BACKGROUND: Chemokine receptor 5 (CCR5) plays an important role in the recruitment of monocytes and T cells in inflammation and experimental studies suggest that CCR5 might be involved in the pathogenesis of IgA nephropathy. A mutation in the CCR5 gene (CCR5 Delta32), leading to a nonfunctional receptor, was recently described. We therefore evaluated the potential role of this mutation on renal survival in patients with IgA nephropathy. METHODS: The distribution of the CCR5 Delta32 genotype was determined by polymerase chain reaction (PCR) analysis in 228 patients with biopsy-proven IgA nephropathy. In 190 patients with available demographic and clinical follow-up data, the effect of the mutation on the clinical outcome was analyzed using the Log-rank test and the Cox proportional hazard model. In vitro, the influence of the CCR5 Delta32 genotype on the chemotactic response of monocytes was assessed. RESULTS: Of the 190 patients, 158 (83.2%) had a CCR5 wild-type genotype, 29 (15.3%) were heterozygous, and three patients had a homozygous CCR5 Delta32 genotype (1.6%). Renal survival was significantly longer in patients with the CCR5 Delta32 genotype than in the wild-type group (Log-rank P < 0.001). Using the multivariate Cox proportional hazard model, the CCR5 Delta32 genotype was identified as an independent factor associated with a lower risk to develop end-stage renal disease (ESRD) [hazard ratio (HR) 0.23, 95% CI 0.09 to 0.57, P= 0.002]. In vitro analysis of monocytes from CCR5 Delta32 carriers showed a reduced chemotactic response to CCR5 ligands in vitro. CONCLUSION: Our study demonstrates an independent role of the CCR5 Delta32 genotype for the clinical outcome in IgA nephropathy. In vitro experiments revealed a reduced chemotactic response of monocytes from CCR5 Delta32 carriers, thus pointing out a possible pathophysiologic explanation for the beneficial effect of the CCR5 Delta32 genotype.
BACKGROUND:Chemokine receptor 5 (CCR5) plays an important role in the recruitment of monocytes and T cells in inflammation and experimental studies suggest that CCR5 might be involved in the pathogenesis of IgA nephropathy. A mutation in the CCR5 gene (CCR5Delta32), leading to a nonfunctional receptor, was recently described. We therefore evaluated the potential role of this mutation on renal survival in patients with IgA nephropathy. METHODS: The distribution of the CCR5Delta32 genotype was determined by polymerase chain reaction (PCR) analysis in 228 patients with biopsy-proven IgA nephropathy. In 190 patients with available demographic and clinical follow-up data, the effect of the mutation on the clinical outcome was analyzed using the Log-rank test and the Cox proportional hazard model. In vitro, the influence of the CCR5Delta32 genotype on the chemotactic response of monocytes was assessed. RESULTS: Of the 190 patients, 158 (83.2%) had a CCR5 wild-type genotype, 29 (15.3%) were heterozygous, and three patients had a homozygous CCR5Delta32 genotype (1.6%). Renal survival was significantly longer in patients with the CCR5Delta32 genotype than in the wild-type group (Log-rank P < 0.001). Using the multivariate Cox proportional hazard model, the CCR5Delta32 genotype was identified as an independent factor associated with a lower risk to develop end-stage renal disease (ESRD) [hazard ratio (HR) 0.23, 95% CI 0.09 to 0.57, P= 0.002]. In vitro analysis of monocytes from CCR5Delta32 carriers showed a reduced chemotactic response to CCR5 ligands in vitro. CONCLUSION: Our study demonstrates an independent role of the CCR5Delta32 genotype for the clinical outcome in IgA nephropathy. In vitro experiments revealed a reduced chemotactic response of monocytes from CCR5Delta32 carriers, thus pointing out a possible pathophysiologic explanation for the beneficial effect of the CCR5Delta32 genotype.
Authors: Gabriel Catano; Zoya A Chykarenko; Andrea Mangano; J-M Anaya; Weijing He; Alison Smith; Rosa Bologna; Luisa Sen; Robert A Clark; Andrew Lloyd; Ludmila Shostakovich-Koretskaya; Sunil K Ahuja Journal: J Infect Dis Date: 2011-01-15 Impact factor: 5.226