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Prostaglandin H Synthase 2 Variant (Val511Ala) in African Americans May Reduce the Risk for Colorectal Neoplasia¹

Division of Medical Genetics, Department of Pediatrics and the Research and Education Institute at Harbor-University of California Los Angeles Medical Center, Torrance, California 90502 [H. J. L., A. D. L., I. H. K., H. Z., J. S. Y. G., H. L. M., C. F. M., A. D., H-F. H., A. M. M.]; Department of Biochemistry, Michigan State University, East Lansing, Michigan 48824 [K. M. L., R. M.G., W. L. S.]; Division of Digestive Diseases and Nutrition, Department of Medicine, University of North Carolina, Chapel Hill 27599 [T. O. K., R. S. S.]; Division of Cardiology, Department of Medicine [S. T. R.], Department of Pathology and Immunogenetics Center [S. I. H.], and Department of Biological Chemistry and the Molecular Biology Institute [H. R. H.], University of California Los Angeles School of Medicine, Los Angeles, California 90095; Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, California 90089 [J. H. L., B. E. H., R. W. H.]; Department of Gastroenterology, Kaiser Permanente, Los Angeles, California 90027 [H. D. F.] and Bellflower, California 90706 [E. R. L.]; and Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813 [L. N. K., L. L. M.]

Prostaglandin H synthase 2 (also known as cyclooxygenase-2) is thought to play a role in the prevention of colon cancer by aspirin, an inhibitor of the enzyme. We used DNA heteroduplex analysis to screen the prostaglandin H synthase 2 gene, to search for naturally occurring enzyme variants that may simulate the effects of aspirin. We found among African-Americans a single-nucleotide polymorphism that changes valine to alanine at residue 511 (V511A; GTT>GCT; g.5939T>C; allele frequency 0.045). The polymorphism was also seen among Asian-Indians (allele frequency, 0.03) but not among Chinese, Filipinos, Hispanics, Japanese, Koreans, Samoans, and Caucasians. The amino acid change is predicted to open a 53 cubic angstrom cavity near the active site of the enzyme, but no change in V_max, K_m, or thermal stability was observed for the variant enzyme in COS-1 cell transfection assays. Case-control analysis of African-Americans from two different study populations showed a 0.56 odds ratio for colorectal adenomas among polymorphism carriers (95% confidence interval, 0.25–1.27; 161 cases and 219 controls). A similar analysis of African-Americans nested in the Multiethnic Cohort Study showed a 0.67 odds ratio for colorectal cancer (95% confidence interval, 0.28–1.56; 138 cases and 258 controls). Consistency of the results across all three of the studies is potentially compatible with a protective effect of the polymorphism, mimicking aspirin.

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