Online today on @jamanetworkopen.com our new paper on the role of #APOL1 M1 in increasing precision diagnosis for CKD in individuals from African ancestry.
Collaboration with
@kidneyomicsamps.bsky.social @gbadegesinlab.bsky.social @kirylukk.bsky.social et al
jamanetwork.com/journals/jam...
🚀 Multiple open post-doc positions in our lab
If you're a driven scientist with a strong interest in human genomics related to kidney disease & want to advance genetic discoveries, therapeutic hypotheses, & precision medicine for them, I hope you apply! tinyurl.com/kidneyomics-...
In 2020, we started to question whether #idiopathicnephroticsyndrome is strictly a 'pure' podocytopathy. Today, I am happy to share our new manuscript proposing a role of the glomerular endothelium in the disease pathogenesis.
urldefense.com/v3/__https:/...
Congrats!
From a chance encounter years ago, far away, to this milestone today. Proud to have been involved in this research! Breakthroughs happen when we share ideas and challenge paradigms. Science moves forward when we work together—and this is just the beginning. #Nephrology #Research #TeamScience
Thanks for doing this, Matt! I am so excited to get this out finally!
Huge thanks to the patients, the NEPTUNE study network, and our team, including co-lead authors Ana Onuchic-Whitford, Junmo Sung, and Eric Sakkas @thesampsonlab.bsky.social @bostonchildrens.bsky.social @broadinstitute.org @harvardmed.bsky.social @isgd.bsky.social
Summary: (1) ASE in the kidney is compartment-specific. (2) It is sequence-mediated and reflects regulatory architecture. (3) High Glomerular ASE (GTAR) serves as a marker of adaptive transcriptional activity and predicts improved clinical survival.
Why does high ASE predict better outcomes? Functional analysis shows that high-GTAR patients exhibit upregulation of ribosome biogenesis and ATP synthesis, alongside downregulation of fibrosis genes. It marks an active, adaptive transcriptional response to disease.
The clinical impact was unexpected: High ASE is not a marker of injury or “dysregulation.” Instead, it appears protective. Patients with a high GTAR showed significantly slower disease progression and faster remission of proteinuria
We observed a striking pattern: proteinuric kidneys exhibit from NEPTUNE patients had significantly higher genome-wide ASE in the GLOM compared to TUBE. We quantified this using a new metric, the GLOM-to-TUBE ASE Ratio (GTAR), to capture this compartment-specific imbalance
Is ASE stochastic? Our data suggests it is predominantly deterministic. Common ASE events are driven by eQTLs, sQTLs, or imprinting. Rare ASE events are significantly enriched for rare promoter variants. ASE accurately reflects an individual’s underlying regulatory architecture
Technical precision is vital for ASE. We developed a rigorous pipeline including a new tool,TOGA, to resolve overlapping genes. This is a major source of mapping bias affecting ~48% of expressed genes, which can lead to false ASE calls if not properly addressed.
ASE is a fundamental regulatory mechanism, yet its role in kidney dz is less understood. We studied ~200 biopsies from proteinuric kidney disease pts in the Nephrotic Syndrome Study Network (NEPTUNE), microdissected into glomerular (GLOM) & tubulointerstitial (TUBE) compartments
Supervised by @dongwon-lee.bsky.social we're excited to share our preprint on the landscape of allele-specific expression (ASE) in human kidneys. Using paired WGS and RNA-seq from kidney biopsies, we mapped ASE in proteinuric kidney disease in the #NEPTUNE study www.biorxiv.org/content/10.6...
A long engaging and amazing journey for me in Kidney Genetics !!
@isgd.bsky.social @bostonchildrens.bsky.social @harvardmed.bsky.social @broadinstitute.org @broadmpg.bsky.social
@janewit-thekidgene.bsky.social led this project wonderfully. Thanks also to @pnatarajanmd.bsky.social @sagarnigs.bsky.social for help w/MGBB, @genetickidneydoc.bsky.social & @jasayer.bsky.social for their collaboration, PIs contributing pts @gbadegesinlab.bsky.social & @thesampsonlab.bsky.social
While we don't definitively implicate MEFV as a causal FSGS gene here, we're keen to pursue this further. That MEFV is on commercial panels will help future studies. It's also intriguing that FMF therapies exist. Could these be repurposed for FSGS-MEFV even w/o signs of FMF?
Using @genomicsengland.bsky.social @jasayer.bsky.social found 8 pts negative for other monogenic explanations w/glomerular dz w/monoallelic MEFV variants. In @genetickidneydoc.bsky.social case-control study, there was 3.8x⬆️odds of SRNS in those w/1 P/LP MEFV variant. These support our hypothesis
(3)While FMF was considered autosomal recessive, it's now known that single MEFV variants can be pathogenic (4) Pyrin has known podocyte expression & involvement in glomerular dz. Altogether, this led us to try to replicate our discovery with @jasayer.bsky.social & @genetickidneydoc.bsky.social
(1)These are bona fide disease variants previously implicated in Familial Mediterranean Fever (FMF) (2) While proteinuria in FMF is usually attributed to renal amyloid, there are reports of pts w/FMF due to MEFV with proteinuria d/t glomerular disease, including FSGS.
There were striking similarities - diffuse podocytopathy on light microscopy & histolopathologic evidence of thrombotic microangiopathy. And no evidence of amyloid. Were we seeing FSGS due to monoallelic MEFV variants? Was there existing evidence to support this hypothesis?
Janewit went back to the 12 patients w/ACMG classified P/LP variants we had initially dismissed as unrelated to FSGS. Intrigued that 6 of them had variants in the same gene, pyrin (MEFV) - a part of the inflammasome. So he reviewed the biopsies of the 5 patients who had this data
Because we had long follow-up, we could model kidney survival (ESKD) between those with Mendelian, APOL1, & no known genetic disease. Unsurprisingly, those with either genetic form did worse. At this point, we thought we were done. Until.....
Path reports were illuminating. Surprisingly, 80% of patients with Mendelian disease & FSGS (18/22) were classified with secondary FSGS. Of the 10 pts w/a COL4A pathogenic variant & EM, only 20% had signs of a collagenopathy. (Don't use histology to rule out genetic testing!)
There were 618 qualifying pts; 319 w/exome sequencing. We evaluated 192 genes previously implicated in monogenic proteinuric kidney dz + APOL1. 17% of adults had either a known monogenic NS or APOL1 disease. Unsurprisingly, COL4A variants were the most common category seen
But 1st, we had to find the rare NS patients among the 130k member MGBB. ICD-10s & a computable phenotype performed poorly. So Janewit did a keyword search on 112k path reports, followed by a deep review of 2k biopsies & charts to establish our gold-standard cohort. 93% had FSGS
Perhaps most importantly: Compared to other biobank studies, as a MassGeneral Brigham investigator, Janewit
could conduct deep, individual-level chart review. We though that this would allow us to gain insights and make connections that would have been difficult otherwise
We thought doing this study in the MassGeneralBrigham Biobank (MGBB) would be interesting b/c (1) MGBB didn't focus on recruiting NS pts, thus avoiding ascertainment bias (2) exome sequencing allowed creation of synthetic proteinuria panels (3) we had histology &detailed longitudinal data
