William Whitehead PhD
Co-Director UNC Chapel Hill FGID

NIH Grant to Study Genetic Risk Factors for IBS

The Center was recently awarded a 5-year, $3.3 million grant from the National Institutes of Health (NIH) to study genetic risk factors in irritable bowel syndrome. This represents a competitive renewal of the “Psychophysiology of Irritable Bowel Syndrome” grant (R01 DK031369) which Dr. Whitehead has held for more than 20 years. Each of the 5-year cycles of this grant has built on previous grants from the NIH.

In the most recent 5-year cycle, we tested the hypothesis that IBS is not a single disorder but represents a collection of health problems with different causes that produce similar symptoms. By systematically collecting information on more than 50 physiological and psychological variables from 300 IBS patients and 60 healthy individuals, we were able to identify 4 different phenotypes or clusters of IBS patients: one group was defined by pain hypersensitivity, a second group had high levels of psychological distress but few physiological abnormalities, and the third and fourth groups were defined by predominant bowel habits of constipation and diarrhea. The symptoms and physiological findings that distinguish these IBS patient subgroups from each other were stable over years of follow-up. These results strongly support the notion that IBS has different causes for different clusters (subgroups) of patients, and that simple tests may in the future be able to show which IBS cause is at work in each patient.

In the previous grant we collected DNA from our subjects but did not have enough funding to test genetic risk factors except for the serotonin reuptake transporter gene. The new grant will enable us to carry out a systematic genetic analysis of the previous samples and to collect DNA and physiological and clinical data from a new sample of 300 IBS patients and 300 healthy controls. The goals of the new 5-year grant project are (1) to identify particular genetic patterns (i.e., certain polymorphisms) that are associated with each of the clusters of IBS patients found in our previous study and show that these are also found in the new sample; (2) to develop, for each of the clusters of IBS patients, a causal model to explain how IBS is generated, that includes gene-environment interactions as well as interactions between genes; and (3) to refine and validate these causal models through advanced statistical techniques such as structural equation modeling.

The importance of this research is that it may eventually improve the treatment of IBS. If there are different underlying causes for symptoms in subgroups of patients, it is likely that they will respond to different treatments. Our hope is that this research will eventually enable us to individualize treatment by using simple tests to match patients to the treatments that are most likely to benefit them.

This study of genetic risk factors is technically complex and involves three teams of research staff: The phenotyping group which tests and identifies the patient subgroups includes investigators with expertise in GI physiology (Bill Whitehead, Motoyori Kanazawa, Lisa Gangarosa, and Doug Drossman) and psychology (Miranda van Tilburg and Oli Palsson), as well as research nurses (Lenore Keck and Jane Tucker) who do the actual testing. The genetics team includes Tope Keku, Luda Diatchenko, and William Maixner. Data management is overseen by Oli Palsson with assistance from Gae Caudill, and study administration is the responsibility of Bill Whitehead and Marsha Turner. This area of research interest, supported by 20 years of grant support from NIH, has led to a number of publications, including the following:

•  Dorn SD, Palsson OS, Thiwan SIM, Kanazawa M, Clark WC, Van Tilburg MAL, Drossman DA, Scarlett Y, Levy RL, Ringel Y, Crowell MD, Olden KW, Whitehead WE. Increased colonic pain sensitivity in irritable bowel syndrome is the result of an increased tendency to report pain rather than increased neurosensory sensitivity. Gut 2007;56:1202-1209. PMID 17483191.

•  Whitehead WE, Palsson OS, Levy RL, Feld A, Turner M, Von Korff M. Comorbidity in irritable bowel syndrome. Am J Gastroenterol 2007;102:2767-76. PMID 17900326.

•  Grover M, Kanazawa M, Palsson OS, Drossman DA, Whitehead WE. Small intestinal bacterial overgrowth in irritable bowel syndrome: Association with colon motility, bowel symptoms, and psychological distress. Neurogastroenterology Motil 2008;20:998-1008. PMID 18482250.

•  Kanazawa M, Palsson OS, Thiwan SIM, Turner MJ, Van Tilburg MAL, Gangarosa LM, Chitkara DK, Fukudo S, Drossman DA, Whitehead WE. Contributions of pain sensitivity and colonic motility to IBS symptom severity and predominant bowel habits. Am J Gastroenterol 2008;103:2550-61. PMID 18684175.