A-Z of renal genetics - WordPress.com · Liddle’s syndrome: gain of function mutation in...
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A-Z of Renal Genetics
Prof Peter Maxwell
Nephrology SpR club
Belfast 26 February 2011
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A-Z of Renal Genetics
• Single gene renal disorders
• Polygenic kidney diseases
• Gene-environment interactions
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Glomerular Filtration System.
Tryggvason K et al. N Engl J Med 2006;354:1387-1401.
Single-gene kidney disorders
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Single-gene kidney disorders
• Genotype: mutation
• Phenotype: the description (“syndrome”)
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Single-gene kidney disorders:
• Recessive
• Penetrance – full
• Onset – fetus, child
• Frequency – rare
• Dominant
• Penetrance –sometimes incomplete
• Onset – adult
• Frequency – quite rare
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Single-gene kidney disorders:potential clinical presentations
1. Proteinuria (fault in glomerular structure)
2. Loss of electrolytes, sugar, amino acids (tubular defects)
3. Blobs on ultrasound (cysts & tumours)
4. Seen on an X-ray (calculi and nephrocalcinosis)
5. Unusual anatomy (congenital – CAKUT kids)
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Single gene glomerular disorders
• A is for........
• Alport’s syndrome – a defect in Type 4 collagen assembly
• X-linked: COL4A5
• Autosomal recessive: COL4A3 or COL4A4
• Autosomal dominant: COL4A3 or COL4A4
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Single gene glomerular disorders
• Congenital and steroid-resistant nephrotic syndromes
• Mutations in genes encoding slit diaphragm proteins
• Nephrin (NPHS1)
• Podocin (NPHS2)
• Laminin 2 (LAMB2)
• actinin (ACTN4)
• CD-2 associated protein (CD2AP)
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Single gene kidney disorders:potential clinical presentations
1. Proteinuria (fault in glomerular structure)
2. Loss of electrolytes, sugar, amino acids (tubular defects)
3. Blobs on ultrasound (cysts & tumours)
4. Seen on an X-ray (calculi and nephrocalcinosis)
5. Unusual anatomy (congenital – CAKUT kids)
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Loop diuretic
Thiazide
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Bartter’s
Gitelman’s
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Na+
Na+
K+
K+
Aldosterone sensitive: epithelial sodium channel
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Na+
Na+
Na+
Na+
Na+
Na+
Liddle’s syndrome: gain of function mutation in epithelial sodium channel
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Single gene renal tubular disorders
• BaGiL syndromes
• Bartter’s (loop of Henle)
• Gitelman’s (distal tubule)
• Liddle’s (collecting duct)
• Is this stuff on the curriculum?
• Yes!
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Single gene kidney disorders:potential clinical presentations
1. Proteinuria (fault in glomerular structure)
2. Loss of electrolytes, sugar, amino acids (tubular defects)
3. Blobs on ultrasound (cysts & tumours)
4. Seen on an X-ray (calculi and nephrocalcinosis)
5. Unusual anatomy (congenital – CAKUT kids)
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Polycystic kidney disease
• Prevalence 1/500 – 1/1000
• Most common monogenic cause of ESRD
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UK Renal Registry data, 2008
New patients starting dialysis
Diabetes 24.0%Aetiology uncertain 20.7%
Glomerulonephritis (biopsy) 11.8%
Pyelonephritis 7.8%
Polycystic kidney disease 7.3%
Renal vascular disease 6.9%
Hypertension 6.0%
Other 15.6%
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PKD: Clinical Implications of Genetics
• Different prognosis of PKD1 vs. PKD2 gene defect
• PKD1 (~85% of cases) – Earlier onset of ESRD (more severe phenotype)
– PKD1 females have better renal survival (58 yr vs 54 yr)1
– Higher prevalence of hypertension (compared to PKD2)
• PKD2 (~15% cases) – Later onset ESRD (PKD1 54.3 yr; PKD2 74.0 yr)2
– PKD2 females have better renal survival (76yr vs. 68 yr)3
1. Reed BY et al. Am J Kid Dis 51: 173-183, 20082. Hateboer N et al. Lancet 1999; 353: 103-1073. Magistroni R et al. J Am Soc Nephrol 2003; 14: 1164-1174
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PKD: Practical issues with genetic testing
• Complex genetics to unravel witin the NHS!
• PKD1 > 270 mutations reported
• PKD1 gene is also highly polymorphic
• PKD2 > 70 mutations reported
• Majority of mutations are “unique” to family tested
• PKD1 gene is adjacent to multiple “pseudogene” copies on chromosome 16
• Some correlations between location of mutation and clinical phenotypes (age of ESRD onset; risk of ICA)
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Why are only some tubules affected by cystic change?
• Several theories
1. A “two-hit” mechanism
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Individual cyst formation in ADPKD is a “two-hit” phenomenon
PKDPKD
PKDPKD
ADPKD
At conception (a germline mutation)
After birth (a somatic mutation)
N
C
PKD = mutant PKD gene
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Individual cyst formation in ADPKD is a “two-hit” phenomenon
PKDPKD
PKDPKD
ADPKD
At conception (a germline mutation)N
C
PKD = mutant PKD gene
PKDPKD
C PKDPKD
C PKDPKD
CPKDPKD
C
The abnormal cell with two mutantcopies of the PKD gene can now multiply rapidly
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• In this “two hit model” ADPKD is recessive at the level of an individual cell
• Somatic mutational events (the “second hit”) increase exponentially with age
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Epithelial cells from individual cysts in ADPKD are monoclonal in origin
Single epithelial cell derived from renal tubule
Expanded cell mass leads to outpouching from renal tubule
Individual cyst eventually forms havingsevered its connection with the renal tubule
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Rossetti, S. et al. J Am Soc Nephrol 2007;18:1374-1380
Relative contributions of various factors to the resulting phenotypes in autosomal dominant PKD
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Familial renal cancer syndromes
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Birt-Hogg-Dubé syndrome (BHD)renal cancer, skin lesions and pneumothoraces
associated with folliculin gene mutation
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Single gene kidney disorders:
1. Proteinuria (fault in glomerular structure)
2. Loss of electrolytes, sugar, amino acids (tubular defects)
3. Blobs on ultrasound (cysts & tumours)
4. Seen on an X-ray (calculi and nephrocalcinosis)
5. Unusual anatomy (congenital – CAKUT kids)
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Single gene kidney disordersStones and abnormal X-rays
• Cystinuria
• Nephrocalcinosis
Neild GH et al. Nephrol Dial Transplant 2005; 20:2284-5
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Single gene kidney disorders
• What’s your approach?
• Google Dent’s disease!
• X-linked recessive
• Hypercalciuria
• Nephrolithiasis
• Nephrocalcinosis
• Fanconi’s syndrome
• Check out www.orpha.net.org
• Dear Dr Smart
• Renal clinic, Ivory Tower
Teaching Hospital
• Please arrange follow up
for this young chap with
Dent disease who recently
joined our general practice
• Regards Dr Muggins
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Single gene kidney disorders:potential clinical presentations
1. Proteinuria (fault in glomerular structure)
2. Loss of electrolytes, sugar, amino acids (tubular defects)
3. Blobs on ultrasound (cysts & tumours)
4. Seen on an X-ray (calculi and nephrocalcinosis)
5. Unusual anatomy
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Single gene disorders and chromosomal mix-ups
Congenital Abnormalities of Kidney and Urinary Tract (CAKUT)
vesicoureteral reflux
multicystic renal dysplasia
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Annotated chromosome maps for renal disease. Human Mutation 2009 Mar;30(3):314-20.
McKnight AJ, O'Donoghue D, Maxwell AP.
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A-Z of Renal Genetics
One gene at a time
• All genes at once
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Adjusted incident rates of ESRD
due to diabetes, by age & race
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Adjusted incident rates of ESRD due to diabetes, by age & race
Counts & rates of ESRD
due to polycystic kidney disease
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Identifying the genetic contribution to complex polygenic kidney disease
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Genomewide Association Study (GWAS)
Manolio TA. N Engl J Med 2010;363:166-176.
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Meta-Analysis of Genomewide Association Studies
Manolio TA. N Engl J Med 2010;363:166-176.
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Genomewide Association Scans relevant for Renal Disease
• Hypertension
• Chronic kidney disease
• GFR
• Albuminuria
• IgA nephropathy
• Membranous nephropathy
• Diabetic nephropathy
• Renal transplant dysfunction
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2009; 41:712
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IgA
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Strong signal of association on chromosome 6p
with IgA nephropathy.
Feehally J et al. JASN 2010;21:1791-1797
©2010 by American Society of Nephrology
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Multiple SNPs are associated with IgA nephropathy across
the MHC region on chromosome 6p.
Feehally J et al. JASN 2010;21:1791-1797
©2010 by American Society of Nephrology
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Original Article
Risk HLA-DQA1 and PLA2R1 Alleles in Idiopathic Membranous Nephropathy
Horia C. Stanescu, M.D., Mauricio Arcos-Burgos, M.D., Ph.D., Alan Medlar, M.Sc., Detlef Bockenhauer, M.D., Ph.D., Anna Kottgen, M.D., M.P.H., Liviu
Dragomirescu, Ph.D., Catalin Voinescu, B.Sc., Naina Patel, B.Sc., Kerra Pearce, M.Sc., Mike Hubank, Ph.D., Henry A.F. Stephens, Ph.D., Valerie
Laundy, F.I.M.L.S., Sandosh Padmanabhan, M.D., Ph.D., Anna Zawadzka, Julia M.
Hofstra, M.D., Marieke J.H. Coenen, Ph.D., Martin den Heijer, M.D., Ph.D., Lambertus A.L.M. Kiemeney, Ph.D., Delphine Bacq-Daian, M.Sc., Benedicte Stengel, M.D., Ph.D.,
Stephen H. Powis, Ph.D., F.R.C.P., Paul Brenchley, Ph.D., John Feehally, D.M., F.R.C.P., Andrew J. Rees, F.R.C.P., F.Med.Sci., Hanna Debiec, Ph.D., Jack F.M.
Wetzels, M.D., Ph.D., Pierre Ronco, M.D., Ph.D., Peter W. Mathieson, Ph.D., F.R.C.P., and Robert Kleta, M.D., Ph.D.
N Engl J MedVolume 364(7):616-626
February 17, 2011
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Study Overview
• Independent genomewide association studies were carried out to investigate the genetic basis of idiopathic membranous nephropathy in three groups of white patients.
• An HLA–DQA1 allele on chromosome 6p21 was found to be significantly associated with this disease.
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Manhattan Plots for Genomewide Association Studies of Idiopathic Membranous Nephropathy (IMN) in Three Groups of Patients and Racially
Matched Controls.
Stanescu HC et al. N Engl J Med 2011;364:616-626
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Manhattan Plots for the Joint Genomewide Association Study.
Stanescu HC et al. N Engl J Med 2011;364:616-626
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Odds Ratios for Idiopathic Membranous Nephropathy, According to Single-Nucleotide Polymorphism (SNP) and Genotype Combinations.
Stanescu HC et al. N Engl J Med 2011;364:616-626
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Conclusions
• An HLA-DQA1 allele on chromosome 6p21 is most closely associated with idiopathic membranous nephropathy in persons of white ancestry.
• This allele may facilitate an autoimmune response against targets such as variants of PLA2R1.
• Our findings suggest a basis for understanding this disease and illuminate how adaptive immunity is regulated by HLA.
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More GWAS data coming!
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Renal transplant dysfunction GWASWTCCC3 study of UK and Ireland patients
• 2,500 kidney donor-transplant recipient pairs
• 5000 DNA samples in initial GWAS
• Exploring the interaction of donor’s genome (the graft) with the recipient’s genome (host)
• Replication of “top hits” in up to 8000 further DNA samples from renal transplant recipients in UK and Ireland
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Genetic association is NOT causation!
• SNPs associated with kidney diseases are either directly implicated in pathogenesis or are markers for the genomic regions harbouring gene variants that are important in disease causation
• Resequencing of the genomic regions required to identify biologic candidate genes (and variants) to test in cell and animal models
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A-Z of Renal Genetics
Single gene renal disorders
Polygenic kidney diseases
• Gene-environment interactions
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DNA is not static but is constantly being modified in response to environmental stimuli
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Dutch Hunger Winter: Calories
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Adverse fetal environment followed by plentiful food in adulthood may be a recipe for adult chronic disease
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Dutch famine of winter 1944
• children of pregnant women exposed to famine were more susceptible to diabetes, obesity, cardiovascular disease, microalbuminuria and other health problems
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Epigenetic modifications
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What might we do with this stuff in 10 years?
• Genomics
• Transcriptomics
• Proteomics
• Metabolomics
• “It’s all just economics”• Sidney Brenner, Nobel laureate
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Has fantasy collided with reality?
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http://www.decodeme.com/chronic-kidney-disease
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But........
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GWAS(s) for eGFR & CKD
Kottgen et al., New loci associated with kidney function and chronic kidney disease Nature Genetics 42, 376 - 384 (2010)
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For only
$985 we
scan over
one million
variants in
your
genomedeCODEme
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Next generation sequencing
Complete genome sequence
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Genome Sequencing A Reality
http://www.scientificamerican.com/blog/60-second-science/post.cfm?id=single-bidder-
pays-68000-to-sequenc-2009-05-06
$68,000 was cost
in early 2009
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Whole Genome Sequence Costs
Sept 2009: $23,000 (~ £14 K)
2010: $10,000 (~ £6 K)
Feb 2011: $7,000 (~£4 K)
Dec 2011: ???
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Coming to your clinic within 10 years?
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• Epigenetics
• Pharmacogenetics
• Whole exome sequencing (rare variants)
• Whole genome sequencing (rare variants) and personal genome
• Extreme phenotype studies e.g. rapid progression to ESRD
• Gene expression profiles e.g. predictive of transplant outcomes
Renal genetics: much more to unravel !
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A-Z of Renal Genetics
Time to go
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Questions??A-Z of Renal Genetics
• Alport’s syndrome• Birt Hogg Dube syndrome• Chromosome• Diabetic nephropathy• Epigenetics• Folliculin gene• Genome-wide association scan• Hunger• IgA nephropathy• Junk food• Kidney stones• Liddle’s syndrome• Membranous nephropathy
• Next generation sequencing• Orpha.net.org• PLA2R1• Q-Q plot• Renal transplant GWAS• Sodium channel• Tests• Uromodulin• Vorderman• WTCCC3• X-linked disease• Your future practice?• Zebedee