Dr. Susan Neuhausen is leading an NIH-funded grant to identify non-HLA genes causing celiac disease. Celiac disease (also known as sprue, gluten-sensitive enteropathy, gluten intolerance, or celiac sprue) is a common familial autoimmune disease. She and her colleagues and staff have been studying celiac disease for the past 8 years. The study is designed to identify factors associated with celiac disease and to find genes that may predispose individuals and their relatives to develop this condition. The discovery of such genes may one day lead to better diagnosis, treatment, and possibly even prevention of celiac disease. For this study, they are enrolling families with celiac disease. Families eligible to participate must have at least two relatives (with the exception of simple parent-child pairs) diagnosed with celiac disease or dermatitis herpetiformis by at least one of the following methods: a positive small intestinal biopsy, a positive IgA anti-tissue transglutaminase (tTG) antibody test, a positive IgA anti-endomysial (EMA) antibody test, or a positive skin biopsy (for dermatitis herpetiformis). After meeting the eligibility criteria to enroll a family, all first-degree relatives of those who have been diagnosed with celiac disease or dermatitis herpetiformis will be invited to participate in the study. Participants will receive a free antibody test for screening of celiac disease if they are not currently on a gluten free diet and have not recently been tested for celiac disease.

Celiac disease is now recognized to be a common disease, with a disease frequency of 1:133 to 1:250 in the US. Before the advent of serological testing, it was considered a rare disease. It is a familial, autoimmune disease, with significant morbidity if untreated. It is caused by sensitivity to the dietary protein gluten, which is present in wheat, rye and barley. The term gluten-sensitive enteropathy refers to the histologic abnormality of the small intestine, which ranges from minimal lymphocytic infiltration of the intestinal epithelium to severe atrophy of the villi. It results in intestinal malabsorption of nutrients. Dermatitis herpetiformis is the skin manifestation of celiac disease. Celiac disease is one of the most significant causes of chronic malabsorption in children. Symptoms include growth failure, abdominal pain, and diarrhea. The majority of people presents with minimal symptoms or signs. Complications of this disease include lymphoma, osteoporosis, anemia, pregnancy problems, and seizures. The only treatment is a gluten-free diet, which will improve symptoms, but recurrence of symptoms and complications may occur after minor dietary indiscretions.

Celiac disease has a strong genetic association with the HLA class II DQ2 genotype composed of the DQA1*05 and DQB1*02 alleles. This genotype is found in greater than 90% of Northern European celiac disease patients and in approximately 12-26% of controls. However, the HLA association alone is insufficient to explain the hereditary nature of the disease, and is estimated to explain less than half the sibling risk, indicating the presence of one or more additional susceptibility loci. Celiac disease may serve as a model for autoimmune diseases because, in contrast to most other HLA-associated autoimmune diseases, the trigger (gliadin) and the highly specific autoimmune response (autoantibodies to tissue transgluaminase) are known. Furthermore, the familial risk is higher than in other autoimmune diseases.

The overall goal of our study is to identify genes that cause celiac disease. Our specific aims are to: 1) continue to collect families with multiple cases of celiac disease, including Bedouin families with our Israeli collaborator; 2) perform a genome-wide search and linkage analysis in the families to identify regions harboring genes; 3) follow-up genetic regions with evidence for linkage from the genome-wide analysis through a multi-stage approach of additional genotyping and more complex statistical analysis in order to confirm regions; and 4) refine localization in regions with significant evidence for linkage by a combination of transmission disequilibrium testing and recombinant mapping in order to next isolate the actual gene. We now have one of the largest, most powerful family resources with which to localize genes for this complex disease.

Once genes for celiac disease are identified, we will be able to define genotype/phenotype correlations and better understand the immunopathogenesis of celiac disease and possibly, its associated autoimmune diseases. This knowledge could eventually lead to the development of preventative strategies and therapies directed at the molecular defect(s). Development of a genetic diagnostic test for celiac disease could prevent the current situation in which family members are self-diagnosed and are unnecessarily adhering to a gluten-free diet.

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2. Book L, Hart A, Black J, Feolo M, Zone JJ, Neuhausen SL: (2001) Prevalence and clinical characteristics of celiac disease in Down syndrome in a U.S. study. Am J Med Gen, 98: 70-74.
3. Feolo M, Fuller TC, Taylor M, Zone JJ, Neuhausen SL: (2001) A strategy for high throughput HLA-DQ typing. J Immunol Methods, 258: 65-71.
4. Neuhausen SL, Feolo M, Farnham J, Black J, Book L, Zone JJ: (2001) Linkage analysis of HLA and candidate genes for celiac disease in a North American family-based study. BMC Med Genet, 2 (1):12.
5. Neuhausen SL, Weizman Z, Camp NJ, Elbedour K, Sheffield VC, Zone JJ, Carmi R: (2002) HLA DQA1-DQB1 genotypes in Bedouin families with celiac disease. Hum Immunol, 63: 502-507.
6. Neuhausen SL, Feolo M, Camp NJ, Farnham J, Book L, Zone JJ: (2002) Genomewide linkage analysis for celiac disease in North American families. Am J Med Gen, 111:1-9.
7. Book L, Zone JJ, Neuhausen SL: (2003) Prevalence of celiac disease among relatives of sib pairs with celiac disease in US families. Am. J. Gastroenterol. 98:377-381.