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/
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.
In our new preprint, we present the largest genomic exploration of arterial aging to date, leveraging photoplethysmography (PPG)–derived pulse waveforms from 115,000 UK Biobank participants.
Our results provide insights into potential strategies to mitigate arterial aging👇
Our results provide insights into potential strategies to mitigate arterial aging👇
November 23, 2025 at 10:51 AM
In our new preprint, we present the largest genomic exploration of arterial aging to date, leveraging photoplethysmography (PPG)–derived pulse waveforms from 115,000 UK Biobank participants.
Our results provide insights into potential strategies to mitigate arterial aging👇
Our results provide insights into potential strategies to mitigate arterial aging👇
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
If you're up for a niche read on challenges in translating anti-inflammatory therapies for atherosclerotic stroke prevention, have a look at our review in Neurology
October 5, 2025 at 8:56 PM
If you're up for a niche read on challenges in translating anti-inflammatory therapies for atherosclerotic stroke prevention, have a look at our review in Neurology
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...
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.
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
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!
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.
Aggregating these 12 variants into a genetic score was associated with lifelong reductions in CRP (up to 24% for the upper vs lower percentie), comparable in magnitude to those observed with an IL6R genetic proxy.
August 27, 2025 at 2:02 PM
Aggregating these 12 variants into a genetic score was associated with lifelong reductions in CRP (up to 24% for the upper vs lower percentie), comparable in magnitude to those observed with an IL6R genetic proxy.
Genetic variation in IL6R, the receptor for IL-6, has long been linked to risk of atherosclerotic cardiovascular disease (ASCVD).
This has motivated the development of anti-inflammatory therapies targeting IL6 signaling for ASCVD.
This has motivated the development of anti-inflammatory therapies targeting IL6 signaling for ASCVD.
August 27, 2025 at 2:02 PM
Genetic variation in IL6R, the receptor for IL-6, has long been linked to risk of atherosclerotic cardiovascular disease (ASCVD).
This has motivated the development of anti-inflammatory therapies targeting IL6 signaling for ASCVD.
This has motivated the development of anti-inflammatory therapies targeting IL6 signaling for ASCVD.
I'm often asked how human genetic data can be used to validate drug targets.
In our new @natcardiovascres.nature.com paper, we provide an end-to-end framework for genetically validating IL-6 inhibition for atherosclerotic cardiovascular disease outcomes 🧵
In our new @natcardiovascres.nature.com paper, we provide an end-to-end framework for genetically validating IL-6 inhibition for atherosclerotic cardiovascular disease outcomes 🧵
August 27, 2025 at 2:02 PM
I'm often asked how human genetic data can be used to validate drug targets.
In our new @natcardiovascres.nature.com paper, we provide an end-to-end framework for genetically validating IL-6 inhibition for atherosclerotic cardiovascular disease outcomes 🧵
In our new @natcardiovascres.nature.com paper, we provide an end-to-end framework for genetically validating IL-6 inhibition for atherosclerotic cardiovascular disease outcomes 🧵
Amid the hype of using polygenic scores for embryo selection, some thoughts on their implementation potential in real-world settings (and problems) 👇
August 19, 2025 at 9:26 PM
Amid the hype of using polygenic scores for embryo selection, some thoughts on their implementation potential in real-world settings (and problems) 👇