new genetic developments in steroid sensitive nephrotic...
TRANSCRIPT
![Page 1: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/1.jpg)
New Genetic Developments in Steroid Sensitive Nephrotic Syndrome
Matt Sampson, MD MSCEAssociate Professor of PediatricsCenter for Computational Medicine & Bioinformatics University of Michigan School of Medicinesampsonlab.org
@kidneyomicsamps
![Page 2: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/2.jpg)
• Presented with edema• 4+ proteinuria• Hypoalbuminemia• Hypercholesterolemia
• Mom’s questions• Why did this happen?• What’s going to happen?• Can you help him?
2009
![Page 3: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/3.jpg)
![Page 4: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/4.jpg)
Current classification-descriptive & imprecise
Response to Steroids
Steroid Sensitive NS“SSNS”
Steroid Resistant NS“SRNS”
HistologicDescription
Minimal Change Disease“MCD”
Focal Segmental Glomerulosclerosis
“FSGS”
Tyagi 2013; Dijkman 2005
![Page 5: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/5.jpg)
What’s going to happen?
Swaminathan 2006; El-Bakkali 2007
• Variable outcomes• Single event (no relapses) • Relapses • Chronic kidney disease (CKD)/End stage (ESRD)
• +/-Recurrence of NS in transplanted kidney
• Morbidity and mortality from;• NS itself (quality of life, infection, venous
thromboembolism, end stage renal disease)• Treatment of the NS
• Steroids, cyclophosphamide, calcineurin inhibitors, mycophenolate, rituximab
2011 2016
2018
![Page 6: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/6.jpg)
Benefits of a genetic understanding of nephrotic syndrome• Deliver novel insights regarding NS biology• Identification of new targets for medicines• Discover clinical impact for those harboring disease variants• Support the selection of patients for clinical trials• Ultimately, match patients with treatments most likely to benefit them
![Page 7: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/7.jpg)
x
X
STEP 1: DISCOVER KNOWN AND NOVEL NS-ASSOCIATED GENETIC VARIANTS
Genomic discovery in nephrotic syndrome: Conceptual model
![Page 8: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/8.jpg)
Baseline characteristicsDemographics
characteristics
Longitudinal outcomes
x
X
Identify targets for therapeutic intervention
STEP 1: DISCOVER KNOWN AND NOVEL NS-ASSOCIATED GENETIC VARIANTS
Send to specificclinical trials
Genomic discovery in nephrotic syndrome: Conceptual model
X
X
STEP 2A: GENETIC EPIDEMIOLOGY
STEP 2B: MOLECULAR & MECHANISTIC CHARACTERIZATION
Define biology & molecular subtypes
![Page 9: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/9.jpg)
Nephrotic syndrome discovery from a population-based, complex trait approach
Families Populations
![Page 10: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/10.jpg)
A
T
Genome-wide association study (GWAS)-discover genomic regions that differ between cases & controls
GWAS of Membranous NephropathyStanescu et al, NEJM
![Page 11: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/11.jpg)
Nephrotic syndrome as a rare, complex disease; small sample size & big effects
Glomerular disease Ncases Loci Odds ratiosMembranous nephropathy 75-335 HLA-DQA1
PLA2R14.32.3
Focal segmental glomerulosclerosis 188-430 APOL1 6-11
Stanescu et al, 2011Winkler et al 2008 Genovese et al 2010Tzur et al 2010
![Page 12: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/12.jpg)
![Page 13: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/13.jpg)
Exome-chip association study pediatric SSNS
Common Allele214 Cases, 149 ControlsOR: 2.1
Gbadegesin et al, 2015
![Page 14: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/14.jpg)
Limitations
• Sparse markers for Exome Chip done in Sri Lankan population• no imputation• No fine-mapping at HLA region
![Page 15: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/15.jpg)
Outstanding questions
• What are genetic risk factors for SSNS outside of those with South Asian Ancestry?
• If we can find risk alleles for SSNS, what are the • Molecular consequences• Clinical consequences
![Page 16: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/16.jpg)
June 14, 2018
![Page 17: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/17.jpg)
**
*
Replication112 EUR Children
Discovery273 Children• 132 EUR• 85 North African• 54 Sub-Saharan African
![Page 18: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/18.jpg)
Rationale for trans-ethnic meta-analysis
![Page 19: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/19.jpg)
Fixed effects, trans-ethnic meta-analysis(385 children, three ancestries)
![Page 20: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/20.jpg)
Odds ratio: 3.3
![Page 21: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/21.jpg)
Odds ratio: 2.2
![Page 22: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/22.jpg)
Odds ratio: 3.5
![Page 23: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/23.jpg)
Genomic position of SSNS risk alleles
Pleiotropy with other immune dysregulation disorders
![Page 24: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/24.jpg)
neptune-study.orgGadegbeku et al, KI
• Epidemiologic associations: 97 children • Glomerular transcriptomic associations: children• *Note: children mostly FSGS/MCD, small % with IgA
![Page 25: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/25.jpg)
rs1063348 decreased glomerular expression of HLA transcripts
![Page 26: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/26.jpg)
Risk alleles across GWAS SNPs• Combined affects of rs1063348 & rs28366266
• younger age of onset (also in GWAS cohort)• complete remission?
![Page 27: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/27.jpg)
SSNS risk alleles are associated with complete remission across NS conditions
Increased odds of complete remission, regardless of child’s histologic diagnosis
![Page 28: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/28.jpg)
Conclusion
• SSNS impacts a large percentage of our patients with NS• Substantial morbidity associated with this condition as well
• We can use GWAS to pinpoint the genetic contributors to SSNS• A first step towards mechanistic understanding & ”cleaner” treatments
• A patient’s genetic signature may lead to more accurate prognoses & effective therapies than histologic appearance
![Page 29: New Genetic Developments in Steroid Sensitive Nephrotic ...pediatrics.med.miami.edu/documents/Matthew_Sampson... · New Genetic Developments in Steroid Sensitive Nephrotic Syndrome](https://reader030.vdocuments.us/reader030/viewer/2022041106/5f08006c7e708231d41fd5e6/html5/thumbnails/29.jpg)
N I D D K
Funding Sources
Chris Gillies *Cassie Robertson *Michelle McNultyBrendan CrawfordVirginia-Vega WarnerRose PutlerDamien FerminKalyn YasutakeMatthias KretzlerWilliam WenHyun Min KangMike BoehnkeGoncalo Abecasis sampsonlab.org
@kidneyomicsamps