Variants in the alpha-Methylacyl-CoA racemase gene and the association with advanced distal colorectal adenoma.
BACKGROUND
alpha-Methylacyl-CoA racemase (AMACR), an enzyme involved in oxidation of branched chain fatty acids and cholesterol metabolites, as well as ibuprofen metabolism, is overexpressed in colorectal adenomas and cancer. AMACR gene variants have been associated with hereditary prostate cancer, but no studies have evaluated their etiologic role in colorectal carcinogenesis.


METHODS
We conducted a case-control study of 725 advanced distal colorectal adenoma cases and 729 frequency-matched controls from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Seven AMACR polymorphisms were genotyped. Unconditional logistic regression models were used to evaluate the associations adjusting for age at randomization and gender.


RESULTS
The 201L allele of S201L [TT versus CC: odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.15-2.62; TC versus CC: OR, 1.17; 95% CI, 0.93-1.49] and the 277E allele of K277E (GG versus AA: OR, 1.66; 95% CI, 1.03-2.68; GA versus AA: OR, 1.21; 95% CI, 0.96-1.53) were associated with increased risk of advanced distal colorectal adenoma (both P(trend) </= 0.02); the TGTGCG haplotype of six informative single nucleotide polymorphisms was also associated with increased risk (OR, 1.27; 95% CI, 1.03-1.55). Regular ibuprofen users who were homozygous for the variant allele at either M9V or D175G were at reduced risk for adenoma (both P(interaction) < 0.05).


CONCLUSIONS
Our study identified variants in AMACR associated with advanced distal colorectal adenoma and pointed to potential interactions with ibuprofen use.
Divison of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, 6120 Executive Boulevard, EPS Rm 8113, Bethesda, MD 20892, USA. daughers@mail.nih.gov
Sarah E
SE
Daugherty
Elizabeth A
EA
Platz
Yin Yao
YY
Shugart
M Daniele
MD
Fallin
William B
WB
Isaacs
Nilanjin
N
Chatterjee
Robert
R
Welch
Wen-Yi
WY
Huang
Richard B
RB
Hayes
D000236:Adenoma / Q000201:enzymology* / Q000235:genetics; D000368:Aged; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001224:Aspartic Acid / Q000235:genetics; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D018698:Glutamic Acid / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use; D007930:Leucine / Q000235:genetics; D008239:Lysine / Q000235:genetics; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019998:Racemases and Epimerases / Q000235:genetics*; D012004:Rectal Neoplasms / Q000201:enzymology* / Q000235:genetics; D012694:Serine / Q000235:genetics; D014633:Valine / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001224:Aspartic Acid; D018698:Glutamic Acid; D012694:Serine; D008715:Methionine; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase; D007930:Leucine; D014633:Valine; D008239:Lysine; D005998:Glycine; D007052:Ibuprofen