Prostaglandin H synthase 2 variant (Val511Ala) in African Americans may reduce the risk for colorectal neoplasia.
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.
Lin
Henry J
HJ
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
Lakkides
Karen M
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Keku
Temitope O
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Reddy
Srinivasa T
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Louie
Andrew D
AD
Kau
Irving H
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Zhou
Haiyan
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Gim
Jason S Y
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Ma
Hoang L
HL
Matthies
Carl F
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Dai
Aihua
A
Huang
Hsiao-Fen
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Materi
Alicia M
AM
Lin
Jesse H
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Frankl
Harold D
HD
Lee
Eric R
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Hardy
Steven I
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Herschman
Harvey R
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Henderson
Brian E
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Kolonel
Laurence N
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Le Marchand
Loïc
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Garavito
R Michael
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Sandler
Robert S
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Haile
Robert W
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Smith
William L
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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
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