Transcript 掌握相关的疾病基因组学研究技术新进展。

Genetics of Kidney Diseases
张咸宁
[email protected]
Tel：13105819271; 88208367
Office: A705, Research Building
2012/03
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:
Rossetti S, et al. Identification of Gene Mutations
in Autosomal Dominant Polycystic Kidney Disease
through Targeted Resequencing. J Am Soc Nephrol,
2012 (in press).
Recommended Reading
1. 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
• The most common form of PKD with an
estimated incidence of approximately 1/400
to 1/1000 individuals worldwide. It roughly
accounts for 10% of patients with chronic
renal failure requiring hemodialysis or
transplantation.
Autosomal dominant PKD
• PKD1 (16p13.3), accounting for approximately 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’ two-thirds of the PKD1 gene (exons 1–
32) is duplicated six times on chromosome 16
within six 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