis

“…These results are consistent with findings in other previous reports which showed that the CCR5-Δ32 allele has little or no effect on the development of MS (12,34,36,38,57). This would further imply the redundancy in the chemokine system, and the CCR5 ligand must be assumed to function through other closely related chemokine receptors (37).…”

“…Other CCR5 genetic polymorphism studies carried out in MS patients reported contradictory results, with no significant difference in the allelic frequency of CCR5-Δ32 between the MS patients and the control group, and the presence of CCR5-Δ32 homozygous patients among the MS patients indicated that the absence of CCR5 is not protective against MS (36)(37).…”

CCR5-Delta32 Allele is Associated with the Risk of Developing Multiple Sclerosis in the Iranian Population

“…These findings lend credence to the hypothesis that the 32-base pair deletion in the CCR5 gene (delta32 allele) might have a protective role against immune disorders, such as MS. Even though this allelic effect has been contradicted in a recent study by Otaegui et al (2007), controversial results have been reported in many populations (Kantarci et al 2005;Pulkkinen et al 2004;Bennetts et al 1997;Silversides et al 2004;Ristic et al 2006) that indicate the complexity of a genetic basis for MS.…”