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What causes ulcerative colitis? What are the symptoms of ulcerative colitis? How is ulcerative colitis diagnosed? Who is affected by ulcerative colitis? Is there a relationship between smoking cigarettes and developing UC? What is the treatment for ulcerative colitis?
Will I eventually need to have surgery for ulcerative colitis? What type of surgery is done for ulcerative colitis? What is pouchitis? Walters: That's a good question, Rick, and I think it's important to play through because it's a bit of a misconception out there that we can make that very obvious distinction. And why do we think that way?
Because we are used to the idea of genetic diseases and nongenetic diseases, and probably the easiest one to think about is cystic fibrosis. We know that there is a single gene problem in cystic fibrosis. We can test families for it. We talk about the risk of it going through families, and thus your risk is related to your genetics. And we have always talked about, say, heart disease and heart disease being related to smoking or being related to you being overweight.
Walters: When it comes to inflammatory bowel disease we talk about it being a complex disease, a complex genetic disease because what we believe is, number one, you have to have some genetic susceptibility.
If you don't have one of at least 30 different gene problems, then nothing is really going to trigger this disease. However, lots of people have those gene problems and they never get IBD. And so we think, well, for the people with the genetic problem, we think something has to prime you for it early in life.
We think that's probably something really common. Maybe it's because you got gastroenteritis when you were a two year old. Maybe it was because of the different water you were drinking. Maybe it's because of different things you saw in the environment. We really don't know, but we think there is something that primes you. It only matters if you already have the genes, but we know a lot of people would have both of those things, and they still have no problems for the rest of their lives.
What we think is that the person who has the genetic problems, who gets primed early in their life, at some point along the way a trigger event happens to them. Maybe it's they get some sort of infection. Maybe it's they receive some special drug.
Maybe it's they encounter something which lots of people encounter all day, every day and it never causes them a problem, but because they have this genetic susceptibility and then they got primed sometime in their life and now they are encountering this trigger, they develop disease.
And so it's this complex idea, and really it is that interplay between genes and the environment which gives you your risk.
And you really can't draw the line down because without one you probably don't have the other. Walters: And if we think about environmental risk factors, probably our biggest environmental risk factor for Crohn's disease — the other form of IBD — is smoking. It's the one with absolutely the most evidence.
And when we look at some of the common genes, the risk you have from smoking is about the same increase in risk you have from some of the other genes, but if you have both together, then the risk really goes up quite a lot.
Now, this is a highly technical subject, genetic research, but can you describe in layman's terms the basic techniques that are used to do genetic research? What do you do? Walters: To begin with, we do the epidemiology. We just look at people. We look at how the disease moves around, who seems to have it, who seems not to have it. Are there particular groups of people who we could identify because maybe where they live?
Maybe things that have happened to them? Maybe different ethnic groups they come from? An area where maybe there is a higher risk? And that sort of cleans up the playing field, so to speak. But then it comes to the science part, and I suppose most of us know that we have lots of chromosomes, and chromosomes come in pairs, and they are made up of genes. And there are lots of genes in every chromosome, and all of these genes live in a nucleus inside of a cell, and every cell has all of these genes.
When the cell is going to divide, all the genes go and line up and they go back onto the chromosome where they fit, and they move off to the next cell. So as you know, when you have a child, half of their DNA comes from the mother and half of their DNA comes from the father. So when we thought that something might be related to a gene, the first thing we did was go off and find families in which two people had the disease.
And if it's due to the genes, we assume that there must be something similar about them in their genes, because they both got the disease. And so what we did is we got a brother and sister or brother and brother — two affected siblings — and we compared their DNA to their parents'. There are millions or billions of pieces of information, so you just look at the whole thing? Walters: So these days, yeah, but when we started doing this, absolutely not.
There was just no way we could do it. What we discovered was that there are little flags, so to speak, all the way along the DNA and that these little flags can vary between people. And you might say that at, say, chromosome number one at position number eight, there might be four different flags that could be there.
And so because we know that all of those genes on chromosome number one should move together and we know we are looking at at least two of those flags, and we can see the order in which they move — so you are getting flag A at position one and flag B at position two — that if your brother also has flag A at position one and flag B at position two, then he probably has the same chromosome as you do.
Rick: Uh huh. Walters: So we would guess that it's chance whose chromosome you get. If you get mom's chromosome or dad's chromosome, it's completely chance, and so you should have only half of the same chromosomes as your brother.
Walters: So if I go and look at all those flags and I keep finding that at a particular chromosome at a particular location, it doesn't come out to be fifty fifty, that nearly all the time if you have both got disease you always have, say, flag A at position one, then it tells us that that area is linked to disease. And that was the first study we did, which was called a linkage study. We looked at just really big chunks of the chromosome because it was pretty gross.
We only had about of these little flags that we knew about. And we looked to see how many of them weren't shared or were shared too often, according to statistics.
Rick: Yes, to be just mere chance. That was the first thing we could do. As time went on, we could look at more and more of these flags.
And it went from to 1, to 2,, and they got closer and closer together. Eventually we had this thing called a single flag, and so this was just one little area of the chromosome. It was no longer a big region. And so then we said, okay, well, we can just look at that flag, and we can look at that flag in everybody and see how often this flag turns up compared to chance.
And we can compare it to people who don't have disease. And so this was what we called an association. We looked to see whether this flag was not only linked to disease, because it moved around, but was it associated?
If we just got a whole group of people, was it there more commonly with disease than without disease? Walters: And those are the two ways we started looking. Now, as we got more and more technology, we realized that we could start thinking of genes that might be involved and say, you know, if there is a gene to do with inflammation, Well, maybe this gene has something to do with it, and we have got a little single flag for this gene that we know about.
And so you could test that flag, and that was a candidate association. In the last two or three years we have been able to do exactly what you suggested sort of at the beginning of this question, which was look at almost everything on the genome.
And the last sort of snip analysis we did was like half a million snips, and so half a million of these little flags that we are going to compare for people who do and don't have disease.
Rick: Thank goodness for computers, right? And you are talking about running a question which the computer takes maybe two or three days to give you the answer for. And so what's moved us forward in genetics isn't so much us thinking about it any harder, but it's us having much better technology.
Well, good. I think we have a better understanding of how you go about that now. And what have we learned so far using these different techniques of genetic research about colitis? Have we learned, for example, any type of pattern in the disease because of the genetic research? Walters: Again, good question. So prior to all of this, what did we think? Well, we thought that colitis was due to an interaction between something in the environment, which we think is probably like the normal bugs in your intestines and how they react with the normal defense mechanisms, and how when you react to these normal bugs that people who are susceptible to overreact and produce inflammatory chemicals.
And it's this interaction of an overreaction to normal stimuli — normal things in the environment — because of your underlying gene problem. That was a theory until about five years ago when the first gene came along, and that gene was all about how you fight normal bacteria.
And that was our first step in bridging the gap. We had this idea that it had something to do with bacteria and genes, and finally we found a gene which had something to do with fighting bacteria, and that's really been the process that genetic discoveries have had for us.
They have allowed us to confirm what previously were just theories. So some of the more recent genetic discoveries have looked at how the body normally protects itself. If we are talking about the intestines, the lining of the intestine we call the mucosa — and that really is your last barrier between you, inside your body, and the outside world.
And if that were to break down, so to speak, then obviously the bugs in your intestines can get into the body and that can affect how your body responds to them.
Walters: One of the recent genes was all to do with how the cells in that mucosa stick together, and that the genetic defect seemed to make them more leaky. We used to theorize that there was some problem with this barrier and maybe having a leaky gut, and suddenly we found a gene which seems to have something to do with leaky guts. Walters: And okay, so a bug gets in. Surely you should be able to fight it. How do we fight it normally? Well, normally we make inflammation to fight this bug.
If you have got inflammatory bowel disease, you are obviously making too much inflammation. And a recent gene discovery has been all about how the body makes the proteins for one of those inflammatory chemicals and how maybe you make too much of that protein when you get stimulated. And so suddenly again we have got a gene which is all about how you make inflammatory chemicals.
Rick: Do you think it would be helpful, Doctor, if we identified the names you use for some of these genes? Walters: One of the early genes is called NOD2, and NOD2 was this gene to do with the body's normal defense for bacteria, part of our ancient defense system. And we found that there was a common abnormality in people with Crohn's disease and, you know, 10 years later we still don't really understand what this abnormality is, apart from knowing that it affects how you respond to bacteria.
That was NOD2. And that was an exciting discovery in , because it was the first genetic discovery for a complex gene disease, and that disease happened to be Crohn's disease.
Rick: And what was the next one you described? Walters: Another one was a recent one that was published from one of my colleagues here at the Hospital for Sick Children, Dr. Aleixo Muise, and that was a thing called PTPsigma. Now that's exciting for today's talk because this is a gene which we think is related specifically to ulcerative colitis, and what Dr. Muise has demonstrated is that this protein has a lot to do with how the cells of the mucosa walls stick together and how they stop the intestinal leakages from happening.
And could you briefly touch on the others that have been identified that people might want to know about or maybe they are going to hear about? Walters: Probably the exciting one in the recent year is this thing called IL The IL stands for interleukin, and interleukin is one of the chemicals of inflammation, and we found that there was a defect in the way that this was produced, which again seemed to be mostly associated with Crohn's disease, although there is a question as to whether it has some relationship in ulcerative colitis as well.
Walters: An earlier discovery was a thing called DRG5. Now, like all discoveries, some people believe it, some people don't believe it. Some studies have found it to be obviously there; other studies have not been able to replicate it. And this is where you will start seeing a common pattern in genetics, because it probably matters who you look at and where you are looking at as to whether a gene is important or not.
Now, when you look at what this gene does, it's a little bit like PTPsigma. It's all to do with how cells stick together.
Walters: Another one is called MDR1. MDR1 stands for multi-drug resistant number one gene, and despite its name, it probably doesn't have a whole lot to do with drugs but has to do with how the body can make chemicals to fight off bacterial infections or products made by the bacteria which make it into your gut. Again, that would tie into this idea that there is something about the interaction between normal bacteria and you not being able to deal with it.
Rick: So those are just a few of the ones that may be the greatest hits of the genes you have identified so far to be associated with colitis and others forms of IBD.
Walters: Yeah, they are the interesting ones. I mean, every week you start reading about new genes, and it's almost impossible to keep up with what the common ones are or what the best ones are. And I think it depends a little bit on the part of the world you are in as to which ones make people the most excited.
Well, I understand also that in terms of an ethnic population, the Ashkenazi Jewish population has a higher risk and a higher occurrence for colitis.
Has genetic research been able to identify why? This results in swelling and redness inflammation of body tissue in the infected area. Genetics It also seems inherited genes are a factor in the development of ulcerative colitis.
It's believed many of these genes play a role in the immune system. Environmental factors Where and how you live also seems to affect your chances of developing ulcerative colitis, which suggests environmental factors are important. This suggests that reduced exposure to bacteria may be an important factor. Several of the genes that may be associated with ulcerative colitis are involved in the protective function of the intestines.
The inner surface of the intestines provides a barrier that protects the body's tissues from the bacteria that live in the intestines and from toxins that pass through the digestive tract. Researchers speculate that a breakdown of this barrier allows contact between the intestinal tissue and the bacteria and toxins, which can trigger an immune reaction.
This immune response may lead to chronic inflammation and the digestive problems characteristic of ulcerative colitis. Other possible disease-associated genes are involved in the immune system, particularly in the maturation and function of immune cells called T cells. T cells identify foreign substances and defend the body against infection. Certain genetic variations may make some individuals more prone to an overactive immune response to the bacteria and other microbes in the intestines, which may cause the chronic inflammation that occurs in ulcerative colitis.
Another possible explanation is that ulcerative colitis occurs when the immune system malfunctions and attacks the cells of the intestines, causing inflammation. The inheritance pattern of ulcerative colitis is unknown because many genetic and environmental factors are likely to be involved.
Even though the inheritance pattern of this condition is unclear, having a family member with ulcerative colitis increases the risk of developing the condition. Genetics Home Reference has merged with MedlinePlus. Learn more. The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.
Ulcerative colitis.
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