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After reading this case study, you should be able to
- Identify key characteristics of the study population (cases and controls) that should be described when reporting results of gene-disease association studies.
- Summarize gene-disease associations in terms of absolute, relative and attributable risks.
- Discuss possible implications of the findings for researchers, people with Crohn disease, and people with one or more of the newly described
NOD2 variants.
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Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract that commonly presents with recurrent abdominal pain, diarrhea, and rectal bleeding. Most affected people receive a clinical diagnosis of either Crohn disease or ulcerative colitis, depending on the pattern of symptoms and the results of radiologic, endoscopic, and histologic examinations. Crohn disease usually involves the small bowel, whereas ulcerative colitis is limited to the colon; however, up to 10% of patients with colitis have “indeterminate” IBD because they have some features of both disorders. No system of diagnostic criteria has been universally adopted.
Crohn disease usually begins in late adolescence or early adulthood and follows an erratic course of relapse and remission. Anti-inflammatory drugs (particularly sulfasalazine and glucocorticoids) are mainstays for preventing and managing intermittent exacerbations. Antibiotics are often used empirically, but few controlled studies have been conducted to evaluate their efficacy. Although surgery is eventually necessary in most patients, it is not curative. People with Crohn disease have near-normal life expectancy, but the early onset of illness, severe complications, and side effects of long-term therapy produce significant morbidity.
Factors in the etiology and pathogenesis of Crohn disease have remained frustratingly obscure despite 50 years of clinical and laboratory investigation. Epidemiologic studies suggest a role for environmental factors (such as diet, smoking, infectious agents, stress, higher socioeconomic status, and geography) and regularly demonstrate family clustering, although without a clear pattern of inheritance. Thus, Crohn disease is thought to result from a complex interaction between genetic susceptibility and environmental exposures.
Recent advances in molecular biology have intensified the search for genetic factors and pathogenetic mechanisms in Crohn disease and ulcerative colitis. In 1996, Hugot et al. reported the results of a genome-wide linkage analysis that identified a susceptibility region on chromosome 16, which they termed IBD1. In 2001, Ogura et al. identified the NOD2 gene, mapped it to chromosome 16q12, and demonstrated that it activated nuclear factor kappa B (NF-kB), a component of the innate immune response.
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