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CCR2 V64I polymorphism: morbidity and mortality in PREVEND

B reedtestrategie. CCR2 V64I polymorphism: morbidity and mortality in PREVEND. 18-04-2005 Mike Zuurman, Department of Internal Medicine, Section Nephrology University Medical Centre Groningen, The Netherlands. Chemokines and their receptors: families.

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CCR2 V64I polymorphism: morbidity and mortality in PREVEND

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  1. Breedtestrategie CCR2 V64I polymorphism: morbidity and mortality in PREVEND 18-04-2005 Mike Zuurman, Department of Internal Medicine, Section NephrologyUniversity Medical Centre Groningen, The Netherlands

  2. Chemokines and their receptors: families Classified based on position of conserved cystein residues in the protein structure

  3. CC-motif chemokine receptors: nomenclature Human Mouse Rat Historical names CCR1 Ccr1 Ccr1 CMKBR1, CC-CKR1, HM145, MIP-1a-R, RANTES-R, LD78-R - Ccr1l1 - CMKBR1L1, CC-CKR1-like 1, MIP-1a-R-like 1 CCR2 Ccr2 Ccr2 CMKBR2, CC-CKR2, CCR2A, CCR2B, MCP-1-R, mJE-R CCR3 Ccr3 Cmkbr3 CMKBR3, CC-CKR3, CC-CKR1-like 2, MIP-1a-R-like 2, eotaxin receptor CCR4 Ccr4 Ccr4 CMKBR4, CC-CKR-4, K5-5 CCR5 Ccr5 Ccr5 CMKBR5, CC-CKR5, ChemR13, CD195, HIV-1 fusion coreceptor CCR6 Ccr6 Ccr6 CMKBR6, STRL22, GPR29, GPR-CY4, CKR-L3, DRY6, LARC-R CCR7 Ccr7 Ccr7 CMKBR7, BLR2, EBI1, CDw197, AMG1 CCR8 Ccr8 - CMKBR8, CMKBRL2, CKR-L1, TER1, GPR-CY6, ChemR1, CC CKR-type 2 CCR9 Ccr9 Ccr9 CMKBR9, GPR-9-6, CC-CKR-9, CCR9A, CCR9B< GPR2 Gpr2 - CCR10, CCR9, CCR10A, CCR10B CCRL1 Ccrl1 - CCR11, VSHK1, CCBP2, CCX-CKR, GPCR14 CCRL1P - - - CCRL2 Ccrl2 - CC CKR-like 2, HCR, CRAM-A, CRAM-B, CKRX, E01, L-CCR HRH4 Hrh4 Hrh4 histamine receptor H4, HH4R, GPRv53, GPCR105 FPRL1 Fprl1 Fprl1 formyl peptide receptor-like 1, HM63, lipoxin A4-R, FPR2A, FMLP-R-II, Lxa4r

  4. Chemokines Chemokine function: classical Chemokines

  5. Chemokine function: recent • Intercellular communication (brain) • Angiogenesis (f.i. tumour related) • Orchestration of the immune response • * Pro- and anti-inflammatory • -Hematopoiesis • -Organogenesis • -Ovulation, luteal regression

  6. Chemokines in pathology: atherosclerosis

  7. Chemokines in pathology: renal disease J Am Soc Nephrol 11: 152-176, 2000

  8. CC-motif chemokine receptor 2 comes in two flavours Ligands: -MCP-1 (CCL2) -MCP-2 -MCP-3 -MCP-4 -MCP-5 Nakayama et al.,AIDS 2004 Mar 26;18(5):729-38.

  9. CCR2 64I: a single nucleotide polymorphism (SNP) Gives rise to a valine to isoleucine substitution

  10. Literature on CCR2 64I and clinical outcome  CCR2 64I is associated with reduced coronary artery calcification suggesting increased risk of unstable plaques (Valdes et al., ATVB 22, 2002)  CCR2 64I is associated with higher prevalence of myocardial infarction (Ortlebb et al., J Mol Med 81, 2003; Petrkova et al., Immunol. Letters, 88, 2003)  The minor allele (I) is associated with delayed progression to AIDS in HIV-1patients (Smith et al., Science 277, 1997)  CCR2 64I shows no protective effect on death after development of AIDS in adults (Ioannidis et al., Ann Intern Med 135, 2001)  CCR2 64I is associated with increased mortality in HIV-1 infected neonates after a survival period of 6 years (Ioannidis et al., J Med Genet. 41, 2004)  Risk of acute renal transplant rejection was reduced in carriers of the CCR2-64I allele (Abdi et al., JASN 13, 2002)

  11. CCR2 64I and receptor function • Initially scientists saw no apparent function difference between CCR2 64Vand CCR2 64I (chemotaxis, intracellular Ca2+ , ligand-binding etc.) • However, classically scientists examined CCR2B, and not CCR2A due to historical results that suggested much lower expression of CCR2A in monocytes Increasing evidence shows CCR2A and CCR2B expression depends on microenvironment ! For instance: * CCR2A ++ in myopathy (Bartoli et al., Acta Neuropath. 102, 2001) * CCR2B ++ in monocytic cellines (Tanaka et al., BBRC 290, 2002) • Indeed, Nakayama et al.(2004) showed neatly that the CCR2A and NOT CCR2B functionality is influenced by the valine to isoleucine substitution: - Increased surface expression of CCR2A - More stable expression of CCR2A - Increased down-regulation of CCR5, the principle co-receptor required by HIV-1 for infection

  12. Previous studies only in patient populations already predisposed with CV-disease CCR2 64I and general population? What about predisposed cardiovascular morbidity? What about mortality?

  13. Prevention of REnal and Vascular ENd-organ Damage Populatie Groningen 85000 individuals 40000 urine samples 8500 in preclinic (MA enriched) Genotyping Phenotyping

  14. Predisposition: hypertension in history

  15. Baseline differences between hypertensives and normotensives in the study population BMI, body-mass index; MAP, mean arterial pressure; LLD, lipid lowering drugs; UAE: urinary albumin excretion. Continuous values show mean and standard deviation, except for UAE (median and 25th – 75th percentile). a: ANOVA P-value < 0.05; b: Pearson Chi square P-value < 0.05; c: Mann-Whitney U-test P­-value < 0.05.

  16. Characteristics of hyper- and normotensives by CCR2-V64I

  17. Distribution of cardiovascular events

  18. * 30 VV II+IV 20 % 10 0 Non-hypertensives Hypertensives Prevalence of cardiovascular events during follow-up 12 VI + II VV 10 8 % of genotype group 6 4 2 0 1 2 3 4 5 Number of CE

  19. Relative risk of cardiovascular events in hyper- and normotensive CCR2V64I I-carriers versus VV homozygotes. RR: relative risk, P: P-value of the genotype term in the logistic regression analyes. The full model includes, besides subject age, significant contribution of: usage of lipid-lowering drugs, sex, HDL-cholesterol, LDL+VLDL-cholesterol, mean arterial pressure and urinary albumin excretion..

  20. Conclusion: CCR2 64I associates with CV-events when subjects already suffer from hypertension

  21. Baseline characteristics and risk factors for mortality according to CCR2-V64I genotype

  22. Table 2. Distribution of Causes of Death (COD) among CCR2-V64I genotype, subdivided in Malignant COD, Cardiovascular COD and Other (unrelated) COD.

  23. All-cause mortality hazard ratios of CCR2 VI subjects using Cox regression models and CCR2V64I VV-individuals as reference.

  24. Cox competing risk models

  25. Conclusions: 1. CCR2 64I associates with CV-events when subjects already suffer from hypertension 2. CCR2 64I associates with all-cause mortality, but does not predict CV-mortality 3. Results suggest an association of CCR2 64I with cancer-related mortality

  26. Acknowledgements Medical Biology Gerrit van der Steege Elvira Oosterom Marcel Mulder Ron Korstanje Trial Coordination Centre Hans HillegeInternal Medicine, Nephrology Gerjan Navis Paul E. De Jong

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