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Comment by WhatsTheBigIdea | Hacker News Reader

This paper's core idea is based on the assumption that circulating LDL is the cause of heart disease. That assumption is false.

Taking satins is proven to reduce heart disease rates, but there are lots of other drugs that lower LDL... many with much more efficacy than satins.

These non-satin drugs do not reduce heart disease rates significantly.

There something else going on here. High LDL is correlated with the development of heart disease, but it does not cause heart disease. Satins do reduce the risk of heart disease and they do reduce LDL, but their positive effect on heart disease rates is not caused by reduced LDL.

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There are multiple independent risk factors for heart disease. The major ones are:

  - LDL / ApoB
  - Blood pressure
  - inflammation (hs-CRP)
  - Insulin resistance (HbA1c)
  - Lp(a): strongest hereditary risk factor.
  - eGFR: a measure of kidney function

Non-statin drugs like PCSK9 inhibitors have been shown to reduce heart attacks, strokes, and other cardiovascular events on top of statin therapy. One randomized control trial was FOURIER in 2017: https://www.nejm.org/doi/full/10.1056/NEJMoa1615664

Why do we see consistent dose response between LDL lowering SNPs and cardiovascular disease in Mendelian randomisation studies, then?

Heart disease is clearly not Mendelian. So, unless you have a specific well-designed study to cite, that is a non-argument.

https://www.jacc.org/doi/10.1016/j.jacc.2012.09.017

Across different genetic variants, lower lifetime LDL -> lower risk of death. Check out figure 3.

The causality of LDL -> plaque buildup -> 55-60% [1] of heart disease related deaths is also well understood, so it seems clear to me that preventing plaque buildup in the first place prevents over half of heart disease related deaths.

Would like to know if you disagree, "Minimize LDL at all costs" goes current mainstream medical guidance, so I'd like to disconfirm my beliefs if possible.

[1] Number from deep research.

Graboy has provided the citation I would have given, as well as an excellent explanation. I’m not sure what you mean by “heart disease is clearly not Mendelian”.

Mendelian is characterized by effects having strong influence from a single gene. Heart disease is clearly more complex than gene -> heart disease. I thought that was basic enough that I didn't need to explain it. But here goes...

A clinical score changing with treatment is not unconfounded by mendelian randomization. When the genetics are clearly more complex than what you are mathematically randomizing for, the control doesn't solve the confounding. eg you haven't suddenly "proven" the effects are non-genetic. We already knew heart disease is non-mendelian. But showing something is non-mendelian doesn't mean you've shown it's not genetic. I hope that clarifies, because I'm not sure I can explain it to you in simpler terms.

> I thought that was basic enough that I didn't need to explain it. But here goes...

This is quite the tone to take when the actual point being made has demonstrably sailed over your head, considering the reference provided to you explains it very clearly.

Which is more likely - nigh on every lipidologist, cardiologist and nutrition researcher is wrong, or you might have made a mistake yourself?

> Mendelian is characterized by effects having strong influence from a single gene. Heart disease is clearly more complex than gene -> heart disease

This seems like a misunderstanding. A single SNP clearly can affect CVD risk, that’s precisely what the paper shows. The assumptions required for an MR study to be valid do not include “the outcome must only be affected by a single gene and no other gene”. It’s required that there’s no pleiotropy present in the exposure (I.e. the SNPs). The exposure here isn’t heart disease, it’s SNPs that affect LDL-c levels, and the outcome being measured is CVD. So your point doesn’t pose an issue for the study and the inferences it makes.

But honestly - just read the paper. I think both that paper and the EAS consensus paper are very approachable.

I think maybe you are saying that there may be some way that the genes affect heart disease not through LDL, and therefore MR does not apply because the "exclusion restriction" [1] fails here? Or are you talking about a different assumption?

The cited study addresses this, which is why I pointed to figure 3. They argue that if genes were causing heart disease not through LDL in any meaningful way, you wouldn't expect such a clean dose-response consistency across different genetic variants - it would be more jagged.

[1] https://en.wikipedia.org/wiki/Mendelian_randomization#Defini...

It seems you are confusing mendelian randomization for specific alleles associated with LDL-C production and conflating that with mendelian randomization somehow controlling genetic confounding of heart disease. The control is for the LDL production, not heart disease.

Here is a simple primer on mendelian randomization: https://www.psomagen.com/blog/what-is-mendelian-randomizatio...

Please review the key principles and assumptions section. Using MR to control for genetic confounding of heart disease fails all assumptions. Thats why it quite directly does not follow.

This is why the paper presented does not support the claim that LDL is the sole source of heart disease. I'd be interested to hear what the authors of that paper (which is legitimate) think about it being used to support the OP's claim because "mendelian randomization".

> This is why the paper presented does not support the claim that LDL is the sole source of heart disease

Is that what we were arguing about? I guess it was. At some point in thinking about this my frame must have shifted into agreement with you. Of course there are other causes of heart disease besides LDL, like blood pressure, duh. The smooth dose response is about the particular gene not being linked to heart disease through something other than LDL, roughly.

What do you think of Dr. Schooling's response that the Mendellian effects might be inflated? I think they had a good defense but was not entirely convinced they hadn't sidestepped the issue that Schooling was getting at, wasn't sure either way.

https://www.jacc.org/doi/epdf/10.1016/j.jacc.2013.01.067

I wasn’t aware of that critique, thanks for sharing. Before I read the response my first thought was “why such consistency across different SNPs, then?”, so I would certainly agree with that aspect of the defence.

In general, Ference’s explanation just seems more parsimonious than Schooling’s. It’s possible that they’re right, but I think they would need to show that the specific genes in Ference’s study are affected by age in this way.

I wouldn’t claim to be a great expert in MR, though. I can just about keep up with surface level understanding of them but once you get into the nitty gritty stats, pleitropy testing etc it’s a bit over my head tbh.

> [that circulating LDL is the cause of heart disease] is false.

I think your comment really owes the rest of us more explanation of this part.

*statins?

The fact that this word is misspelt every single time makes me want to dismiss the entirety of the comment.

My browser underlines the word statin to indicate a misspelling, but does not underline satin. We've been trained to believe the computer is always right when it flags an error, but unfortunately it's not 100% accurate.

Simplifying, we are all essentially born with heart disease. It's just a game of how long it takes for it to kill us. No way around it.

Unfortunately, our biology isn't perfect.

That’s not really a helpful attitude to take when trying to prevent heat disease though

Reality is like that.

Before hoping for a miracle, may I suggest adding more walks into your week?

The article goes on to say it's not all LDL. Keep reading. The first part agrees with my cardiologist, at any rate

> High LDL is correlated with the development of heart disease, but it does not cause heart disease.

You realize this sentence is an oxymoron?

Unless you meant to say "it does not cause the development of heart disease". I agree correlation is not causation.

I don't think it is. Something can either be correlated and causal or correlated and non-causal. It makes sense to talk about which.

> You realize this sentence is an oxymoron?

No it isn't.

Think of heart disease as slow, long-term damage to the cardiovascular system, and cholesterol is what the body uses as a bandaid.

If you have a lot of LDL cholesterol available, your body will use a lot of it, and you'll have stiffer arteries. If you don't have much available, it takes longer for the bandaids to build up.

This is one of the reasons statins reduce the number of heart attacks, but don't always seem to reduce all-cause mortality.

The band aid analogy doesn’t make sense when we consider the MR studies showing the lower your genetically determined LDL-c, the lower your risk of CVD. If everything was randomised except the number of band aids, why would having fewer band aids result in lower CVD risk?

> This is one of the reasons statins reduce the number of heart attacks, but don't always seem to reduce all-cause mortality.

That’s one potential explanation, but I don’t think it’s the most likely one. We tend to see non significant ACM in smaller, less powered trials, or those with lower LDL-c lowering. ACM is simply a less sensitive endpoint - if you have a treatment that reduces CVD incidence, then the “CVD incidence” endpoint will give you significant results with fewer CVD event differences between study arms compared to ACM since your power to detect differences is diluted by other fatal events that aren’t affected by statins (cancer, motor accidents etc).

You realize correlation does not imply causation?

Edit: this was written before OP edited their comment

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