Dr. Judy Cho (left) and B. Monica Bowen

Yale School of Medicine researcher delves into Jewish connection to Crohn’s Disease

By Cindy Mindell

NEW HAVEN – First identified by physicians at Mount Sinai Hospital in New York in 1932, Crohn’s disease is a type of inflammatory bowel disease and is characterized by intestinal inflammation causing pain, diarrhea, and weight loss. The Center for Disease Control estimates that more than 600,000 Americans have the disease; currently, there is no permanent cure.

Research beginning in the 1990s has shown that Crohn’s disease is five to seven times more prevalent among Ashkenazi Jewish individuals, and that siblings and children of Jewish patients with Crohn’s disease are more likely to develop the condition than relatives of non-Jewish patients. Although the reasons for this difference are poorly understood, they are almost certainly genetic, rather than the result of behavior or environment.

Dr. Judy Cho of the Yale School of Medicine is the Henry J. and Joan W. Binder Professor of Medicine (Digestive Diseases) and Professor of Genetics and of Pediatrics (Gastroenterology), and director of the Inflammatory Bowel Disease Center. She is principal investigator in the school’s work on the genetics of inflammatory bowel disease (IBD).

Cho’s current research demonstrates overlaps between genes related to IBD and those related to fighting bacteria, therefore suggesting a historical connection between the two diseases. Specifically, it is conceivable that tuberculosis, which was a major presence in human civilization throughout history, drove natural selection to favor people with more active immune systems. Around 100 years ago, when tuberculosis was eliminated as a major health concern in the developed world, those overactive immune systems, without any infection to fight, manifested as autoimmune diseases – notably Crohn’s.

B. Monica Bowen is a senior graduate student in the Biological and Biomedical Sciences PhD Program at Yale. Her thesis work on population differences in the genetic architecture of Crohn’s disease is being conducted in the Department of Genetics, one of the departments in which Cho has a professorial appointment.

Bowen spoke with the Ledger about her work with Cho and the new understanding that is emerging around Crohn’s.

Q: Aside from Ashkenazi Jews, are there other ethnic groups among whom Crohn’s is prevalent? In those cases, is it a genetic disease?

A: There have been a number of epidemiologic studies done in different populations over the years, and in each case, the prevalence of Crohn’s Disease (CD) is highest in the Ashkenazim – about six times more common than the next most-affected population, Europeans. Interestingly, there hasn’t been a significant difference in the prevalence of CD between Orthodox and Reform Jews, suggesting that the disease risk is not driven primarily by environmental or behavioral differences. Even among populations where CD is less prevalent – for example, in Hispanic populations – there is still evidence of a genetic component. We know this because we collect information from families, and the risk of developing Crohn’s if you have a sibling with the disease – what we call the “sibling relative risk” – is much higher than the risk of developing the disease if you have no affected siblings – what we call the “population risk.” The risk is even higher if the sibling is an identical twin. When sibling relative risk is much higher than population risk, that indicates that the disease has a genetic basis. What we are interested in is, what genes explain the much higher prevalence of CD in the Ashkenazim, and how did those genes become so common in the population?

Q: How did you each develop an interest in this work?

A: I developed an interest in the genetics of immune-mediated diseases when I was an undergraduate at the University of Chicago. It fascinated me to learn about how evolutionary histories and population migrations shaped our current patterns of DNA. Some might consider genetics to be a very “on” or “off,” “present” or “absent” kind of science, but that applies mostly to Mendelian genetics, where one gene determines whether or not you develop the disease. Immune-mediated diseases like Crohn’s disease are complex genetic diseases, because our immune system is complex: there are hundreds, some would say thousands, of genes involved in regulating the inflammatory response. And these genes don’t exist in a vacuum; our bodies receive and interpret signals from the environment that influence what our genes are doing. This is especially true in the gut, which has the largest distribution of immune cells in the body, and spends the most time in contact with whatever we ingest from our environment. The key part is figuring out not if a disease is genetic or environmental – because it is both; the interesting part is determining what environmental factor(s) influence the genetics of immunity, and how.

I recall that Dr. Cho gave a presentation on a newly discovered CD gene at the American Society of Human Genetics Meeting, and in that presentation she highlighted not only how that gene was involved in Crohn’s, but how it interacted with every other known gene involved in Crohn’s, and I thought to myself, “Wow, she really sees the big picture. It would be great to work with someone like her…” so I started working with her. It’s very rewarding to work with someone who is so committed to understanding the unknown, and it’s exciting to be asking questions no one has asked before, and getting answers no one could have imagined.

Q: What is your role in this research?

A: The majority of my work is performed in Dr. Cho’s laboratory and centers around analyzing blood samples from different populations, which provides us with a lot of information we can use to study Crohn’s disease. With one blood sample, we can isolate DNA to identify new mutations associated with the disease in each population, we can measure serum levels for inflammatory markers in the blood, and we can compare the activity of different immune cells, like macrophages and lymphocytes. My role is to put together all these levels of biological data and create a model that identifies how these genes interact in healthy people compared to CD patients across populations. Patient-derived blood cells are crucial because with those we can actually answer some of the “how” questions related to CD. Better still, with DNA from each population, we can reconstruct the history of that population to identify genes that were essential at specific times in the past, which can help us explain why some versions of genes became so common in some populations, like the Ashkenazim.

Q: What are some treatments or studies that look promising in the quest to cure Crohn’s?

A: Currently the main therapeutic option available for Crohn’s patients is anti-TNF therapy, which is a blanket immunosuppresant. The caveat is that, while this therapy greatly reduces inflammation, it makes you more susceptible to bacterial and fungal infections, and it doesn’t work for everyone. Our genetic studies have identified other genes that are significantly associated with CD, and one of those genes is currently being investigated as a drug target in clinical trials. Our experience, and our expectation, is that genetics research points us to more specific and effective drug targets that can expand and improve treatment options for Crohn’s patients.

Q: Are you still seeking participants in your research?

A: At the Yale University Inflammatory Bowel Disease Program, we have been pulling together expertise in various fields to study this question and understand specifically the reasons for the greater Crohn’s disease risk in the Ashkenazim. We are actively recruiting healthy people and CD patients for our genetics research, because the more people we study, the more we learn about this disease. There are genetic interactions that are not detectable if you study 10 people, but if you study 1,000 people, or 10,000 people, you have a much fuller picture of the mechanisms involved. We are planning a blood drive at the Slifka Center at Yale this August so that we can raise awareness about Crohn’s disease and encourage public participation in research, which is truly essential in order to discover anything of clinical use.

We invite individuals of Ashkenazi Jewish heritage who have been diagnosed with Crohn’s disease or have no family history of the disease to participate in our research via mail or in person at no cost; interested participants will be reimbursed for their time and can contact us at ibd@yale.edu / (203) 785-7573.

 Comments? email cindym@jewishledger.com.