Aus dem Department für Biometrie, Epidemiologie und Medizinische Bioinformatik Institut für Genetische Epidemiologie des Universitätsklinikums Freiburg im Breisgau Associations between Known Genetic Risk Variants and CKD Stage and Etiology in the GCKD Study INAUGURAL - DISSERTATION zur Erlangung des Medizinischen Doktorgrades der Medizinischen Fakultät der Albert-Ludwigs-Universität Freiburg im Breisgau Vorgelegt 2017 von Sebastian Wunnenburger, geboren in Leipzig - 1 - Dekanin: Prof. Dr. Kerstin Krieglstein Erste Gutachterin: Prof. Dr. Anna Köttgen, M.P.H. Zweiter Gutachter: Prof. Dr. Wolfgang Kühn Jahr der Promotion: 2018 - 2 - Table of contents List of Abbreviations ........................................................................................................................... - 5 - List of Tables ....................................................................................................................................... - 6 - 1 Introduction ................................................................................................................................. - 8 - 1.1 Chronic kidney disease (CKD) – definition, epidemiology, clinical presentation, diagnosis and treatment .............................................................................................................................................. - 8 - 1.2 Specific etiologies of CKD .................................................................................................... - 12 - 1.2.1 Introduction ....................................................................................................................... - 12 - 1.2.2 Glomerular diseases .......................................................................................................... - 13 - 1.2.3 IgA nephropathy ................................................................................................................ - 13 - 1.2.4 Membranous nephropathy (MN) ....................................................................................... - 15 - 1.2.5 Systemic lupus erythematosus (SLE) and lupus nephritis ................................................. - 15 - 1.2.6 Granulomatosis with polyangiitis (GPA) .......................................................................... - 17 - 1.2.7 Diabetes mellitus ............................................................................................................... - 17 - 1.2.8 Hypertensive chronic kidney disease ................................................................................ - 20 - 1.3 Genetic epidemiology: Genome-wide association studies and SNP associations ................. - 21 - 1.4 Aims of the thesis .................................................................................................................. - 25 - 2 Methods ..................................................................................................................................... - 27 - 2.1 Study populations .................................................................................................................. - 27 - 2.2 Exposure ................................................................................................................................ - 29 - 2.2.1 Genotyping and sequencing .............................................................................................. - 29 - 2.2.2 Quality control and filtering .............................................................................................. - 29 - 2.2.3 Imputation ......................................................................................................................... - 30 - 2.3 Outcome ................................................................................................................................ - 30 - 2.3.1 eGFR/UACR ..................................................................................................................... - 30 - 2.3.2 Case and control groups .................................................................................................... - 30 - 2.3.2.1 Case groups ....................................................................................................................... - 31 - 2.3.2.2 Control groups ................................................................................................................... - 31 - 2.3.3 Covariates .......................................................................................................................... - 33 - 2.4 Statistical analyses ................................................................................................................. - 33 - 2.4.1 Literature search for previously reported SNPs associated with kidney function and disease .. ........................................................................................................................................... - 33 - 2.4.2 Descriptive statistics .......................................................................................................... - 37 - 2.4.3 Regression analyses ........................................................................................................... - 37 - 2.4.4 Covariates .......................................................................................................................... - 37 - - 3 - 2.4.5 Sensitivity and conditional analyses .................................................................................. - 38 - 2.4.6 Statistical significance ....................................................................................................... - 38 - 2.4.7 Software............................................................................................................................. - 38 - 3 Results ....................................................................................................................................... - 39 - 3.1 Demographic data and baseline characteristics ..................................................................... - 39 - 3.2 CKD etiologies ...................................................................................................................... - 40 - 3.3 GFR/UACR as kidney function measures ............................................................................. - 40 - 3.4 Hardy-Weinberg equilibrium test .......................................................................................... - 41 - 3.5 Genetic associations .............................................................................................................. - 42 - 3.5.1 Associations of SNPs identified in population-based studies with advanced CKD .......... - 42 - 3.5.2 Associations of SNPs identified in population-based studies with hypertensive and diabetic kidney disease.................................................................................................................................... - 43 - 3.5.3 Associations of SNPs with specific CKD etiologies ......................................................... - 44 - 3.5.3.1 Associations of CKD etiology-specific risk variants with the previously reported CKD etiology ........................................................................................................................................... - 44 - 3.5.3.2 Associations of CKD etiology-specific risk variants across different CKD etiologies ..... - 46 - 3.5.3.3 Conditional analysis of independence of CKD etiology specific SNPs ............................ - 49 - 3.5.3.4 Conditional analysis to assess independence of risk variants or T1DM-attributed CKD and T1DM ........................................................................................................................................... - 51 - 3.5.3.5 Linkage disequilibrium calculations .................................................................................. - 52 - 4 Discussion ................................................................................................................................. - 53 - 4.1 Summary of results ................................................................................................................ - 53 - 4.2 Interpretation in the context of the literature ......................................................................... - 54 - 4.3 Clinical interpretation ............................................................................................................ - 57 - 4.4 Strengths and limitations ....................................................................................................... - 59 - 4.5 Conclusion ............................................................................................................................. - 60 - 5 Abstract (English) ...................................................................................................................... - 61 - 6 Abstract (German) ..................................................................................................................... - 62 - 7 Acknowledgement ..................................................................................................................... - 63 - 8 Eidesstaatliche Versicherung..................................................................................................... - 64 - 9 Supplementary Tables ............................................................................................................... - 65 - 10 Bibliography .........................................................................................................................