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Genetics of Renal Disorders

Genetics of Renal Disorders. 张咸宁 zhangxianning@zju.edu.cn 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.

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Genetics of Renal Disorders

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  1. Genetics of Renal Disorders 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: C303, Teaching Building 2015/04

  2. 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。

  3. 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.

  4. Recommended Reading • 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. • Xu X, et al. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell 2012;148(5):886-895.

  5. 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)

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. Autosomal dominant PKD (ADPKD) PKD1(16p13.3), 46 exons, accounting for ~85% of affected individuals PKD2 (4q21-q23): 15 exons, ~15%

  11. Distribution of PKD1 mutations identified in Thai patients with ADPKD→Polycystin

  12. 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.

  13. 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.

  14. Linkage: Genes on the same cs are linked if they are transmitted together in meiosis more frequently than chance would allow.

  15. 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)

  16. 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.

  17. 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。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。

  18. Cell, 2012;148(5):886-895

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