Ulcerative colitis (UC) is a chronic, debilitating, inflammatory disorder of the colon that usually begins in childhood or early adulthood. The causes of UC are not known. Thus, therapy generally involves nonspecific anti- inflammatory and immunomodulator medications, or surgery when medical therapy fails. Epidemiological data suggest that genetic factors are important in the pathogenesis. To understand the pathogenesis, identification of the underlying genetic factors is critical. Identification of UC susceptibility genes may provide direct clues about pathogenetic mechanisms and will permit identification of individuals at risk for developing UC who can then be studied to understand early pathogenetic mechanisms. This can lead to development of specific therapies to treat disease at an early stage or perhaps event prevent disease. Identification of UC susceptibility genes or linked genetic markers will also permit more accurate genetic counseling for affected individuals and their families. The search for UC susceptibility genes is complicated by complex genetics, including incomplete penetrance, probable genetic heterogeneity, and probable multilocus inheritance. However, because the immune system mediates the tissue damage in UC, genes that regulate immunity and inflammation, including the HLA class II genes, are excellent candidates for conferring the genetic susceptibility. In addition, because the HLA class II genes are highly polymorphic and located near many other loci on chromosome six that regulate immunity and inflammation, the HLA class II genes may be excellent genetic markers linked to UC susceptibility genes. Therefore, we hypothesize that susceptibility genes for UC are located in or genetically linked to the HLA class II region. Furthermore, we hypothesize that UC is a genetically heterogeneous syndrome. If UC is genetically heterogeneous, then definition of distinct, genetically more homogeneous UC subsets will greatly simplify identification of the susceptibility genes. Preliminary studies demonstrate associations between specific HLA class II alleles and subsets of the UC syndrome defined by perinuclear ant neutrophil cytoplasmic antibodies (autoantibodies that may be markers of genetic heterogeneity in UC), a family history of UC, and extent of colonic involvement with UC. We now propose to obtain clinical data and blood samples from 200 affected relative pairs with UC; genotype the HLA class II loci and determine perinuclear antineutrophil cytoplasmic antibody status in the UC affected relative pairs; test for linkage between familial UC and the HLA class II loci using the affected pedigree-member method of linkage analysis; determine whether there is increased concordance for perinuclear antineutrophil cytoplasmic antibodies, extent of colonic involvement with UC, or need for colectomy because of medically refractory disease in the affected relative pairs with UC; and stratify the linkage analysis by any parameters that are found with increased concordance in the UC affected relative pairs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK050993-05
Application #
2905838
Study Section
Special Emphasis Panel (SRC (05))
Program Officer
Hamilton, Frank A
Project Start
1995-09-30
Project End
2000-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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