Dr. Richard Spritz, a pediatrician and geneticist at the University of Colorado, is an interesting guy who not only does important research in genetics, but also does vintage car racing as a hobby (see arrows in pictures above, LEFT driving a 1967 Porsche 912, RIGHT at our dinner table in Rome for the Vitiligo International Symposium). He recently published his third genomewide association study (GWAS) to identify genes involved in the development of vitiligo. It was a beautiful study, which added another 23 risk alleles (genes that increase the risk of getting disease), increasing the total known vitiligo susceptibility genes to about 50. This effort represents many years of work, and collaboration with physicians from all over the world who helped to recruit patients to donate their DNA, enabling the studies to identify these genes.
Why is this so important? Well, we know that most of the risk of getting vitiligo is genetic, because relatives and identical twins of vitiligo patients have a higher likelihood of getting vitiligo than the general population. This means that part of the risk of getting disease is coded in our genes. But we also know that the genes don't completely determine getting the disease, similar to other diseases such as heart disease and cancer. Even though reading your genes can’t tell you for sure whether you’ll get vitiligo, understanding which ones influence getting the disease tells us a lot about what causes it, and maybe gives us clues into how to better treat it.
I spend a lot of time discussing Dr. Spritz’s results with him at meetings, and thought it might be best to let him tell you about these latest results in his own words. So I sat down with him and asked him a few questions, which are listed along with his answers below!
Me: This is your 3rd GWAS study to find genes involved in vitiligo. Why have you reported the results in separate studies over the years? Why not just do one big study?
Dr. Spritz: That is simply not how science is done. Each study is self-contained. That is always true in science. But an important feature of the GWAS approach is that the results of each GWAS can be directly added to the results of previous GWAS to discover more than any one study could alone. Doing this provides greater “power” to discover new genes, greater “precision” to discover what are the gene differences that relate to causing vitiligo, and help verify (or refute) previous conclusions about specific genes.
Me: How many vitiligo patients did it take to find all these genes? Where did they come from?
Dr. Spritz: The total three GWAS studies involved about 5000 vitiligo patients, or “cases”, and about 40,000 non-vitiligo “controls”.
Me: Now that you’ve done all this work, what can you tell us about the role of genetics in getting vitiligo? How important are genes in this disease?
Dr. Spritz: Well, we actually knew the answer to this even before we started formal genetic studies. About 20 years ago we and others carried out studies to define the epidemiology of vitiligo. It turns out that about three-fourths of the risk of getting vitiligo is determined by genes. Geneticists call this “heritability”, which for vitiligo appears to be about 75%. The genes we’ve discovered account for about a quarter of this risk. That is quite a lot, compared to other such “complex diseases”. It is a major puzzle what determines the rest of the genetic risk. Is it more genes, with even smaller effects? Is it other specific abnormalities of these genes, different in different people (which are very hard to detect scientifically)? Is it specific high-risk combinations of gene abnormalities? We simply don’t know.
Me: When you find “vitiligo genes” they’re called “risk alleles”. What does that mean?
Dr. Spritz: There are many genetic differences in the genome; that is what makes us all different. Equivalent spots in the genome, at which there are specific differences in different people, are called “alleles”. When one does a genetic study of disease risk in people, one is basically studying one spot in the genome at a time, comparing what is predominantly there in cases to what is predominantly there in controls, statistically speaking, looking for differences in disease risk. So, if we find a spot in the genome where genetic differences between people correlate with differences in disease risk, we call the alternative versions “risk alleles”. Some increase risk, while others decrease risk; these latter are called “protective”.
Me: Can we assume that the more of these vitiligo risk alleles that someone has, the more likely they’ll get vitiligo? That someone who inherited 25 out of 50 is at a higher risk than someone who inherited 10 out of 50, for example? What if someone has just one of these genes?
Dr. Spritz: No, that is not correct. And I don’t know the answer to your question. As yet, we don’t know. You can think of what we’ve done as defining the major “parts list” for vitiligo. From that “parts list”, we’ve been able to start to build a vitiligo “blueprint”, though pieces are still missing and we’ve probably put some parts together incorrectly. What you are asking is how does the vitiligo “instruction manual” work? We’re a long way from having a vitiligo instruction manual. That will be necessary before we can do vitiligo “personalized medicine”.
Me: What’s the most important gene to vitiligo that you’ve found?
Dr. Spritz: I don’t think there is one that is “most important”. There is in type 1 (childhood) diabetes, for example. But there really isn’t one that stand out as “most important” for vitiligo. That makes the blueprint and instruction manual all the more important for understanding what is really going on in vitiligo.
Me: I’ve heard you talk about genetic overlap between vitiligo and other autoimmune diseases. Is this true for the new set of genes you’ve discovered? What are the implications of this overlap?
Dr. Spritz: Yes, about a third of the vitiligo susceptibility genes we’ve identified have also been found in GWAS of other autoimmune diseases. This is especially true for the specific autoimmune diseases we and others have shown occur at higher frequencies in vitiligo patients and their relatives: autoimmune thyroid disease (Hashimoto thyroiditis and Graves’ disease), type 1 diabetes, rheumatoid arthritis, pernicious anemia, Addison’s disease, systemic lupus erythematosus, and perhaps coeliac disease. From a genetic standpoint, vitiligo looks quite a bit like type 1 diabetes. That means that these diseases share genetic underpinnings and thus have a lot of biology in common, and so treatments and preventions that are developed for one may also work for others of these diseases.
Me: What was the biggest surprise to you from these studies?
Dr. Spritz: The biggest surprise was that many genes turned up that either are components of melanocytes or that regulate melanocyte function. That shouldn’t have been a surprise, really, since melanocytes are the immune system targets in vitiligo, and all autoimmune diseases involve intimate relationship between the immune system and the target tissues. However, in vitiligo those same genes have also been shown to mediate risk of melanoma. Furthermore, in every case, the vitiligo risk alleles and melanoma risk alleles are opposite. We think that may mean that vitiligo is protective with respect to melanoma, and even that vitiligo may represent a normal process of protecting us from early melanomas, which has somehow gone awry.
Me: I noticed in your reports that you list “gene deserts” as risk alleles for vitiligo. What is a gene desert?
Dr. Spritz: Gene deserts are areas of the genome in which there are clear risk alleles, but there are no genes. And in fact, the regions are so big it is hard to even imagine they contain control points for nearby genes, since there are no genes nearby. Again, this has been found for almost every complex disease such as vitiligo, and they are total puzzles. Fortunately, we have very few gene deserts in vitiligo. The great majority of vitiligo risk alleles turn out to be within or very close to genes, and most of those genes make good sense with respect to potential vitiligo biology.
Me: What’s the next step after finding these genes? Are you going to look for more? Is there a way to find out what these genes are actually doing in vitiligo?
Dr. Spritz: Speaking only for myself, I don’t plan to search for many more vitiligo susceptibility genes. I think we’ve already picked the low-hanging fruit. If we can’t figure out what we already know, I’m not sure it makes sense to just keep going after more. My goals are to figure out what are the exact risk alleles of these genes, figure out how those alleles contribute to risk, figure out how what are the high and low-risk combinations, and why that is the case in terms of major biological pathways of vitiligo, and identify potential novel treatment targets.
Me: This has been great, thank you Rich. Anything else you want to tell us before we go?
Dr. Spritz: For any patients reading this who actually participated in our studies, thank you. We have come a very long way, to the point that we are starting to really understand how vitiligo works, and so how it might be treated or even prevented. None of this would have been possible without your help.