Thread by @POhukainen

This is a pretty cool and elegant study: Monogenic vs Polygenic Hypercholesterolemia and Atherosclerotic #Cardiovascular Disease Risk ja.ma/2UYCZ4G

A brief 🧵 (1/11)

Key point was to compare the risk between three groups:

1️⃣ LDL high because of a pathogenic single-gene variant
2️⃣ LDL high because of a particularly strong effect from a combination of variants in 223 genes
3️⃣ LDL high but neither of the above genetic effects

(2/n)

In other words the comparison is between:

1️⃣ One physiological LDL pathway malfunctioning
2️⃣ Some combination of multiple pathways producing high LDL
3️⃣ LDL high mainly due to non-genetic effects (most likely diet, exercise, the usual)

(3/n)

As we know from previous literature over many decades, these are all bad - but in what order? Turns out the order is from highest to lowest risk: 1️⃣2️⃣3️⃣

(4/n)

Key question is why like this? There’s a lot more to dig in here and I’m sure there’ll be a lot of fascinating papers coming up to elucidate the details. But for now, the IMO the most likely explanation is that these differences simply reflect lifetime LDL exposure.

(5/n)

If one LDL pathway is f’d up, it’s there since embryonic time. But the polygenic case.. well, that’s a bit of a black box. It’s calculated by giving a weighted sum from 223 gene variants that are all known to have SOME (often mechanistically unknown) association with LDL.

(6/n)

The result is a score from 0-10 and as we can see, the score can produce a wide spread of outcome LDL concentration. But the higher the score, the higher the risk:

(7/n)

This doesn’t appear to be as risky as having that one-gene hypercholesterolemia variety, even though serum were similar at baseline of this study:

(8/n)

As the authors point out, a very likely explanation is that polygenic high LDL may not be “active” since you’re an embryo. The combination of genes can mean that you’re susceptible to developing high LDL later in life. Or you respond differently to lifestyle/environment.

(9/n)

And by comparison, non-genetic high LDL is the least harmful of the 3 because that one’s the most likely to be affected by lifestyle choices. You may have physiological LDL for a good many years until something happens. Athero is on a less steep development trajectory.

(10/n)

Key takeaway is that no matter how your LDL goes up, it’s always worse than if it didn’t. But timing matters, too. To minimise the risk of heart disease, it’s always best to start paying attention to your numbers as early as possible 😊👍🏼

(11/11)