Understanding Your Heart Attack Risk: Mendelian Randomization, CRP & Obesity

November 17, 2019 0 By Ewald Bahringer

Read studies about the science of heart
attack and stroke prevention. You’re gonna see this term sooner or later –
Mendelian randomization. Now, what the heck is that? and why is it important?
what’s it used for? Well, the age of genetics is clearly upon us and one of
the things that epidemiologists study – study authors in multiple areas, ranging
from bone transplant, to drug development, to prevention. All are beginning to
discover this technique and what is it? It’s – it basically takes the fact that
genes tend to be distributed at random. So, let’s say your father has one one
blue-eyed gene and one brown-eyed gene. So he’s got brown eyes and your mother
has blue-eyed genes, so she’s got two blue-eyed genes. Your father’s got one
blue-eyed gene, one brown-eyed gene. So at – both his eyes are brown because brown is
dominant. Your mother – it has two blue-eyed genes, so both eyes are blue.
What will the kids be? Well, we know brown is dominant. So, half the kids have
brown eyes, half the kids will have blue because half of them will have gotten
the father’s brown-eyed gene, and the mother’s blue-eyed gene. So, they’ll be
brown-eyed. Half of (them)will have gotten the father’s blue-eyed gene and the mother’s
blue-eyed gene, and they will be blue-eyed.
Here’s what we don’t know – which half. And so, that’s what we mean by a random
distribution of genes – Genetics. What researchers have begun to realize is
they can take that randomization and, in many ways, use that to replace some of
the function that we see in randomized clinical trials. Let me give you an
example – Does being obese cause a heart attack or is the same something else
that’s causing obesity all cause that heart attack? Well, they’ve
actually done studies on that and that’s how this came up in our – in our channel.
I’ll talk about those studies in just a minute, but let’s go back. Again, a little
bit more into the history of Mendelian randomization. It’s credited to these two
authors Gray and Wheatley. And as you can see, they’re not so much epidemiologists
as they are bone marrow transplant guys and they came up with this idea on how
to avoid bias when comparing bone marrow transplant – transplantation with
chemotherapy. Now, actually there was an author before that – Katan. He was in
more of the prevention area. He was talking about apolipoprotein E
isoforms and cholesterol and cancer. Again, I’m not going to go into either of
those studies. Right now, I’m gonna talk a little bit more, just about – though, the
whole concept of Mendelian randomization. Now, we again – we first talked about it as
we were going through the obesity paradox when thinner means
sicker and heavier means healthier. I’m not going to get deep into those studies
or those concepts other than to say that as we studied that, we found that this
was very much related to the issue of lethal sarcopenia and, again, we had
several videos that covered those issues. We’re not going to spend any time on
those. We’re going to go straight to the article that brought up Mendelian
randomization for us and that had to do with obesity in cardiovascular outcomes. So I just mentioned that a few minutes ago. There was a study in JAMA
cardiology – the network, open network group where they did a meta-analysis. You know… the Cochran studies where you take multiple studies and you pull them
together to see what they show. But these were a unique type of study and
they only found 5 of them, it’s a study where you do this. You take a large
population. These were called GWAS – Genetic –
Genome Wide Association Studies. So they took a large population, each of these
studies did that. They looked at genes that are associated that appeared to
cause obesity and there are some – if you didn’t know that – yes, obesity does have,
clearly, a genetic component. So they separated those out here and looked at
the – the race of heart disease. They compared that in the race of the heart
disease in the control group. The people that did not have the genes for obesity.
Here’s what they found: Yes, the people that had the genes for
obesity had increased risk for not only heart attack but diabetes as well. So,
very interesting and in many ways not surprising. There was one surprise twist
which I don’t think we can explain. If you want to – if you want to bottom line
on that, I think the bottom line is still a mystery. In that same study that – they did not find that relationship with stroke. You saw the same amount of strokes in
both of these populations. The study population and the control. Now, were
these big studies? Yes, the total was almost a million. So, statistically – very
powerful studies. And, again, it over – Now, why did they have to use this
technique and, again, as we began to discuss it, I think it becomes clearer
what Mendelian randomization is about. Let’s say we wanted to find out – Does
obesity cause heart attack and stroke? Well, if you’re gonna do a randomized
clinical trial, first you have to get a large group and you have to randomly
assign obesity to one group and not to another. You can’t do that. How are you
going to say “Okay, we’ve picked a 100,000 people and this 50,000 is going to be – is going to become obese. You can’t do that.
Obesity and its relationship to something like heart attack – it’s always
going to be what we call an observational study. But let’s go on.
Let’s just humor us – humor ourselves here and say “There’s a way that we can
randomly assign and make somebody obese.” You know there’s a thing called blinding
as well. In other words, you have to blind the patient and the healthcare provider –
the doctor, to the fact that this person has the exposure and this one doesn’t. In
other words, how are you going to blind the patient and the doc to the fact that
you’ve made them obese? Again, just will not happen. That’s why we get into this
question of randomization and bias and confounding and using – since you can’t
use randomized clinical trials, use the randomization of genetic distribution. So
if that’s still making your head feel kind of hurting and turning inside out,
trying to link those two – you’re not the only one. There’s whole textbooks on how
to do this. I will also share – there’s a Mendelian randomization Bootcamp at
Columbia University later on in 2019, if you really want to go. You can spend a
few days talking about exactly how to do that but it might be helpful if I go
back and – and use another example of Mendelian randomization in prevention
and it has to do with C reactive protein. Now, those of you who’ve seen any of my – well, have seen many of my videos, will remember C reactive protein.
I’ve got several videos on it and if you don’t know what it is, take the
inflammation course. In the inflammation course, I tell you how to find out
whether or not you have cardiovascular inflammation. One of the key studies for
cardiovascular inflammation – one of the key labs is CRP (C reactive protein). C
reactive protein is made by the liver when there is inflammation going on in
the body. The guy that came up with this whole idea that cardiovascular
inflammation causes heart attack and stroke, Paul Ridker, a very smart guy
at Harvard – that’s really all he uses. I tend to use more than c-reactive protein.
I also use microbium and creatinine ratio, MPO, Lp(a). But, let’s go back to CRP and
Mendelian randomization. So there are genes that are, as we said before – excuse
me, randomly distributed genes which cause
high CRP so let’s ask the question: Does having an elevated c-reactive protein
cause heart attack or is there a confounder? Something that biases the
study for people that have elevated CRP? Well, since we know there are genes that
will create elevated CRP in people, there are genes that – for example, slow down the breakdown of c-reactive protein. If we can look at those, find those genes and
– what we can do is this: Again, take a large population. Find those that have
genetic elevated CRP. Now, if that group has higher heart attack and stroke
risk, then we know that CRP actually causes it. If it doesn’t have a higher
heart attack and stroke risk, it’s the same as the group that does not have
genetically elevated CRP then it’s not the CRP that’s causing it because you
got a higher CRP in the genetic risk group. So, again, that risk group – if the
CRP were causing it, should have more heart attacks and strokes. And here’s
exactly what you see on the – on the image behind me. When we do random – when we do testing, if your CRP begins to elevate – Yes, you are much more likely to
have a heart attack or stroke. However, if you do… Again, a genome – why does GWAS or if you just do a genetic study, you pull these groups and you look at it. The
groups that have genetically elevated CRP do not have an increase in heart
attack and stroke. Their relative risk is one. So what we know is that CRP – elevated CRP is a marker, not a cause of heart attack and stroke. So, for those of you
that have made it this far, as usual and this time especially, we did some
mind-bending stuff. I’m not the greatest public speaker as I get reminded
routinely on in the comments section but I do have a passion for helping people
understand the science behind prevention. I hope this has been helpful and maybe
even just a little bit eye opening in terms of the science and what’s
happening out there today. Thank you for your interest.