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/
🔗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.
The primary safety concern for anti-IL-6 therapies is infection risk.
In previous work, we have shown that genetically proxied IL6R inhibition increases risk of bacterial infections, consistent with clinical experience with tocilizumab.
In previous work, we have shown that genetically proxied IL6R inhibition increases risk of bacterial infections, consistent with clinical experience with tocilizumab.
August 27, 2025 at 2:02 PM
The primary safety concern for anti-IL-6 therapies is infection risk.
In previous work, we have shown that genetically proxied IL6R inhibition increases risk of bacterial infections, consistent with clinical experience with tocilizumab.
In previous work, we have shown that genetically proxied IL6R inhibition increases risk of bacterial infections, consistent with clinical experience with tocilizumab.
We also observed metabolic effects:
👉an association w/ lower risk of type 2 diabetes
👉significant increases in HDL particles
Across multiple metabolomic measurements, the effects were highly consistent with those of an IL6R instrument, indicating convergence downstream of IL-6 signaling
👉an association w/ lower risk of type 2 diabetes
👉significant increases in HDL particles
Across multiple metabolomic measurements, the effects were highly consistent with those of an IL6R instrument, indicating convergence downstream of IL-6 signaling
August 27, 2025 at 2:02 PM
We also observed metabolic effects:
👉an association w/ lower risk of type 2 diabetes
👉significant increases in HDL particles
Across multiple metabolomic measurements, the effects were highly consistent with those of an IL6R instrument, indicating convergence downstream of IL-6 signaling
👉an association w/ lower risk of type 2 diabetes
👉significant increases in HDL particles
Across multiple metabolomic measurements, the effects were highly consistent with those of an IL6R instrument, indicating convergence downstream of IL-6 signaling
These findings were highly consistent in East Asian individuals from Biobank Japan.
August 27, 2025 at 2:02 PM
These findings were highly consistent in East Asian individuals from Biobank Japan.
We then tested associations with cardiovascular endpoints.
Like an IL6R instrument, IL6 perturbation was associated with lower risk of atherosclerotic outcomes:
👉 Coronary artery disease (CAD)
👉 Peripheral artery disease (PAD)
👉 Large artery atherosclerotic stroke
👉 Carotid atherosclerotic plaque
Like an IL6R instrument, IL6 perturbation was associated with lower risk of atherosclerotic outcomes:
👉 Coronary artery disease (CAD)
👉 Peripheral artery disease (PAD)
👉 Large artery atherosclerotic stroke
👉 Carotid atherosclerotic plaque
August 27, 2025 at 2:02 PM
We then tested associations with cardiovascular endpoints.
Like an IL6R instrument, IL6 perturbation was associated with lower risk of atherosclerotic outcomes:
👉 Coronary artery disease (CAD)
👉 Peripheral artery disease (PAD)
👉 Large artery atherosclerotic stroke
👉 Carotid atherosclerotic plaque
Like an IL6R instrument, IL6 perturbation was associated with lower risk of atherosclerotic outcomes:
👉 Coronary artery disease (CAD)
👉 Peripheral artery disease (PAD)
👉 Large artery atherosclerotic stroke
👉 Carotid atherosclerotic plaque
In other words, our proxy predicts effects on biomarkers measured in the trial, with a correlation of 0.9 bet/ genetic & trial effects!
Similarly, the IL-6 genetic proxy showed effects on rheumatoid arthritis & polymyalgia rheumatica, for which IL-6 inhibition has been proven clinically effective.
Similarly, the IL-6 genetic proxy showed effects on rheumatoid arthritis & polymyalgia rheumatica, for which IL-6 inhibition has been proven clinically effective.
August 27, 2025 at 2:02 PM
In other words, our proxy predicts effects on biomarkers measured in the trial, with a correlation of 0.9 bet/ genetic & trial effects!
Similarly, the IL-6 genetic proxy showed effects on rheumatoid arthritis & polymyalgia rheumatica, for which IL-6 inhibition has been proven clinically effective.
Similarly, the IL-6 genetic proxy showed effects on rheumatoid arthritis & polymyalgia rheumatica, for which IL-6 inhibition has been proven clinically effective.
When indexed to CRP reduction, the effects of our genetic instrument on 8 tested biomarkers (data leveraged through publicly available GWASs) were highly concordant with ziltivekimab treatment!
August 27, 2025 at 2:02 PM
When indexed to CRP reduction, the effects of our genetic instrument on 8 tested biomarkers (data leveraged through publicly available GWASs) were highly concordant with ziltivekimab treatment!
Can such a genetic proxy be used to study the effects of pharmacological IL-6 inhibition?
While phase 3 data are not yet available, phase 2 results from the RESCUE trial (ziltivekimab) provide biomarker evidence.
While phase 3 data are not yet available, phase 2 results from the RESCUE trial (ziltivekimab) provide biomarker evidence.
August 27, 2025 at 2:02 PM
Can such a genetic proxy be used to study the effects of pharmacological IL-6 inhibition?
While phase 3 data are not yet available, phase 2 results from the RESCUE trial (ziltivekimab) provide biomarker evidence.
While phase 3 data are not yet available, phase 2 results from the RESCUE trial (ziltivekimab) provide biomarker evidence.
Indeed, most variants showed proportionally concordant effects on circulating IL-6 protein levels, supporting an effect on IL-6 abundance.
August 27, 2025 at 2:02 PM
Indeed, most variants showed proportionally concordant effects on circulating IL-6 protein levels, supporting an effect on IL-6 abundance.
All selected variants were non-coding, yet all were associated with IL6 expression in one or more cell types or tissues. This suggests they may modulate downstream signaling by altering IL6 RNA expression.
August 27, 2025 at 2:02 PM
All selected variants were non-coding, yet all were associated with IL6 expression in one or more cell types or tissues. This suggests they may modulate downstream signaling by altering IL6 RNA expression.