title: Prostaglandin H synthase 2 variant (Val511Ala) in African Americans may reduce the risk for colorectal neoplasia.
abstract: 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.
authors.affiliation: 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. henry_lin@humc.edu
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Lin
authors.forename: Karen M
authors.initials: KM
authors.lastname: Lakkides
authors.forename: Temitope O
authors.initials: TO
authors.lastname: Keku
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Louie
authors.forename: Irving H
authors.initials: IH
authors.lastname: Kau
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhou
authors.forename: Jason S Y
authors.initials: JS
authors.lastname: Gim
authors.forename: Hoang L
authors.initials: HL
authors.lastname: Ma
authors.forename: Carl F
authors.initials: CF
authors.lastname: Matthies
authors.forename: Aihua
authors.initials: A
authors.lastname: Dai
authors.forename: Hsiao-Fen
authors.initials: HF
authors.lastname: Huang
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Materi
authors.forename: Jesse H
authors.initials: JH
authors.lastname: Lin
authors.forename: Harold D
authors.initials: HD
authors.lastname: Frankl
authors.forename: Eric R
authors.initials: ER
authors.lastname: Lee
authors.forename: Steven I
authors.initials: SI
authors.lastname: Hardy
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.forename: R Michael
authors.initials: RM
authors.lastname: Garavito
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sandler
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: William L
authors.initials: WL
authors.lastname: Smith
mesh_terms: D000236:Adenoma / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use; D044383:Black People / Q000235:genetics*; D016022:Case-Control Studies; D003062:Codon / Q000187:drug effects / Q000235:genetics; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency / Q000187:drug effects / Q000235:genetics; D020180:Heteroduplex Analysis; D006801:Humans; D007527:Isoenzymes / Q000145:classification / Q000187:drug effects* / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000145:classification / Q000187:drug effects* / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D020539:Sequence Analysis, Protein; D014162:Transfection; D001741:Black or African American
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003062:Codon; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin