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Genetics of Renal Disorders 张咸宁 [email protected] Tel:13105819271; 88208367 Office: C303, Teaching Building 2015/04 Learning Objectives • 了解泌尿系统疾病的遗传学研究现状。 • 掌握相关的疾病基因组学研究技术新进 展。 Autosomal dominant polycystic kidney disease Thompson &Thompson Genetics in Medicine, 7th Ed (双语版,2009) ● Clinical Case Studies: 32. Polycystic Kidney Disease ● Pages 355 Recommended Reading: Qi X-P, …, Zhang X-N*. Genetic diagnosis of autosomal dominant polycystic kidney disease by targeted capture and next-generation sequencing: utility and limitations. Gene, 2013; 516(1):93-100. Recommended Reading 1. Wuttke M, et al. Genome-wide association studies in nephrology: using known associations for data checks. Am J Kidney Dis 2015;65(2):217-22. 2. Xu X, et al. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell 2012;148(5):886-895. Introduction • Kidney diseases pose a significant global disease burden • The most common form, chronic kidney disease (CKD), affects an estimated 10% of adults in many countries and the prevalence is increasing • Over 250 syndromes and monogenic disorders have been reported to have an increased risk for congenital anomalies of the kidney and urinary tract (CAKUT) The role of a genetic contribution to kidney disease is supported by • The presence of monogenic diseases with renal manifestations • Heritability studies of kidney function measures • Familial aggregation studies of complex kidney diseases Heritability studies of kidney function measures • Heritability estimates for the most commonly used measure of kidney function, GFR (肾小球滤过率), range from 0.33 to 0.82, indicating that 33%82% of the interindividual variation in GFR estimates in these studies could be explained by additive genetic effects. Familial aggregation studies of complex kidney diseases • Familial aggregation studies show that end-stage renal disease (ESRD) and earlier stages of CKD cluster in families. The presence of monogenic diseases with renal manifestations • Autosomal dominant polycystic kidney disease (ADPKD) • The most common form of PKD with an estimated incidence of approximately 1/400 to 1/1 000 individuals worldwide. It roughly accounts for 10% of patients with chronic renal failure requiring hemodialysis (血液透 析) or transplantation. Autosomal dominant PKD (ADPKD) • PKD1 (16p13.3), 46 exons, accounting for ~85% of affected individuals • PKD2 (4q21-q23): 15 exons, ~15% Distribution of PKD1 mutations identified in Thai patients with ADPKD →Polycystin ADPKD Database, PKDB: http://pkdb.mayo.edu • PKD1:已发现了436种突变 。 • PKD2:已发现了115种突变 。 • The 5’ 2/3 of PKD1 (exons 1–32) is duplicated six times on chromosome 16 within 6 pseudogenes (PKD1 P1-P6). The PKD1 P1-P6 pseudogenes share a 97.7% sequence identity with the genuine PKD1, although they carry some large deletions compared with the genuine PKD1. Genome-wide association studies (GWAS) • GWAS test for association, or linkage disequilibrium, between a disease and a marker (or several markers) by testing many thousands of markers across the genome. • Typically this is accomplished with microarray analysis of disease cases and unaffected controls. • As in all case-control studies, considerable care must be taken to avoid spurious results by closely matching cases and controls. Linkage: Genes on the same cs are linked if they are transmitted together in meiosis more frequently than chance would allow. Linkage disequilibrium (LD) • The occurrence together of 2 or more alleles at closely linked loci more frequently than would be expected by chance. • D’: 0(no LD)~±1 (complete association) Association • A tendency of two characters (diseases, marker alleles, etc.) to occur together at non-random frequencies. • Association is a simple statistical observation, not a genetic phenomenon, but can sometimes be caused by linkage disequilibrium. IgA肾病是最常见的原发性肾小球肾炎,也是引起终末期肾脏疾 病的一个重要原因。 Cell, 2012;148(5):886-895