Marios Georgakis
@mariosgeorgakis.bsky.social
Physician-scientist leading a lab @lmumuenchen.bsky.social, visiting scientist
@broadinstitute.org | Writing about genetics, omics, deep phenotyping, precision medicine
https://www.deepvasc.com/
@broadinstitute.org | Writing about genetics, omics, deep phenotyping, precision medicine
https://www.deepvasc.com/
Amazing work by Lingling Xu and the rest of the team!
🔗link to our preprint: www.medrxiv.org/content/10.1...
🔗link to our preprint: www.medrxiv.org/content/10.1...
A photoplethysmography-based aging clock reveals genetic determinants of arterial aging
Arterial aging, marked by progressive vascular stiffening, is a contributor to cardiovascular disease. Photoplethysmography (PPG) waveforms offer an easily accessible signal of arterial function, enab...
www.medrxiv.org
November 23, 2025 at 10:51 AM
Amazing work by Lingling Xu and the rest of the team!
🔗link to our preprint: www.medrxiv.org/content/10.1...
🔗link to our preprint: www.medrxiv.org/content/10.1...
Rare variant burden testing further implicated damaging variants in COL21A1, LMNA, TP53BP2, RXRB, and FLOT2, also converging on extracellular matrix remodeling and fibrosis-related pathways.
November 23, 2025 at 10:51 AM
Rare variant burden testing further implicated damaging variants in COL21A1, LMNA, TP53BP2, RXRB, and FLOT2, also converging on extracellular matrix remodeling and fibrosis-related pathways.
TWAS using RNA-seq data from human aorta & coronary arteries identified 28 genes, incl, RSG19 and ULK4, whose expression likely drives these genetic associations. ScRNA-seq revealed strong enrichment of these genes in fibroblasts, implicating fibrotic remodeling mechanisms in arterial aging.
November 23, 2025 at 10:51 AM
TWAS using RNA-seq data from human aorta & coronary arteries identified 28 genes, incl, RSG19 and ULK4, whose expression likely drives these genetic associations. ScRNA-seq revealed strong enrichment of these genes in fibroblasts, implicating fibrotic remodeling mechanisms in arterial aging.
We then performed GWAS and rare variant burden testing.
We found 60 loci in GWAS and 5 genes in rare variant analyses. Of them, 34 loci were novel, not previously linked to vascular traits. The expression of nearby genes was strongly enriched in human arterial tissues.
We found 60 loci in GWAS and 5 genes in rare variant analyses. Of them, 34 loci were novel, not previously linked to vascular traits. The expression of nearby genes was strongly enriched in human arterial tissues.
November 23, 2025 at 10:51 AM
We then performed GWAS and rare variant burden testing.
We found 60 loci in GWAS and 5 genes in rare variant analyses. Of them, 34 loci were novel, not previously linked to vascular traits. The expression of nearby genes was strongly enriched in human arterial tissues.
We found 60 loci in GWAS and 5 genes in rare variant analyses. Of them, 34 loci were novel, not previously linked to vascular traits. The expression of nearby genes was strongly enriched in human arterial tissues.
Furthermore, it was predictive of future cardiovascular events (stroke, myocardial infarction, heart failure), incident hypertension, cardiovascular death, and all-cause mortality, independently of chronological age.
November 23, 2025 at 10:51 AM
Furthermore, it was predictive of future cardiovascular events (stroke, myocardial infarction, heart failure), incident hypertension, cardiovascular death, and all-cause mortality, independently of chronological age.
The difference of the derived predictions from chronological age was correlated with known features of arterial aging, as well as vascular risk factors.
November 23, 2025 at 10:51 AM
The difference of the derived predictions from chronological age was correlated with known features of arterial aging, as well as vascular risk factors.
Using PPG waveforms and blood pressure measurements, we developed an arterial aging clock by training a deep learning model to predict chronological age.
November 23, 2025 at 10:51 AM
Using PPG waveforms and blood pressure measurements, we developed an arterial aging clock by training a deep learning model to predict chronological age.
While aging of the large arteries, characterized by progressive stiffness, is a well-established risk factor for cardiovascular disease, the mechanisms driving this pathology remain poorly understood. We lack targeted interventions that could slow or prevent arterial aging.
November 23, 2025 at 10:51 AM
While aging of the large arteries, characterized by progressive stiffness, is a well-established risk factor for cardiovascular disease, the mechanisms driving this pathology remain poorly understood. We lack targeted interventions that could slow or prevent arterial aging.
🔗link to the paper 🔓: www.deepvasc.com/s/georgakis-...
www.deepvasc.com
October 5, 2025 at 8:56 PM
🔗link to the paper 🔓: www.deepvasc.com/s/georgakis-...
Stroke prevention is more nuanced than that of atherosclerosis in other vascular beds due to heterogeneity in underlying etiology.
In this paper we discuss the implications of recent trials for stroke prevention, as well as future perspectives for under development anti-inflammatory treatments
In this paper we discuss the implications of recent trials for stroke prevention, as well as future perspectives for under development anti-inflammatory treatments
October 5, 2025 at 8:56 PM
Stroke prevention is more nuanced than that of atherosclerosis in other vascular beds due to heterogeneity in underlying etiology.
In this paper we discuss the implications of recent trials for stroke prevention, as well as future perspectives for under development anti-inflammatory treatments
In this paper we discuss the implications of recent trials for stroke prevention, as well as future perspectives for under development anti-inflammatory treatments
Great work by Lanyue Zhang, Murad Omarov, and Lingling Xu.
Grateful for the partnership with @tourmalinebio.bsky.social (developing an anti-IL6 antibody) and the collaboration with
Pradeep Natarajan.
🔗link to study (open access🔓): www.nature.com/articles/s44...
Grateful for the partnership with @tourmalinebio.bsky.social (developing an anti-IL6 antibody) and the collaboration with
Pradeep Natarajan.
🔗link to study (open access🔓): www.nature.com/articles/s44...
August 27, 2025 at 2:02 PM
Great work by Lanyue Zhang, Murad Omarov, and Lingling Xu.
Grateful for the partnership with @tourmalinebio.bsky.social (developing an anti-IL6 antibody) and the collaboration with
Pradeep Natarajan.
🔗link to study (open access🔓): www.nature.com/articles/s44...
Grateful for the partnership with @tourmalinebio.bsky.social (developing an anti-IL6 antibody) and the collaboration with
Pradeep Natarajan.
🔗link to study (open access🔓): www.nature.com/articles/s44...
However, each target and indication have unique nuances that necessitate individual tailored approaches for proper validation.
A scalable, one-size-fits-all approach risks overlooking important context and already acquired knowledge.
A scalable, one-size-fits-all approach risks overlooking important context and already acquired knowledge.
August 27, 2025 at 2:02 PM
However, each target and indication have unique nuances that necessitate individual tailored approaches for proper validation.
A scalable, one-size-fits-all approach risks overlooking important context and already acquired knowledge.
A scalable, one-size-fits-all approach risks overlooking important context and already acquired knowledge.
3⃣ Large-scale retrospective analyses of target-indication pairs (e.g. Minikel et al, Nature 2024) offer big picture evidence that genetically supported targets are more likely to lead to approved drugs.
August 27, 2025 at 2:02 PM
3⃣ Large-scale retrospective analyses of target-indication pairs (e.g. Minikel et al, Nature 2024) offer big picture evidence that genetically supported targets are more likely to lead to approved drugs.
2⃣ Nearly all data used in this study are publicly available.
In principle, this framework could be applied to genetically validate any drug target, particularly those developed for chronic, aging-related diseases.
In principle, this framework could be applied to genetically validate any drug target, particularly those developed for chronic, aging-related diseases.
August 27, 2025 at 2:02 PM
2⃣ Nearly all data used in this study are publicly available.
In principle, this framework could be applied to genetically validate any drug target, particularly those developed for chronic, aging-related diseases.
In principle, this framework could be applied to genetically validate any drug target, particularly those developed for chronic, aging-related diseases.
We hope this work will provide prospective validation for the use of human genetics to predict trial-relevant clinical outcomes.
August 27, 2025 at 2:02 PM
We hope this work will provide prospective validation for the use of human genetics to predict trial-relevant clinical outcomes.
Thoughts for broader implications:
1⃣ Often, human genetic studies, replicate trial findings retrospectively.
The results of ZEUS, a phase 3 cardiovascular outcomes trial testing ziltivekimab in patients with ASCVD and high CRP, are expected in 2026.
1⃣ Often, human genetic studies, replicate trial findings retrospectively.
The results of ZEUS, a phase 3 cardiovascular outcomes trial testing ziltivekimab in patients with ASCVD and high CRP, are expected in 2026.
August 27, 2025 at 2:02 PM
Thoughts for broader implications:
1⃣ Often, human genetic studies, replicate trial findings retrospectively.
The results of ZEUS, a phase 3 cardiovascular outcomes trial testing ziltivekimab in patients with ASCVD and high CRP, are expected in 2026.
1⃣ Often, human genetic studies, replicate trial findings retrospectively.
The results of ZEUS, a phase 3 cardiovascular outcomes trial testing ziltivekimab in patients with ASCVD and high CRP, are expected in 2026.
Regarding side-effects, notable and consistent signals included:
👉 Glaucoma
👉 Perinatal & postpartum maternal hemorrhage
These may be relevant for specific populations and warrant further investigation.
👉 Glaucoma
👉 Perinatal & postpartum maternal hemorrhage
These may be relevant for specific populations and warrant further investigation.
August 27, 2025 at 2:02 PM
Regarding side-effects, notable and consistent signals included:
👉 Glaucoma
👉 Perinatal & postpartum maternal hemorrhage
These may be relevant for specific populations and warrant further investigation.
👉 Glaucoma
👉 Perinatal & postpartum maternal hemorrhage
These may be relevant for specific populations and warrant further investigation.
The main risk-lowering effects of the IL-6 proxy were replicated across:
👉 cardiovascular & metabolic endpoints
👉 autoimmune disease outcomes
👉 respiratory infections (pneumonia, influenza, COPD-related)
We also observed novel protective associations with:
👉 depression
👉 gallstone disease
👉 cardiovascular & metabolic endpoints
👉 autoimmune disease outcomes
👉 respiratory infections (pneumonia, influenza, COPD-related)
We also observed novel protective associations with:
👉 depression
👉 gallstone disease
August 27, 2025 at 2:02 PM
The main risk-lowering effects of the IL-6 proxy were replicated across:
👉 cardiovascular & metabolic endpoints
👉 autoimmune disease outcomes
👉 respiratory infections (pneumonia, influenza, COPD-related)
We also observed novel protective associations with:
👉 depression
👉 gallstone disease
👉 cardiovascular & metabolic endpoints
👉 autoimmune disease outcomes
👉 respiratory infections (pneumonia, influenza, COPD-related)
We also observed novel protective associations with:
👉 depression
👉 gallstone disease
Finally, we performed a phenome-wide association study (PheWAS) in FinnGen to systematically assess whether our IL-6 genetic proxy is associated with any additional outcomes beyond those already studied.
August 27, 2025 at 2:02 PM
Finally, we performed a phenome-wide association study (PheWAS) in FinnGen to systematically assess whether our IL-6 genetic proxy is associated with any additional outcomes beyond those already studied.
Interestingly, our IL-6 genetic proxy showed no significant increase in the infection endpoints tested.
On the contrary, there was even evidence of risk-lowering effects on pneumonia hospitalization.
On the contrary, there was even evidence of risk-lowering effects on pneumonia hospitalization.
August 27, 2025 at 2:02 PM
Interestingly, our IL-6 genetic proxy showed no significant increase in the infection endpoints tested.
On the contrary, there was even evidence of risk-lowering effects on pneumonia hospitalization.
On the contrary, there was even evidence of risk-lowering effects on pneumonia hospitalization.