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A genetic variant of the CC-chemokine CCL2 is associated with renal function decline in PREVEND

B reedtestrategie. A genetic variant of the CC-chemokine CCL2 is associated with renal function decline in PREVEND. Mike W. Zuurman, Inter.Med./Nephrology, U MC Groningen 4-1-2006. B reedtestrategie. Renal function: determinants. age blood pressure smoking inflammatory state sex?.

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A genetic variant of the CC-chemokine CCL2 is associated with renal function decline in PREVEND

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  1. Breedtestrategie A genetic variant of the CC-chemokine CCL2 is associated with renal function decline in PREVEND Mike W. Zuurman, Inter.Med./Nephrology, UMC Groningen 4-1-2006

  2. Breedtestrategie Renal function: determinants • age • blood pressure • smoking • inflammatory state • sex?

  3. Breedtestrategie Females Males Sex differences in renal pathology A murine example: Park et al. JBC 279, 50:52282- 2004

  4. Breedtestrategie Sex differences in renal pathology

  5. Breedtestrategie Renal function: determinants Sex Observed differences between males and females in renal pathology underline importance of separating by sex in analyses of renal function

  6. Breedtestrategie Renal function: determinants Inflammatory state • Albuminuria (proteinuria) • CCL2 -2518 pro-inflammatory genotype

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

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

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

  10. Breedtestrategie CCL2 • Monocyte chemoattractant protein-1 • CC-chemokine(group of chemokines that are chemoattractants for • lymphocytes, monocytes, eosinophils, basophils, • but not neutrophils.) • Pro-inflammatory • Leukocyte recruitment • Angiogenesis

  11. Breedtestrategie Chemokines in pathology: renal disease

  12. Breedtestrategie CCL2 in renal pathology Association between circulating monocyte chemoattractant protein-1 and urinary albumin excretion in nonobese Type 2 diabetic patients, J Diabetes Complications. 2006 Mar-Apr;20(2):98-104. Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice, Kidney Int. 2006 Jan;69(1):73-80. Reactive oxygen species-mediated signaling pathways in angiotensin II-induced MCP-1 expression of proximal tubular cells. Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1261-8. Renal response to repetitive exposure to heme proteins: chronic injury induced by an acute insult. Kidney Int. 2000 Jun;57(6):2423-33.

  13. Breedtestrategie CCL2 -2518 A/G functional expression consequences HIV: CCL2 CSF up, plasma trend Letendre et al. J Neuroimmunol. 2004 Dec;157(1-2):193-6. Tissue Antigens. 2004 Jul;64(1):70-3 Fenoglio et al.Neurobiol Aging. 2004 Oct;25(9):1169-73. MS: CCL2 plasma trend (P=0.08) CCL2 plasma up in AD patients

  14. Breedtestrategie CCL2 -2518 in renal pathology The polymorphism of monocyte chemoattractant protein-1 is associated with the renal disease of SLE. Kim HL, Lee DS, Yang SH, Lim CS, Chung JH, Kim S, Lee JS, Kim YS. Am J Kidney Dis. 2002 Dec;40(6):1146-52. Monocyte chemoattractant protein-1 A-2518G gene polymorphism and renal survival of Japanese patients with immunoglobulin A nephropathy. Mori H, Kaneko Y, Narita I, Goto S, Saito N, Kondo D, Sato F, Ajiro J, Saga Clin Exp Nephrol. 2005 Dec;9(4):297-303. Association of the MCP-1 gene polymorphism A-2518G with carpal-tunnel syndrome in hemodialysis patients. Omori K, Kazama JJ, Song J, Goto S, Takada T, Saito N, Sakatsume M, Narita I, Gejyo F. Amyloid. 2002 Sep;9(3):175-82. A Monocyte chemoattractant protein-1 (MCP-1) polymorphism and outcome after renal transplantation. Kruger B, Schroppel B, Ashkan R, Marder B, Zulke C, Murphy B, Kramer BK, Fischereder M. J Am Soc Nephrol. 2002 Oct;13(10):2585-9.

  15. Breedtestrategie Kruger et al. J Am Soc Nephrol. 2002 Oct;13(10):2585-9.

  16. Breedtestrategie Renal function: determinants Inflammatory state • Albuminuria (proteinuria) • CCL2 -2518 pro-inflammatory genotype • Sex (differential regulation of inflammation)

  17. Breedtestrategie Hypothesis Renal function decline is modified by CCL2 -2518 A/G in an albuminuria and sex dependent manner

  18. Breedtestrategie Research population (1) PREVEND (n=8502) General population-based Enriched for albuminuria Selection: Succesful genotype, Caucasian descent (n=7504) Follow-up: 4 years on average Renal function: BSA adjusted Creatinine clearance (CrCl) based on serum Cr and 2x24h urine concentractions Renal damage/Inflammation: Urinary albumine excretion (2x24h)

  19. Breedtestrategie Research population (2) Main outcome parameter: Renal Function Decline (RFD) : More than 10% decrease in CrCl since baseline

  20. Table 1. Baseline characteristics by CCL2 -2518 A/G genotype Breedtestrategie Baseline characteristics by CCL2 -2518 A/G Shown are arithmetic means and standard deviations, median and 25th – 75th percentiles in case of skewed distributions, and group percentages. No characteristics differed significantly between genotype groups.

  21. Breedtestrategie Renal function and change by genotype

  22. Breedtestrategie Baseline characteristics by RFD

  23. Breedtestrategie Logistic regression model for RFD Note that in this model sex and CCL2 -2518 genotype are not independent factors

  24. Breedtestrategie Multivariable fractional polynomial model for RFD

  25. Breedtestrategie Multivariable fractional polynomial model for RFD

  26. Breedtestrategie Correlations Mean Urinary Mean Urinary Correlations Albumin Albumin Excretion Excretion Creatinine Creatinine (UAE) (UAE) clearance clearance Mean Urinary Albumin Pearson Correlation 1 ,719 ** (ml/min/1,7 (ml/min/1,73 Excretion (UAE) Sig. (2-tailed) ,000 3m**2) m**2) NC2 Sum of Squares and Creatinine clearance Pearson Correlation 1 ,528 ** 166593808,9 86494005,816 Cross-products (ml/min/1,73m**2) Sig. (2-tailed) ,000 Covariance 21093,164 13681,431 N 7349 5766 N 7899 6323 Creatinine clearance Pearson Correlation ,528 ** 1 Mean Urinary Albumin Pearson Correlation ,719 ** 1 (ml/min/1,73m**2) NC2 Sig. (2-tailed) ,000 Excretion (UAE) Sig. (2-tailed) ,000 N 5766 5832 Sum of Squares and 86494005,816 144101986,2 **. Correlation is significant at the 0.01 level (2-tailed). Cross-products Covariance 13681,431 22739,780 N 6323 6338 **. Correlation is significant at the 0.01 level (2-tailed). Correlations nc1 vs nc2 UAE CrCl

  27. Breedtestrategie Impaired renal function – univariate Measured versus predicted

  28. Breedtestrategie Multivariable fractional polynomial model for RFD (Cockroft) Logistic regression Number of obs = 5306 LR chi2(10) = 329.43 Prob > chi2 = 0.0000 Log likelihood = -2841.3476 Pseudo R2 = 0.0548 ------------------------------------------------------------------------------ cock_del~c_b | Odds Ratio Std. Err. z P>|z| [95% Conf. Interval] -------------+---------------------------------------------------------------- Iage___1 | 1.006379 .0004285 14.94 0.000 1.00554 1.007219 Icock__1 | 4.571734 .8421515 8.25 0.000 3.186269 6.55963 Icock__2 | .0035736 .0018236 -11.04 0.000 .0013144 .0097159 sex | 2.029337 .5176993 2.77 0.006 1.230853 3.345817 ccl22518_g | .8152031 .2230756 -0.75 0.455 .4768035 1.393773 Ilnln__1 | 1.394434 .2640953 1.76 0.079 .9620257 2.021199 Iint___1 | .7489486 .2049527 -1.06 0.291 .4380437 1.280521 int_SEX_CCL2 | 1.304824 .469326 0.74 0.459 .6447441 2.640685 Iint_a_1 | 1.356773 .3682877 1.12 0.261 .7969918 2.309727 Iint_b_1 | .7595832 .2913697 -0.72 0.473 .3581473 1.610976 ------------------------------------------------------------------------------ Deviance: 5682.695.

  29. Breedtestrategie De Novo IRF De novo Cockroft < 60 NC2 : ------------------------------------------------------------------------------ cock_2_de~60 | Odds Ratio Std. Err. z P>|z| [95% Conf. Interval] -------------+---------------------------------------------------------------- Iage___1 | 1.138783 .0110555 13.39 0.000 1.117319 1.160658 sex | 1.399462 .2379566 1.98 0.048 1.00283 1.952965 ccl22518_g | .947831 .156412 -0.32 0.745 .6859063 1.309776 UAE15 | 1.413706 .2426113 2.02 0.044 1.009907 1.97896 ------------------------------------------------------------------------------ Deviance: 1181.832. ------------------------------------------------------------------------------ cock_2_de~60 | Odds Ratio Std. Err. z P>|z| [95% Conf. Interval] -------------+---------------------------------------------------------------- Iage___1 | 1.138128 .011092 13.28 0.000 1.116594 1.160077 sex | 1.758046 .5305301 1.87 0.062 .9731076 3.176139 ccl22518_g | .9569597 .3532386 -0.12 0.905 .4641871 1.972851 UAE15 | 1.852891 .586917 1.95 0.052 .9959224 3.447262 int_SEX_CCL2 | .8027043 .3740964 -0.47 0.637 .322001 2.001031 intUAE15_SEX | .3144433 .1678408 -2.17 0.030 .1104576 .8951366 intUAE15_C~2 | .7700184 .3677037 -0.55 0.584 .3020163 1.963233 intUAE15_S~2 | 4.583692 3.334675 2.09 0.036 1.101436 19.07531 ------------------------------------------------------------------------------ Deviance: 1174.213. UAE 15 UAE15*CCL2*SEX

  30. Breedtestrategie Conclusions Mild to severe renal function decline (RFD) in the general populationis associated with a complex interaction between gene and environment Inflammation plays a role in RFD as suggested by the observed interaction Results are suggestive of an interaction between the CCL2 promoter SNP and albuminuria as an independent predictor of RFD and de novo IRF, that is different in males and females. The exact nature of this relationship is unclear.

  31. Breedtestrategie Discussion (1) Limitations: Definition of renal function decline There is no golden standard for estimation of renal function decline. Due to the nature of the analyses, a three-way interaction including a SNP, there’s a possible conflict between biological relevance and statistical power. A decline of more than 10% is aplausible estimate, since it will separate “normal” decline from putative pathological decline. Exactness of CrCl-measurements Regression to the mean and technical/compliance errors during collection of urine to estimate CrCl provide a statistical challenge. deltaCrCl shows a normal distrbution curve with CrCl-increase matching decrease in proportion. However, correlation of the two points is at a very low.

  32. Breedtestrategie Discussion (2) Limitations: Follow-up time and population The observed univariate association of genotype with impaired renal function (<60 ml/min) in males is not found at the second visit. However, a large number of people that were at CV/renal risk at baseline did not return for the second visit. Thus, a high risk group was lost to follow-up. A period of 4 years was the ultimate goal between first and second visit, yet there’s individual variety in actual time between first and second Visit. Correcting our results for actual follow-up time did not alter the results.

  33. Breedtestrategie Theoretical Discussion (2)

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