Integrative analysis in human VSMCs identifies pleiotropic genes including FES that regulate vascular remodeling; pooled CRISPR and mouse knockout show FES loss increases MMPs, atherosclerosis and blood pressure.
0:00Welcome to Base by Base, the papercast that brings genomics to you, wherever you are. Thanks for listening, and don't forget to follow and rate us in your podcast app. So today, we're taking a journey deep inside the body's infrastructure, the plumbing, you could say.
0:14The plumbing, I like that. But we're not just looking at the pipes. No, we're looking at the blueprints. The genetic instructions that decide how those pipes get built and, you know, how they're maintained.
0:25And to really set the stage for this deep dive, I want you to imagine a kind of nightmare scenario. You're a plumber, okay? You go into a basement and it is just total chaos. Uh oh. Yeah. The pipes are clogging up with gunk, they're getting narrower, but, and this is the crazy part.
0:42At the exact same time, the water pressure is just skyrocketing. threatening to blow all the joints. Right. So in a normal situation, you'd see those as 2 totally separate problems, you've got a clog, which is a drainage issue, and you've got a pump problem, a pressure issue, you'd call 2 different people.
0:57Exactly. And that's pretty much how medicine often treats cardiovascular disease. If I have sogged arteries, I see a specialist for that, if I have high blood pressure, that's a different specialist. I'm on a statin for the clog, maybe an ACE inhibitor for the pressure.
1:10It's all compartmentalized. But the paper we're getting into today, it really challenges that whole way of thinking. It asks this really fundamental question. Which is? What if there's a single master switch hidden away in our DNA?
1:23A single broken part that's causing the clog and the high pressure all at once? That's a huge idea. So we're diving into a study that suggests these huge killers, heart attacks, strokes, hypertension. They might not be separate issues.
1:39They might just be different symptoms of the very same genetic root cause. This is the hunt for what we call pleotropy. Plei entropy. It's a term we hear a lot in genetics, but I think it's worth just quickly defining it here.
1:50Sure. It's from the Greek for more ways. In genetics, it means a single gene that influences 2 or more traits that seem totally unrelated. And this study found a whole panel of these, these multitasking genes that control the fate of our blood vessels.
2:07Before we get into the how. We have to just acknowledge the sheer scale of this work. This was not a small lab study. No, not at all. This was a massive team effort, a collaboration between researchers at the University of Leicester in the UK and the National University of Singapore.
2:22And we should definitely give a shout out to the key contributors. Absolutely. Big credit to Charles U. Solomon, David G. McVeigh and Shu Yay. What they did was, I mean, it's a real tour de force. They didn't just use databases.
2:34They combined these huge cell biobanks with cutting edge gene editing to actually test their ideas. Okay, so let's set up the problem they're tackling. We've got the big 4 of vascular diseases, right? Yep.
2:44Coronary artery disease, hypertension, stroke, and abdominal aortic aneurysm. Clinically, those all seem pretty different. An aneurysm is a vessel ballooning out. CAT is it narrowing? One is blowing up, the other is clogging up.
2:59But we've known for a while now that genetically the lines are... Well, they're a lot blurrier. And that's things to GWAs, right? The Genome White Association studies. Exactly. GWAs has given us these maps of risk neighborhoods in our DNA.
3:15We know if you have a certain genetic variant, say, on chromosome 6, your risk for heart disease goes up. But that's where the problem starts, isn't it? Because GWAs gives you the neighborhood, but it doesn't tell you which house is the problem.
3:28That's the perfect analogy. And because most of these risk variants are in the non-coding DNA, the so-called dark matter, we just didn't know which gene was actually being affected. It's like knowing a crime habit on a specific street, but you don't have the house number.
3:42Or, you know, it's like finding a light switch on a wall. You know, flipping the switch is linked to the lights going out, but you can't see the wiring behind the wall. Does it control the ceiling light?
3:51The fan, a plug in the next room. And in the genome, that wiring is everything, a switch or a regulatory element might be right next to one gene. But it's actually controlling another gene a 1000000 base pairs away because the DNA is all folded up.
4:06So to trace that wiring, you have to look at the right cells, the ones actually involved. And for vascular diseases, the prime suspect is the vascular smooth muscle cell, the VSMC. People probably think of arteries as just rubber tubes.
4:20Passive. Oh, not at all. They are so dynamic. VSMCs have this kind of split personality. In a healthy artery. They're in a contractile state. They sit still, they hold the structure, they squeeze and relax to control blood pressure.
4:33The muscle on the plumbing. Exactly. But if they get injured or stressed, they do this thing called a phenotypic switch, they change into a synthetic state. Meaning they stop acting like muscle and start acting more like, um, a construction crew.
4:47Or maybe a demolition crew. They start dividing, moving around, secreting stuff. Which is good if you have a wound that needs healing. Right. You want cells to rush in and patch things up. But if that happens uncontrollably inside an artery wall, that's plaque.
5:01The idea here is that these genetic glitches are pushing the cells into that rogue mode when they should be staying put. So how on earth did the team prove this? This gets us to the methods, which are really, really impressive.
5:14They started with a biobank of VSMCs from the umbilical chords of 1486 different donors. 1486. That's a huge number. But why umbilical cords? It's about getting a clean signal. If you take cells from a 60 year old's artery, those cells have seen a lot, diet stress aging, it's hard to separate genetics from environment.
5:35But umbilical cord cells are pristine. They're a clean slate. They reflect the person's genetic baseline without all that, you know, lifestyle baggage. Okay, so they have all these genetically distinct cell lines.
5:46What do they do with them? They mapped what are called EQTLs? That's a bit of a mouthful. It stands for expression quantitative trait, losi. Let's break that down. Think of it like connecting a genetic spelling change to a volume knob on a stereo.
6:00They sequenced every donor's DNA, and then they measured how much protein each gene was making. So they could say, okay, everyone who has a T at this spot makes 50% less of Gen X. Ah, so you're directly linking the variant to a change in the genes activity.
6:16Exactly. Then they overlay that map with the big disease maps from G-Was, they use these clever statistical tools to ask, is the variant that turns down the volume on Gene X the exact same variant that G-Wa says causes heart disease?
6:30That's the connected dots moment. It is, but correlation isn't always causation, right? So they went even further. They mapped the physical 3D structure of the DNA. See the wiring behind the wall. Yep. Yep.
6:40Using techniques like Hudship and Atex Ec. They could actually see the DNA looping around so that the risk variant was physically touching the gene it controlled, even if it was far away on the linear sequence.
6:51That is just incredibly thorough, but it's still observation, did they? Do they poke the scissor? Yeah, they did. That was the final test. They used pooled CRISPR Cast 9 screens. They took their list of suspect jeans and just knocked them out one by one in the cells.
7:06to see what would break. To see if the cell's behavior changed. Did they start growing too fast? Did they start migrating? They moved from, this looks suspicious too. We broke this, and the cell went haywire.
7:18And the results? A whole catalog of suspects. They found 134 likely causal genes for coronary artery disease, 74 for hypertension, and so on. Many of them were totally new. New, never linked to vascular disease before.
7:31Right. A lot of old research focused on cholesterol genes, lipid metabolism, but these were different. They were about cell structure, signaling, how cells move. But the most exciting part for me was the pleiotropy, the double agents.
7:44Ah, yes, the heavy hitters. They found 18 genes that were influencing more than one of these diseases at the same time. Like what? Well, a Gene Kong VCAR one, for example, was linked to both coronary artery disease and aortic aneurysm.
7:57That's clogging and ballooning from the same gene. So it's not just bad luck that you get both. It's bad blueprints. Exactly. And the CRISPR screens confirmed it. When they knocked out those genes, the cell's ability to grow changed dramatically. But there was one gene that really stood out from the rest, wasn't there?
8:14The paper spends a lot of time on it. FES. FES is the star of the show, no question. The analysis flagged it as a master regulator linked to both coronary artery disease and hypertension. The clog in the pressure.
8:30The master switch we talked about at the start. That's the one. And the mechanism they found is just, it's fascinating. When they knock down FES in the cells. The smooth muscle cells went crazy. They started migrating all over the place.
8:41Which, in an artery means moving into the wall to form plaque. Yes, but it's how they moved. The cells without FES started churning out these enzymes called MMPs. Matrix Metella protein aces. I've heard them called the body's demolition crew.
8:54A perfect description. The artery wall is held together by the scaffolding of collagen. MMPs chew right through it. This lets the cells move, but it also dissolves the structural integrity of the artery wall.
9:05So without FES to act as a brake, the cells start running around and basically dissolving the floorboards as they go. And at the same time, they lose their identity. The cells with low FES stopped making the proteins that allow them to contract.
9:18And that's the hypertension link. If the cells can't contract and relax properly, the vessel can't regulate blood pressure, it becomes stiff. You got it. One single gene failure causes the vessel to stiffen, which is hypertension, and it encourages plaque formation, which is CAD.
9:34It explains the comorbidity perfectly. So elegant. But this was all in a dish. Did they check it in the living animal? They did. They used fez knockout mice engineer to not have this gene. They put them on a high fat diet, a sort of mouse fast food diet.
9:51said their arteries clog? Big time. The mice missing the fez gene had significantly larger plaques than the normal mice. So check that confirms the CAD link. Okay, what about the pressure? This was the really striking part.
10:03Even on a normal diet. The knockout mice had significantly higher blood pressure. Wow. So just from losing that one gene. Just the gene. And when they tested the blood vessels, they found they couldn't relax properly.
10:15They were just stiff. The plumbing was rigid instead of flexible. Okay, so it works in cells, it works in mice. The final step is to bring it back to people. Right. So they went to the UK biobank, which has genetic and health data on half a 1000000 people.
10:28They looked for people who naturally have a broken copy of the FES gene. It must be rare. It is, but in a group that big, you'll find them. And the data matched perfectly. People with these broken FES variants had higher blood pressure.
10:42But here's the kicker. They had a nearly twofold increased risk of hypertension and a twofold increased risk of a heart attack. Doubling the risk. That is, that's not a small effect. That suggests FES is a major, major player in our vascular health.
10:57It really confirms that this gene is like a load bearing pillar. You take it out and the whole structure starts to have serious problems. So what does this all mean then? We've got this gene, FES, acting as a break.
11:08When it breaks, the cells go rogue. The huge question is, can we fix the break? Is this druggable? That is the multi-billion dollar question. The researchers cross-reference their whole list of genes with drug databases.
11:23They found dozens of potential targets. 63 for CAD, 39 for hypertension. That's a treasure map for pharmaceutical companies. It really is. But for FES specifically, they found something very promising.
11:35FES interacts with pathways like VGF and EGF. And we already have drugs that target those pathways for things like cancer therapy. Exactly. So we might not need to invent a brand new drug from scratch.
11:48We might be able to repurpose or develop drugs that just tweak these pathways to boost what FES is supposed to be doing. So it moves us from just knowing there's a risk to understanding the biological gears that are grinding.
12:00That's the whole point. We're moving from statistical spots on a map to real mechanistic biology. It opens the door for precision medicine. Instead of giving everyone the same statin, maybe you find the people with the FES problem and give them a therapy that targets that specific pathway.
12:16So to wrap this all up, what's the core take-home message from this incredible paper? I'd say this study proves that vascular diseases aren't just a collection of separate problems. By finding master genes like FES.
12:28We now see how a single genetic flaw can drive both the clogging and the stiffening of our arteries. It unifies the disease model. Which leaves me with a final thought. Right now, a lot of heart patients take a whole handful of pills every day, one for pressure, one for cholesterol.
12:47It's called polypharmacy, and it's a real burden. So if a single gene like FES controls both the plumbing and the pressure, are we looking at a future where one single therapy could replace that whole handful of pills?
12:59Could we fix both problems with one turn of a wrench? It's a provocative thought. We're not there yet, of course, but for the 1st time, this paper gives us the map that shows us it might just be possible.
13:09And that's a future definitely worth researching. This episode was based on an open access article under the CCBY 4.0 license. You can find a direct link to the paper and the license in our episode description.
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