Researchers and clinicians have widely noted an intriguing link between some intestinal diseases and some forms of arthritis. In particular, chronic inflammatory bowel disease (IBD) frequently afflicts patients with ankylosing spondylitis (AS), marked by chronic inflammation of the spine and the sacroiliac joints. Separately, both IBD and AS have been shown to run in families. Yet, the specific genetic susceptibility, and whether it is the same for both diseases, remains a mystery.
For studying the genetic links between IBD and AS, the citizens of Iceland are an ideal population. In contrast to not just Americans but most other Europeans, Icelanders are strikingly homogeneous with respect to environmental, cultural, and genetic factors. What's more, Iceland boasts an extensive genealogic database, collected by deCODE Genetics, containing records on every family in the country, plus registries of all patients diagnosed with IBD and AS spanning 50-year periods, along with a highly accessible health care system.
Leveraging these resources, researchers at Landspitali University Hospital, Reykjavik, assessed the occurrence of IBD and AS among relatives and the risk of inheriting either and both disorders. Their results, featured in the August 2007 issue of Arthritis & Rheumatism, provide compelling evidence of a common genetic component for IBD and AS.
Comparing the data on all living Icelanders diagnosed with AS, 205 individuals, and all diagnosed with IBD, 1,352 individuals, with the body of genealogic data on over 790,000 Icelanders, the researchers found significant clustering of each condition within families, extending over 6 generations. To strengthen these findings, they calculated the risk ratio of each disorder for a relative of an affected person, including spouses, as compared with the risk in the population as a whole, for 10,000 sets of matched control subjects.
They also performed cross-risk ratios of AS for relatives of patients with IBD and of IBD for relatives of patients with AS. Finally, they calculated the kinship coefficient (KC) -- the probability that any 2 alleles, genes with specific positions on specific chromosomes, are inherited from one common ancestor -- for all the patients with IBD and all the patients with AS, and compared the KC values with 100,000 sets of matched control subjects.
First-, second-, and third-degree relatives of patients with AS had risk ratios of 94, 25, and 3.5, respectively, indicating an increased risk of developing AS, while first-, second-, and third-degree relatives of patients with IBD had risk ratios for IBD of 4.4, 2.2, and 1.4, respectively. In addition to confirming the genetic risk for AS and IBD independently, the study found elevated cross-risk ratios between IBD and AS in both first- and second-degree relatives.
The cross-risk ratios for IBD in first- and second-degree relatives of patients with AS were 3.0 and 2.1, respectively, and, notably, were the very same for AS in first- and second-degree relatives of patients with IBD. Overwhelmingly, findings applied to blood relatives. Risk ratios for spouses were zero to insignificant. The one exception was an increased risk of having Crohn's disease in spouses of patients with Crohn's disease, suggesting the possible role of an environmental factor.
Based on KC values, patients with IBD were more likely to be related to each other than to population controls. The KC was significant in relatives up to the fourth generation. Similar to the findings from the risk analyses, even stronger relationships among AS patients were evident throughout the first three generations. Furthermore, patients with IBD and patients with AS were more closely related to each other, even after exclusion of second-degree relatives -- grandparents, grandchildren, and first cousins -- than were population controls.
While this study indicates an inherited bond between the risk of AS and IBD, the nature of this genetic abnormality is speculative. "Our results provide strong evidence that a molecular-genetic approach should be utilized in patients with these diseases," observes the study's lead author, Dr. Bjarni Thjodleifsson. "If this approach proves successful, this will open the possibility of identifying a common early pathophysiologic event in both AS and IBD that may be amenable to new and selective treatments."
Article: "A Common Genetic Background for Inflammatory Bowel Disease and Ankylosing Spondylitis: A Genealogic Study in Iceland," Bjarni Thjodleifsson, Αrni J. Geirsson, Sigurdur Bjφrnsson, and Ingvar Bjarnason, Arthritis & Rheumatism, August 2007; (DOI:10.1002/art.22812).
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