Role of CCR5 in the cardiovascular complications of renal disease and diabetes: insights from studies on CCR5Δ32 genotype

PhD ceremony: Mr. F.L.H. Muntinghe, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Role of CCR5 in the cardiovascular complications of renal disease and diabetes: insights from studies on CCR5Δ32 genotype

Promotor(s): prof. G.J. Navis

Faculty: Medical Sciences

In end-stage renal disease (ESRD) and type 2 diabetes, the chronic inflammatory condition of cardiovascular disease is a prominent cause of mortality. In this process chemokine receptors, such as the CC-chemokine receptor 5 (CCR5), play an important role. CCR5 is expressed on T cells, monocytes and endothelial cells; all cell types involved in the chronic inflammatory state of atherosclerosis. This thesis focuses on the role of CCR5 in the chronic inflammatory process of atherosclerotic disease in ESRD and type 2 diabetes. To this purpose we studied the consequences of genetic deficiency of CCR5, which occurs in subjects with the CCR5∆32 genetic variant. First, we studied the epidemiological consequences of the CCR5∆32 variant in ERSD and type 2 diabetes. CCR5∆32 was associated with better survival in type 2 diabetes patients and the CCR5∆32 genotype attenuated the adverse effects of an inflammatory state on overall and cardiovascular mortality in ESRD. The mechanism might be an effect on the inflammatory response with reduced T-helper 1 and increased T-helper 2 type immune response as we found a different cytokine profiles in carriers and non-carriers of the CCR5∆32 genotype, and differences in the response to stimulation of isolated CD4+ and CD8+ T cells from carriers and non-carriers of CCR5∆32. As these data support the relevance of CCR5 as a novel target for intervention, we performed a simulation study on the potential cost-effectiveness of CCR5Δ32 screening and pharmacological CCR5 blockade and showed that from an economic point of view such a strategy is cost-effective in ESRD patients. These studies demonstrate the potency of functional genetics as a dissection tool to support development of individualized therapy, and support the potential of individualized anti-inflammatory therapy for cardiovascular protection in renal patients with chronic inflammation.