Hi, everyone. Thank you, Daron, for the introduction, and thank you everyone for joining us again today. Like Daron said, my name is Ina Liko, and I am the Director of Clinical Pharmacogenomic Operations at RxGenomix. Today, we’ll actually be talking about ACE inhibitors, and I’m excited to introduce this new gene along with an overview of … Actually, sorry, my laptop went a little bit ahead of me, of SLCO1B1, because it does actually affect some of the medications that we’ll be talking about. And then we’ll look to see if, with the literature studies that are out there, if there are any guidelines, any FDA language. And then we’ll come back to our patient case, to see how we can help this patient.
So this is JT. He’s an 80 year old Caucasian male, and for past medical history, he has high blood pressure, hyperlipidemia, and unfortunately, he also had MI. He hasn’t had any surgeries done. His doctor actually put him on all of these medications, especially because he had an MI. He’s taking a statin, he’s taking Atorvastatin, 80 milligrams daily, Clopidogrel, 75 milligrams daily, Enalapril, 40 milligrams daily, and this is the one that we’ll focus on today, and then as well as Metoprolol.
In terms of the medical history, or what he’s complaining about, he actually developed a pretty bad cough, and he comes to the clinic, to us today complaining about that, and saying that he actually has not been taking any of his medications, because he thinks maybe because his doctor put him on all of these medications, one of them could be causing it. And this comes from a patient perspective, safety as well, because this is a very high risk patient who had an MI, and if he stops all of his medications, this could be potentially dangerous for him. But that’s what he thought was the best to do, because he developed this really bad cough right after he started all of these.
Fortunately, he also had a pharmacogenomic testing done. As many of you might have guessed, the cough might have come from Enalapril. You may say, “Okay, it’s just a cough. Not a big deal,” but for this particular patient, it was disturbing enough to him that he just didn’t want to have that, and that’s why it affected his medication adherence overall.
Today, I want to talk a little bit about ACE, and how it affects ACE inhibitors, and SLCO1B1, I’ll bring that in as well, to see how it can affect some of these medications as well. But SLCO1B1, it’s also important here, because this patient is also taking a statin. He’s taking the Atorvastatin. So by having this information, we’ll also be able to assess whether he’s taking the right statin or not.
Just an introduction here for the ACE inhibitors, or just the enzyme itself. ACE, as many of you know, stands for angiotensin converting enzyme. It plays an important role in two pathways, which contributes to the regulation of blood pressure, and those two pathways are the renin-angiotensin-aldosterone system, or that RAAS system, and the kinin-kallikrein cascade. Now, ACE converts the inactive Angiotensin I peptide to the active Angiotensin II. And this Angiotensin two has a variety of functions, including vasoconstriction, as well as stimulation, release of aldosterone, that in turn cause reabsorption of sodium and water from urine, as well as increases blood pressure.
So ACE also inactivates the vasodilator bradykinin, which is a component of the kinin-kallikrein cascade, preventing it from stimulating one of its receptors, and we’ll talk about this gene as well called BDKRB2. This is a bradykinin receptor. And therefore, that subsequent downstream release of nitric oxide, which relaxes the vascular smooth muscle and lowers blood pressure. So because of this, ACE is the target for the ACE inhibitors, that family of drugs, so therefore that’s why we are mainly talking about this today as well, because there could be a potential pharmacodynamic, pharmacogene there, relationship as well.
And then here, I’m bringing you back to chemistry, and some of those pharmaceutical classes we took, but just an overview of ACE inhibitors and this RAAS system. So the ACE inhibitor interaction with the RAAS system here, angiotensin, I’ll just go over this very briefly, but mainly I just want to point out angiotensin is released from the liver into the bloodstream, where it’s converted to Angiotensin I by the kidneys, and also by this molecule called renin. Angiotensin I is converted to Angiotensin II by, of course, angiotensin converting enzyme. And this Angiotensin II is the one that binds to the receptors, which results in that increased blood pressure. So that’s why an ACE inhibitor, see my laser here, that’s why this ACE inhibitor is just blocking this, so then the patient’s blood pressure is decreased.
And then another important cascade here is also angiotensin receptor blockers. That works a little bit differently, but they actually compete with this Angiotensin II at the binding side. And this is also what can also, so that we have the ARB here, that kind of works in a different part of this system, but that can also decrease blood pressure. However, in the presence of this ACE inhibition, bradykinin can accumulate, and that’s what can actually lead to side effects, such as cough, and a little bit more serious ones such as angioedema as well. So that’s why in a lot of cases, we see that if the ACE inhibitor is causing the cough, we’ll switch to an ARB, and then the cough will go away. But I just kind of wanted for us to see the system so that we can see if there is actually any genetic reason for that, or why we see that in some patients and not others.
Now, in terms of the variations of the ACE gene, there are about, they’ve discovered about 78 variants and 13 haplotypes. The most well-known variant is this insertion/deletion in intron 6, and it’s called ACE: I/D, and this is what we’ll actually also continue to talk about in some additional studies, but mainly this is the variant that has been also studied in terms of response and efficacy. There are these other two variants as well that I’ve listed there, and they’re found the ACE promoter, and they have been shown to reduce that transcription and have been associated with some adverse cardiovascular outcomes.
Now, in terms of the frequency here, so again, this is for these two different LDL variants here. So they are actually pretty frequent across populations here. So the first one is about 42% in Americans, and then the second variant is about 57% in Americans. And these are one of the variants, like I said, that do cause those side effects. So mainly the cough. So that’s why a lot of patients complain of cough once they start an ACE inhibitor.
And then here, I just wanted to give us an overview of where exactly the ACE is involved in this mechanism. So we have the ACE inhibitors here, and then you can see that it’s kind of that last converting enzyme here, and then the Angiotensin II antagonists, and what are the enzymes that are involved here in making that conversion? So from Angiotensin I to this other enzyme here as well.
Now, I want to overview SLCO1B1, because it will actually become important for some ACEs as well. There are a couple of other genes that would affect ACE inhibitors, and they affect them in different ways, but mainly SLCO1B1, it’s this protein product of the SLCO1B1 gene, and we mainly know it as it is related to the statins. So if we have a poor metabolizer or intermediate metabolizer, and a patient is taking a statin, particularly the simvastatin, then they’ll have actually more of this statin-induced muscle pain. However, I wanted to bring our attention that it is actually also incorporated in cough as well. If a patient has a certain variation of the SLCO1B1, it can increase their cough to ACE inhibitors, or the risk of them having cough from ACE inhibitors.
And then here, are just an overview again of, what are these genetically mediated SLCO1B1 phenotypes? You may not remember, because this was the first slide, but our patient actually falls into this intermediate function. His genotype is *1/*17, so he has this TC change here. So this will be an individual carrying one normal function allele, plus one decreased functional allele, and then for low function, it will be an individual carrying two decreased function alleles. Again, this is just the frequency. This is the most common variant for SLCO1B1, and it is found in about 13% of Americans as well.
All right. So now I want to bring our attention to, again, focus on ACE, and then what are some of the studies that are associated with drug response? And some of these outcomes, clinical outcomes that we see. So there are a couple of different variants that are associated with effectiveness. The main one I want to focus on today is, again, the ACE, and then like I talked about before as well, is this insertion and deletion, or that ID repeat on intron 16. So I’ve laid out a number of studies here, and just kind of gotten the conclusion from them, because we don’t have that much time today to go all over the details for them, but I have them in the references if you’d like to reference them later.
So one study found that if a patient has actually this D/D variation, they actually have a greater response to ACE therapy. So maybe those are the patients that we should target when we start targeting them on an ACE inhibitor. Also, the second study supports it by saying that there’s an increased ACE serum level, again, in these patients that have this D/D variation, as well as a higher ACE activity. So generally this is talking about pharmacokinetics, and we may be thinking, “Okay, there is higher serum levels, so does that mean that there is an increased toxicity? Will these patients have more cough, or ACE-induced angioedema, which is a serious condition there?”
And actually there is another study. This has not been associated, this variation has not necessarily been associated with ACE-induced angioedema, which is a good thing. These patients, even though they have higher serum levels, they just get a greater response with it, not necessarily the toxicity.
And then the phenotype, this Insertion/Insertion variation, actually these patients responds better to ARBs, particularly irbesartan, and with irbesartan, this is actually … The study was done in Sweden, is the Swedish Irbesartan Ventricular Hypertrophy Investigation, or SILVHIA, and this was a significant study because it identified some of these variants that are associated with blood pressure response to ARBs, and then again, particularly to irbesartan, and it showed that for the ARB, irbesartan conferred a large decrease, especially in the diastolic blood pressure, if the patient had this I/I genotype, compared to if they had this D/D genotype. And then this study also found that patients that had the D/T genotype, they actually responded better to ACE inhibitors.
Now, the other two studies I have referenced here, so these are some other variations. The first one there. So ACE A or G, if the patient has that variation, or actually the lack of that variation, so A/A, suggests that the ACE therapy is more effective because that A/A variant is the major allele. So the patient has the A variant in this rs number on the second blood point over here. It is going to be more effective. And then if the patient is a variation, in these other two variants, this is actually protective against ACE-induced cough. So this is just something to keep in mind, if we see this variation in some of our patients.
I also was curious about, what about safety? What are some variants associated with safety? And when it comes to ACE, it’s more associated with disease, as well as the efficacy portion, not necessarily with safety. The studies that are out there do not suggest any particular variant that’s associated with angioedema or cough. But I thought it’d be interesting to see what other variants are out there from different genes, maybe, that if there are any data associated with safety when it comes to ACE inhibitors. So the two genes that I’ve included there regarding angioedema, is actually they’re genes that are used in the immune system. So angioedema, as we all know, is a potentially life threatening side effect of ACE inhibitors, and there was particularly one study done in 2012, they found that the, if the patient has a variant deal with a T substitution in this PRKCQ, actually it was associated with reduced risk of angioedema. So this is protective. However, if the patient had a G allele in the other gene here, this ETV6, that was associated with an increased risk of angioedema.
And like I said, these two genes, they are more involved in the regulation of the immune system, and actually the ETV6 gene is also in combination with another gene. It’s also involved in prediction of cancer disease for some patients as well.
Now we come back to SLCO1B1 here, when it comes to cough. Again, definitely not life threatening. However, as it was for our patient, it was just very disturbing to him, to the point where he stopped his medications. So lower adherence, therefore that is a problem for that patient. So SLCO1B1, and he actually does have this variation, there is a strong association with an increased risk of especially an enalapril-induced cough, as well as this variation of bradykinin receptor, this BDKRB2, that’s also associated with ACE-induced cough, but the association is stronger when it comes to SLCO1B1.
All right. Now let’s go back to our patient. I referenced him a lot, so I’m sure you remember his story, but the relevant medication we’re focusing on today is enalapril. He had a cough from it. It was really uncomfortable for him. And this is relevant PGx information here. So for ACE inhibitors, he has this I/I phenotype, and then SLCO1B1, he does have this Intermediate/Intermediate function, which again, was associated with that increased risk of having a cough. And then so my plan of course, there are a lot of different alternatives here, but I am suggesting to start to switch him to irbesartan, again, based on that SILVIAH study that had suggested that, found that patients that have this genotype here, they are more likely to respond better to irbesartan.
These are my references, and thank you so much for listening to the presentation. What questions do you have for us?
Daron:
Just a couple things I wanted to make sure everybody knows. I apologize if you’ve heard this seven times, but we also do have an eight-hour education course. If you want to get some of your CE credits from learning about pharmacogenomics, you can just go to rxgenomix.com/education, or if you really enjoyed the sessions, really want to go back and watch some of them, if you missed something, or if you want to check references from any of the past presentations, we are archiving all of those on our website. If you go to rxgenomix.com, under Insights up at the top, you’ll see Clinical Pearls, as soon as you click on that. So all of those are archived usually within the week after they’re first presented. So if you have any questions, want to go back and look at anything, review any session, they’re all there. If you want to share that with anybody, feel free. So with that, I do see one question, if you want to take that, Dr. Liko.
Ina Liko:
Yes. And that is about the references. Sorry about that. I think you can see them now, Amy.
Daron:
Okay. That’s easy enough. So like I said, those are all available. Every all of our past sessions are available online. So you can always go back and review any of those. So that’s it for me, Dr. Lu, if you want to give anybody else a few more seconds to chime in, I’ll just turn it over to you.
Ina Liko:
Sure. Thank you, Daron. Yeah. It looks like we have a quiet group today. But if any questions come up in the future, like Daron said, please feel free to email us. You’re welcome, Misty. Thank you for attending. Thank you, Ruben. Thanks for attending again. All right. Well, I don’t see any questions, so thanks again, everyone, for attending, and we’ll see you next week. Have a great day.
