UGT1A1 and UGT1A9 functional variants, meat intake, and colon cancer, among Caucasians and African-Americans.
Glucuronidation by the UDP-glucuronosyltransferase enzymes (UGTs) is one of the primary detoxification pathways of dietary heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). In a population-based case-control study of 537 cases and 866 controls, we investigated whether colon cancer was associated with genetic variations in UGT1A1 and UGT1A9 genes and we determined if those variations modify the association between colon cancer and dietary HCA and PAH exposure. We measured functional UGT1A1 polymorphisms at positions -53 (28; A(TA)6TAA to A(TA)7TAA), -3156 (G>A), -3279 (T>G) and the UGT1A9-275(T>A) polymorphism, and found no association with colon cancer overall. However, when stratified by race, the UGT1A1-3279 GG/TG intermediate/low activity genotypes were associated with an increased risk of colon cancer (odds ratio (OR)=1.5, 95% confidence interval (CI)=1.1-2.0) in Caucasians. This finding is also supported by haplotype analyses where the UGT1A1-3279G-allele-bearing haplotype is overrepresented in case group. Overall, UGT1A1-53 and -3156 genotypes modified the association between dietary benzo(a)pyrene (BaP) and colon cancer (P for interaction=0.02 and 0.03, respectively). The strongest association was observed for those with <7.7 ng/day BaP exposure and the low activity genotypes, for both UGT1A1 28/28 (OR=1.8, 95% CI=1.1-2.9) and -3156AA (OR=1.7, 95% CI=1.0-3.0), compared to >or=7.7 ng/day and combined high/intermediate genotypes. These data support a hypothesis that UGTs modify the association between meat-derived PAH exposure and colon cancer by their role in the elimination of dietary carcinogens.
Girard
Hugo
H
Pharmacogenomics Laboratory, CHUQ Research Center and Faculty of Pharmacy, Laval University, G1V 4G2 Québec, Canada.
Butler
Lesley M
LM
Villeneuve
Lyne
L
Millikan
Robert C
RC
Sinha
Rashmi
R
Sandler
Robert S
RS
Guillemette
Chantal
C
D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004032:Diet / Q000009:adverse effects; D004435:Eating; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000378:metabolism; D006801:Humans; D008297:Male; D008460:Meat / Q000009:adverse effects*; D008875:Middle Aged; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism; D000090264:UDP-Glucuronosyltransferase 1A9; D044465:White People / Q000235:genetics; D000099148:UGT1A1 Enzyme
D017931:DNA Primers; D014453:Glucuronosyltransferase; D006571:Heterocyclic Compounds; D011084:Polycyclic Aromatic Hydrocarbons; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human