title: Hematopoietic prostaglandin D synthase (HPGDS): a high stability, Val187Ile isoenzyme common among African Americans and its relationship to risk for colorectal cancer.
abstract: Intestinal tumors in Apc(Min/+) mice are suppressed by over-production of HPGDS, which is a glutathione transferase that forms prostaglandin D(2) (PGD(2)). We characterized naturally occurring HPGDS isoenzymes, to see if HPGDS variation is associated with human colorectal cancer risk. We used DNA heteroduplex analysis and sequencing to identify HPGDS variants among healthy individuals. HPGDS isoenzymes were produced in bacteria, and their catalytic activities were tested. To determine in vivo effects, we conducted pooled case-control analyses to assess whether there is an association of the isoenzyme with colorectal cancer. Roughly 8% of African Americans and 2% of Caucasians had a highly stable Val187lle isoenzyme (with isoleucine instead of valine at position 187). At 37°C, the wild-type enzyme lost 15% of its activity in 1h, whereas the Val187Ile form remained >95% active. At 50°C, the half life of native HPGDS was 9min, compared to 42 min for Val187Ile. The odds ratio for colorectal cancer among African Americans with Val187Ile was 1.10 (95% CI, 0.75-1.62; 533 cases, 795 controls). Thus, the Val187Ile HPGDS isoenzyme common among African Americans is not associated with colorectal cancer risk. Other approaches will be needed to establish a role for HPGDS in occurrence of human intestinal tumors, as indicated by a mouse model.
authors.affiliation: Division of Medical Genetics, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA.
authors.forename: Brigette L
authors.initials: BL
authors.lastname: Tippin
authors.forename: A Joan
authors.initials: AJ
authors.lastname: Levine
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Materi
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Song
authors.forename: Temitope O
authors.initials: TO
authors.lastname: Keku
authors.forename: Julie E
authors.initials: JE
authors.lastname: Goodman
authors.forename: Leah B
authors.initials: LB
authors.lastname: Sansbury
authors.forename: Sudipto
authors.initials: S
authors.lastname: Das
authors.forename: Aihua
authors.initials: A
authors.lastname: Dai
authors.forename: Alan M
authors.initials: AM
authors.lastname: Kwong
authors.forename: Amy M
authors.initials: AM
authors.lastname: Lin
authors.forename: John M
authors.initials: JM
authors.lastname: Lin
authors.forename: Jae Man
authors.initials: JM
authors.lastname: Park
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Patterson
authors.forename: Rowan T
authors.initials: RT
authors.lastname: Chlebowski
authors.forename: R Michael
authors.initials: RM
authors.lastname: Garavito
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Cho
authors.forename: John A
authors.initials: JA
authors.lastname: Lawson
authors.forename: Shiv
authors.initials: S
authors.lastname: Kapoor
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sandler
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Lin
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D019943:Amino Acid Substitution; D000818:Animals; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000208:ethnology / Q000235:genetics*; D004795:Enzyme Stability; D055786:Gene Knockout Techniques; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics*; D007527:Isoenzymes / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D054834:Lipocalins / Q000737:chemistry* / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D019076:Transgenes / Q000235:genetics
chemical_list: D007527:Isoenzymes; D054834:Lipocalins; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase