Lin Henry J, Lakkides Karen M, Keku Temitope O, Reddy Srinivasa T, Louie Andrew D, Kau Irving H, Zhou Haiyan, Gim Jason S Y, Ma Hoang L, Matthies Carl F, Dai Aihua, Huang Hsiao-Fen, Materi Alicia M, Lin Jesse H, Frankl Harold D, Lee Eric R, Hardy Steven I, Herschman Harvey R, Henderson Brian E, Kolonel Laurence N, Le Marchand Loïc, Garavito R Michael, Sandler Robert S, Haile Robert W, Smith William L
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, USA.
Cancer Epidemiol Biomarkers Prev. 2002 Nov;11(11):1305-15.
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.
前列腺素H合酶2（也称为环氧化酶-2）被认为在阿司匹林（该酶的一种抑制剂）预防结肠癌中发挥作用。我们使用DNA异源双链分析来筛选前列腺素H合酶2基因，以寻找可能模拟阿司匹林作用的天然存在的酶变体。我们在非裔美国人中发现了一种单核苷酸多态性，该多态性在第511位残基处将缬氨酸变为丙氨酸（V511A；GTT>GCT；g.5939T>C；等位基因频率0.045）。这种多态性在亚洲印度人中也有发现（等位基因频率为0.03），但在中国、菲律宾、西班牙、日本、韩国、萨摩亚和白种人中未发现。预测该氨基酸变化会在酶的活性位点附近打开一个53立方埃的空腔，但在COS-1细胞转染实验中未观察到变体酶的V(max)、K(m)或热稳定性有变化。对来自两个不同研究人群的非裔美国人进行病例对照分析显示，多态性携带者患结直肠腺瘤的优势比为0.56（95%置信区间，0.25-1.27；161例病例和219例对照）。对嵌套在多族裔队列研究中的非裔美国人进行的类似分析显示，患结肠癌的优势比为0.67（95%置信区间，0.28-1.56；138例病例和258例对照）。所有三项研究结果的一致性可能与该多态性的保护作用相符，类似于阿司匹林。
