Genetics of Kidney Diseases 张咸宁 [email protected] Tel : 13105819271; 88208367 Office:...
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Transcript of Genetics of Kidney Diseases 张咸宁 [email protected] Tel : 13105819271; 88208367 Office:...
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Genetics of Kidney Diseases
Tel : 13105819271; 88208367 Office: A705, Research Building
2013/04
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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。
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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.
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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.
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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.
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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
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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.
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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.
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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.
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Autosomal dominant PKD (ADPKD)• PKD1 (16p13.3), accounting for ~85% of affected
individuals• PKD2 (4q21-q23): ~15%
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Distribution of PKD1 mutations identified
in Thai patients with ADPKD →Polycystin
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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.
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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.
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Linkage: Genes on the same cs are linked if they are transmitted together in meiosis more frequently than chance would allow.
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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)
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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.
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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。
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Cell, 2012;148(5):886-895