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Catherine Campbell, M.D. Wendy Post, M.D., M.S. Johns Hopkins University

Renin-Angiotensin System Genes and their Associations with Renal Function in MESA Preliminary Analyses. Catherine Campbell, M.D. Wendy Post, M.D., M.S. Johns Hopkins University

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Catherine Campbell, M.D. Wendy Post, M.D., M.S. Johns Hopkins University

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  1. Renin-Angiotensin System Genes and their Associations with Renal Function in MESA Preliminary Analyses Catherine Campbell, M.D. Wendy Post, M.D., M.S. Johns Hopkins University Co-authors: Joe Coresh, Hunter Young, Michael Shlipak, Carmen Peralta, Bruce Psaty, Stephen Rich, Jerome Rotter, Xiuqing Guo, Belle Fang, Holly Kramer

  2. Measures of Renal Function • Creatinine • Breakdown product of muscle, filtered by the kidney • Levels influenced by muscle mass • Clearance of creatinine measured by MDRD equation • GFR (mL/min/1.73 m2) = 175*(Scr)-1.154*(Age)-0.203**(0.742 if female) x (1.210 if black) • Cystatin C • Also filtered by the kidney, levels not influenced by muscle mass • eGFR = 127.7* (CysC-1.17)*(age-0.13)*(0.91 if female)*(1.06 if black) • Urine albumin excretion

  3. Chronic Kidney Disease • Progressive decline in renal function, rarely reversible • Relatively common disorder: affects about one in nine adults • Over 50% of late-stage chronic kidney disease is due to hypertension or diabetes • African Americans and Hispanics have higher rates of chronic kidney disease than whites

  4. Renin Angiotensin System Angiotensinogen Renin Angiotensin I ACE Angiotensin II AGTR1 AGTR2 vasoconstriction aldosterone release vasodilation growth inhibition renal tubular sodium transport

  5. Purpose • Do polymorphisms in renin-angiotensin system genes contribute to variation in renal function seen in the general population? • angiotensin converting enzyme (ACE) • angiotensinogen (AGT) • angiotensin II receptor type 1 (AGTR1) • angiotensin II receptor type 2 (AGTR2)

  6. Methods • ACE, AGT, AGTR1, and AGTR2 are candidate genes selected for genotyping in 2880 unrelated MESA participants (720 in each ethnic group) using Illumina • SNPs were selected to sample as much of the intrinsic multi-ethnic genetic variation in these genes as possible • MAF, D prime, HWE calculated using automated methods

  7. Methods • Associations between each SNP and measures of renal function determined using multivariate regression, adjusting for age and gender, stratified by race/ethnicity and combined • Additional models also adjusted for hypertension and diabetes • SNP associations • Additive model used if the MAF >10% • Dominant model used if MAF <10% • Haplotype associations • Dominant and recessive models

  8. Methods: Primary outcomes • Estimated GFR (using MDRD based on serum creatinine) • continuous variable • dichotomous variable (<60 ml/min/m2) • Urine albumin excretion (UAE) - albumin/creatinine • continuous variable (log transformed) • dichotomous variable • > 17 mg/g for men • > 25 mg/g for women

  9. Methods: Secondary outcomes • Estimated GFR with cystatin equation • continuous variable • dichotomous variable (<60 ml/min/m2) • Cystatin C • continuous variable (log-transformed) • dichotomous variable (>1mg/L)

  10. Scale: intron exon untranslated region * nonsynonymous 1kb Angiotensinogen rs1326886 rs2148582 rs2478545 rs3789670 rs943580 rs7549009 rs699* rs3789671 rs5044 rs7536290 M235T Chromosome 1

  11. dichotomous continuous Associations between AGT SNPs and renal phenotypes rs7536290 rs943580 rs3789671 rs2478545 rs699 M235T rs5044 rs3789670 rs2148582 rs7549009 rs1326886 eGFR AFA UAE eGFR p 0.05-0.10 CHN UAE p 0.01-0.05 eGFR p 0.005-0.01 EUA UAE p <0.005 * * * MAF<10% eGFR HIS Not in HWE * UAE

  12. Block 3 Block 3 Block 3 M235T Block 2 Block 1 CHN M235T Block 1 Block 2 AFA AFA AGT D’ M235T M235T Block 1 Block 1 Block 2 Block 2 EUA HIS

  13. Associations between AGT SNPs and renal phenotypes rs943580 rs7536290 rs3789671 rs2478545 rs699 M235T rs5044 rs3789670 rs2148582 rs7549009 rs1326886 eGFR AFA UAE Block 1 Block 2 Block 3 eGFR CHN UAE Block 2 Block 1 dichotomous p 0.05-0.10 p 0.005-0.01 continuous p 0.01-0.05 p <0.005

  14. p=0.01 p=0.02 AGT M235T and Renal Phenotypes p=0.001 p=0.04 GG GA AA MAF: AFA-20% CHN-16%, EUA-41% HIS-24%. Means are unadjusted, p values are additive model, adjusted for age and gender. Hispanics were not in HWE.

  15. rs943580 rs7536290 Haplotypes rs3789671 rs2478545 rs699 M235T rs3789670 rs2148582

  16. p=0.01 p=0.04 p=0.02 p=0.002 AGT Haplotype Block 2 - AFA Haplotype 3 carriers Haplotype 3 noncarriers

  17. p=0.01 p=0.03 AGT Haplotype Block 1 - CHN Haplotype 2 noncarriers Haplotype 2 carriers

  18. ACE Polymorphisms rs12720746* rs12720754* rs4351 rs4976* rs4362 rs4363 I/D rs4291 rs4309 rs4316 rs4980* rs4353 rs4359 Isoform 1 rs4305 rs4311 Isoform 2 rs4295 rs4303* rs12709426* Isoform 3 rs4461442 rs8066276 rs4968591 rs4459610* rs4277404 2kb Scale: intron exon untranslated region * nonsynonymous Chromosome 17

  19. ACE D’ AFA CHN EUA HIS

  20. dichotomous p 0.05-0.10 p 0.005-0.01 MAF<10% continuous p 0.01-0.05 p <0.005 Associations between ACE SNPs and renal phenotypes rs4295 rs12720754 rs4305 rs4309 rs4311 rs1270746 rs12709426 rs4316 rs4351 rs4976 rs4359 rs4362 rs4291 rs4303 rs4353 rs4363 rs4980 rs4461142 rs4459610 rs8066276 rrs4277404 rs4968591 eGFR AFA UAE eGFR CHN UAE eGFR EUA UAE eGFR HIS UAE

  21. eGFR AFA UAE eGFR CHN UAE eGFR EUA UAE Block 1 Block 1 Block 2 Block 2 dichotomous p 0.05-0.10 p 0.005-0.01 MAF<10% continuous p 0.01-0.05 p <0.005 Associations between ACE SNPs and renal phenotypes rs4295 rs12720754 rs4305 rs4309 rs4311 rs1270746 rs12709426 rs4316 rs4351 rs4976 rs4359 rs4362 rs4291 rs4303 rs4353 rs4363 rs4980 rs4461142 rs4459610 rs8066276 rrs4277404 rs4968591

  22. AGTR1 A1166C rs2131127 rs4681443 rs3772616 rs389566 rs6801836 rs275646 rs422858 rs2638363 rs4488792 rs2320019 rs409742 rs2638360 rs718858 rs385338 rs275645 2kb Scale: intron exon untranslated region * nonsynonymous Chromosome 3

  23. AFA UAE CHN UAE EUA UAE HIS dichotomous p 0.05-0.10 p 0.005-0.01 UAE MAF<10% * Not in HWE continuous p 0.01-0.05 p <0.005 Associations between AGTR1 SNPs and Renal Phenotypes rs409742 rs422858 rs2638363 rs2131127 rs2638360 rs4681443 rs718858 rs3772616 rs4488792 rs389556 rs385338 rs6801836 rs2320019 rs275646 rs275645 eGFR eGFR eGFR * eGFR

  24. AGTR2 Polymorphisms rs5191* rs5950584 rs1403543 rs5950586 rs5190 rs6608590 1kb Scale: intron exon untranslated region * nonsynonymous X Chromosome

  25. dichotomous continuous Associations between AGTR2 SNPs and Renal Phenotypes rs5950584 rs5950586 rs1403543 rs5190 rs5191 rs6608590 eGFR AFA UAE p 0.05-0.10 eGFR CHN p 0.01-0.05 UAE p 0.005-0.01 p <0.005 eGFR EUA UAE MAF<10% * Not in HWE * eGFR HIS UAE

  26. Conclusions • Many SNPs in the renin-angiotensin system show signficant associations with renal phenotypes • AGT M235T is associated with eGFR and UAE in African Americans and with UAE as a dichotomous variable in Chinese • The haplotype blocks that include this polymorphism also show significant associations with renal phenotypes.

  27. Conclusions • ACE: Many SNPs in ACE Haplotype Block 1 in Caucasians and Chinese show significant associations • AGTR1: Significant associations seen in African Americans and Hispanics • AGTR2: Many SNPs are not polymorphic or have low MAF

  28. To Do • Permutation testing • Haplotype analyses • Interaction tests with diabetes and hypertension • AIMs

  29. Topics for Discussion • HWE in Hispanics • Appropriate genetic model • Interpretation of haplotype blocks

  30. p=0.01 p=0.02 AGT M235T and Renal Phenotypes p=0.001 p=0.04 GG GA AA MAF: AFA-20% CHN-16%, EUA-41% HIS-24%. Means are unadjusted, p values are additive model, adjusted for age and gender. Hispanics were not in HWE.

  31. AGT M235T and Renal Phenotypes additive: p=0.16 dominant: p=0.02 GG GA AA MAF: AFA-20% CHN-16%, EUA-41% HIS-24%. Means are unadjusted, p values are additive model, adjusted for age and gender. Hispanics were not in HWE.

  32. Topics for Discussion • HWE in Hispanics • Appropriate genetic model • Interpretation of haplotype blocks

  33. rs943580 rs7536290 Haplotypes rs3789671 rs2478545 rs699 M235T rs3789670 rs2148582

  34. Acknowledgements • Wendy Post, MD, MS Johns Hopkins University • Xiuqing Guo, PhD Cedars-Sinai Medical Center • Belle Fang, PhD Cedars-Sinai Medical Center • Joe Coresh, MD, PhD Johns Hopkins University • Hunter Young, MD, MHS Johns Hopkins University • Michael Shlipak, MD, MPH UCSF • Carmen Peralta, MD UCSF • Bruce Psaty, MD, PhD University of Washington • Stephen Rich, PhD University of Virginia • Jerome Rotter, MD Cedars-Sinai Medical Center • Holly Kramer, MD Loyola University

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