Testing for colon neoplasia susceptibility variants at the human COX2 locus

Background: Siblings and other first-degree relatives of patients with "spo radic" (i.e., apparently nonfamilial) colorectal cancer or precursor adenom atous colon polyps have an increased risk of developing colon neoplasia. Th is observation suggests the presence of inherited genetic determinants for sporadic colon neoplasia. Mice homozygous for a null cyclooxygenase 2 (COX2 ) (also called PTGS2) allele have a dramatically reduced susceptibility to the development of intestinal adenomas. In humans, use of pharmacologic inh ibitors of COX2 enzyme activity are associated with reduced risk of colon n eoplasia. This study examined whether the human COX2 locus may be linked to colon neoplasia in humans. Methods: We used the affected sibling-pair meth od to test for linkage of the human COX2 locus to colon neoplasia. Results: We examined 74 concordantly affected sibling pairs from 46 sibships with c olon neoplasia. One hundred five siblings from these sibships were diagnose d with either colorectal cancer or colon adenomatous polyps before age 65 y ears. No linkage between COX2 and colon neoplasia was found by use of a mul tipoint model-free linkage analysis (estimate of allele sharing was 0.44; s tandard error = +/-0.04; 95% confidence interval = 0.36 to 0.52). Moreover, even allowing for heterogeneity, the potential that a COX2 colon neoplasia susceptibility variant was present within a substantial subset of these si bships was strongly excluded under either a recessive or a dominant inherit ance model (95% confidence to exclude a model in which 2.7% or more of the sibling pairs harbor a dominant susceptibility allele). Conclusions: This s tudy of concordantly affected sibling pairs thus demonstrates that variatio ns in the COX2 gene are unlikely to be a source of individual susceptibilit y to colon neoplasia in humans.