Genetics of Kidney Diseases

张咸宁zhangxianning@zju.edu.cn

Tel ： 13105819271; 88208367 Office: A705, Research Building

2013/04

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 355Recommended Reading: Rossetti S, et al. Identification of Gene Mutations

in Autosomal Dominant Polycystic Kidney Disease through Targeted Resequencing. J Am Soc Nephrol, 2012; 23:915–933.

Recommended Reading1. Yu XQ, et al. A genome-wide association

study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Nat Genet, 2011;44(2):178-182.

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.

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, 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 or transplantation.

Autosomal dominant PKD (ADPKD)• PKD1 (16p13.3), accounting for ~85% of affected

individuals• PKD2 (4q21-q23): ~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