This proposal is directed toward the elucidation of the genetic susceptibility to the duodenal ulcer diseases using subclinical and polymorphic genetic markers. Though genetic factors have been acknowledged to play a role in the etiology of duodenal ulcer, only recently have promising subclinical markers and genetic heterogeneity been recognized. We propose to confirm and extend our preliminary findings that duodenal ulcer is genetically heterogeneous and can be separated into more homogeneous disorders by the study of subclinical markers in families. We propose, over a 4-year period, to study 200 duodenal ulcer patients and 800 of their first degree relatives for the most promising subclinical and genetic markers presently available - serum pepsinogen I and II, fasting and stimulated gastrin, ABO blood type, secretor status, urinary pepsinogen phenotype, alpha-1-antitrypsin, gastric emptying, and thyrogastric antibodies. By identifying the aggregation of the subclinical markers, and performing segregation and linkage analyses we will: 1) test if duodenal ulcer is genetically heterogenous and can be separated into more homogeneous subgroups using subclinical and genetic markers in families, 2) examine the mode of inheritance of the more specific subgroups, 3) determine whether any of the gene marker associations, blood group 0, nonsecretor status, urinary pepsinogen phenotype A, alpha-1-antitrypsin, are more prominent within specific subgroups, 4) perform genetic marker linkage analysis on the specific duodenal ulcer subgroups with the four gene marker systems, and 5) test the hypothesis of an immunologic form of duodenal ulcer by examining whether subclinical markers of gastritis are found in duodenal ulcer families. Thus, these studies are directed toward verification of our preliminary evidence for genetic heterogeneity of the duodenal ulcer diseases, and toward determination of the mode(s) of inheritance of each component disorder. The ultimate goal of these studies is to develop the means of identifying those individuals in the population who are at genetically high risk for duodenal ulcer. The resultant subclinical markers will be invaluable for the investigation of individual pathogenetic mechanisms, for the study of the interaction of genetic and environmental factors, and for the development of more specific modes of therapy and prevention.
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