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GENECURE

Impact of genetic variation in the chemokine system Possibilities for GENECURE. November 9 2006. GENECURE. Mike W. Zuurman, PhD. Breedte strategie. Genetic determinants of Atherosclerotic (End-Stage) disease in man. Functional analyses In vitro/In vivo Molecular Fundamental.

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GENECURE

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  1. Impact of genetic variation in the chemokine system Possibilities for GENECURE November 9 2006 GENECURE Mike W. Zuurman, PhD

  2. Breedtestrategie Genetic determinants of Atherosclerotic (End-Stage) disease in man • Functional analyses • In vitro/In vivo • Molecular • Fundamental • Genetic epidemiology • Patient cohorts • General population • Sequence variants Bioinformastatistica -Utilization of tools -Development of tools -Solutions

  3. Gene-environment interaction of phenotypic risk factors with genetic variation in chemokine pathways • CCR2 genotype X Framingham risk score • Impact on CV outcome PREVEND • Impact on CV benefits of antihypertensives (PREVEND) • CCR5 genotype X inflammatory status • Impact on outcome in ESRD (Necosad)

  4. CCR2 : G-protein coupled chemokine receptor • CCR2V64I mutation • Valine to isoleucine • Stabilization CCR2A Isoform: Impaired downregulation • Associated with CV disease • Conflicting results

  5. Effect of CCR2 on CV events in PREVEND • PREVEND (general population) N=8592 • CCR2 genotype: VV/VI/II: 84/15/1 % • CV events : 442 (7 year follow up) • Baseline characteristics similar for genotypes • Framingham risk score (FRS) predicts CV events • FRS: CV events • 0-10% : 2.4% • 10-20% : 12.3% • 20-30% : 19.1% • 30% : 26.7%

  6. CV hazard ratio by FRS and I-allele Multivariate hazard analyses: CCR2 VI+II vs VV : 4.89 (P=0.006) FRS : 2.20 (P<0.00001) CCR2 * FRS : 1.69 (P=0.005)

  7. FRS is a better predictor of CV events in I-carriers Sensitivity=specificity AUC 83% (VI+II) 0.87 (0.84-0.90) 73% (VV) 0.80 (0.78-0.82)

  8. CCR2 genotype and CV benefits of antihypertensive treatment • Antihypertensive treatment (AHT) HR Wald P AHT 1.33 (1.05-1.70) 5.44 0.020 CCR2 mutation 0.58 (0.39-0.86) 7.35 0.007 AHT * CCR2 3.13 (1.92-5.39) 16.91 <0.0001 Interference with RAAS-blockade ?

  9. Conclusions CCR2 Risk of CV morbidity conferred by phenotypic risk factors us modified by genetic variation in CCR2. Possible genetic interference with therapeutic efficacy RAAS-blockade Lit: AngII induces CCR expression on monocytes ARB reduces CCR2 expression on monocytes Possibilities for GENECURE: Effects of CCR2 mutation in various populations (WP4) Effects of CCR2 on therapeutic benefit RAAS blockade (WP6) Pharmaco-economic implications?? (WP9)

  10. CCR5 delta32 and inflammation-associated mortality in ESRD patients (NECOSAD) • CCR5 • Involved in atherogenesis and vascular inflammation • CCR5 Δ32: • 32bp deletion leads to CCR5 deficiency/dysfunctionality • Associated with improved renal survival in IgA nephropathy and delayed onset of coronary heart disease in women

  11. C-reactive protein in NECOSAD and CCR5 • Single or repeated measures of serum CRP are associated with all-cause and cardiovascular mortality • Hypothesis: Pro-inflammation (Micro)inflammation CRP CCR5 Mortality

  12. CCR5 and inflammation-associated mortality • NECOSAD population • CCR5 wt/wt wt/Δ32 Δ32/Δ32 • 383 (79.5%) 98 (18.2%) 11 (2.3%) • HW: slight overrepresentation of homozygote Δ32 • Dominant model (wt/Δ32 + Δ32/Δ32 are carriers) • Age difference • wt/wt carriers • 61.40 (48.30-70.80) 65.15 (50.50-72.30) • High CRP defined as CRP>= 10 mg/L

  13. Hazard ratios for mortality by CRP and CCR5 genotype CCR5+CRP Crude overall mortality Adjusted overall mortality wt/wt & CRP<10 1 1 wt/wt & CRP>10 2.25 (1.65-3.05) 1.85 (1.35-2.54) carriers & CRP<10 1.29 (0.84-1.99) 1.17 (0.75-1.81) carriers & CRP>10 1.14 (0.67-1.94) 0.89 (0.52-1.53) CCR5 Crude CV mortality Adjusted CV mortality wt/wt & CRP<10 1 1 wt/wt & CRP>10 2.65 (1.64-4.30) 2.29 (1.38-3.78) carriers & CRP<10 1.42 (0.72-2.81) 1.31 (0.66-2.61) carriers & CRP>10 0.99 (0.39-2.54) 0.82 (0.32-2.12)

  14. Survival for ACM by CRP and CCR5 genotype Years 0 1 2 3 4 5 wt/wt+<=10 260 248 209 157 107 56 carriers+<=10 59 58 47 38 25 13 wt/wt+>10 123 108 85 55 32 19 carriers+>10 39 36 27 19 17 11

  15. Conclusion Association between CRP (marker of inflammation) and CV/overall mortality depends on CCR5 delta32 genotype. Pro-inflammation (Micro)inflammation CRP CCR5 Mortality

  16. Conclusion/implications • CCR5 delta32 as a protective genetic variant supported by > Elder age of onset dialysis of carriers > Slight overrepresentation of homozygote carriers (selection?) > Better survival despite current inflammation • Treatment with CCR5 antagonists attenuates atherogenesis in APOE -/- mice ! Possibilities for GENECURE: Test CCR5 in other populations (WP4) Test modulation by CCR5 for risk associated with other markers (WP4) Study (altered) expression of CCR5 in blood vessels (WP2)

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