Polymorphisms predicted to alter function in prostaglandin E2 synthase and prostaglandin E2 receptors.
OBJECTIVE
Prostaglandin synthesis is the primary target of aspirin and other nonsteroidal antiinflammatory drugs, and thus is a pathway of major interest to pharmacology, pharmacogenetics, and epidemiology. Several lines of evidence implicate prostaglandin E2 in carcinogenesis; this study aimed to identify genetic variants in genes related to prostaglandin E2 synthesis and signaling.


METHODS
We resequenced the coding regions of human prostaglandin E2 synthase (PGES), and prostaglandin E2 receptors EP1, EP2, and EP4 in 48 African-Americans and 47 Caucasians.


CONCLUSIONS
We identified 23 variants, 6 of which cause amino acid changes. The non-synonymous polymorphisms in PGES, EP1, and EP2 were present only among African-Americans; both populations carried non-synonymous polymorphisms in EP4. We used two sequence homology-based programs, SIFT and PolyPhen, to predict the impact of these polymorphisms. These programs predicted that the amino-acid changes p.Phe119Val in EP1, p.Ala44Glu in EP2, and possibly p.Val7Glu in PGES, p.Thr176Ile in EP4 and p.Gly420Asp in EP4 are likely to affect protein function. Thus, these variants may be relevant for inflammatory conditions, carcinogenesis, and pharmacogenetics.
Bigler
Jeannette
J
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. jbigler@amgen.com
Sibert
Justin G
JG
Poole
Elizabeth M
EM
Carlson
Christopher S
CS
Potter
John D
JD
Ulrich
Cornelia M
CM
D019943:Amino Acid Substitution; D001483:Base Sequence; D044383:Black People / Q000235:genetics; D005544:Forecasting; D005787:Gene Frequency; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000502:physiology; D011110:Polymorphism, Genetic; D000071876:Prostaglandin-E Synthases; D018078:Receptors, Prostaglandin E / Q000235:genetics* / Q000502:physiology; D020539:Sequence Analysis, Protein / Q000379:methods; D017386:Sequence Homology, Amino Acid; D012984:Software; D013329:Structure-Activity Relationship; D044465:White People / Q000235:genetics; D001741:Black or African American
D018078:Receptors, Prostaglandin E; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases