[show abstract][hide abstract] ABSTRACT: Acetaminophen (APAP) glucuronidation is thought to occur mainly by UDP-glucuronosyltransferases (UGT) in the UGT1A family. Interindividual variation in APAP glucuronidation is attributed in part to polymorphisms in UGT1As. However, evidence suggests that UGT2B15 may also be important. We evaluated, in a controlled feeding trial, whether APAP conjugation differed by UGT1A6 and UGT2B15 genotypes and whether supplementation of known dietary inducers of UGT (crucifers, soy, and citrus) modulated APAP glucuronidation compared with a diet devoid of fruits and vegetables (F&V). Healthy adults (n = 66) received 1000 mg of APAP orally on days 7 and 14 of each 2-week feeding period and collected saliva and urine over 12 h. Urinary recovery of the percentage of the APAP dose as free APAP was higher (P = 0.02), and the percentage as APAP glucuronide (APAPG) was lower (P = 0.004) in women. The percentage of APAP was higher among UGT1A6*1/*1 genotypes, relative to *1/*2 and *2/*2 genotypes (P = 0.045). For UGT2B15, the percentage of APAPG decreased (P < 0.0001) and that of APAP sulfate increased (P = 0.002) in an allelic dose-dependent manner across genotypes from *1/*1 to *2/*2. There was a significant diet × UGT2B15 genotype interaction for the APAPG ratio (APAPG/total metabolites × 100) (P = 0.03), with *1/*1 genotypes having an approximately 2-fold higher F&V to basal diet difference in response compared with *1/*2 and *2/*2 genotypes. Salivary APAP maximum concentration (C(max)) was significantly higher in women (P = 0.0003), with F&V (P = 0.003), and among UGT1A6*2/*2 and UGT2B15*1/*2 genotypes (P = 0.02 and 0.002, respectively). APAP half-life was longer in UGT2B15*2/*2 genotypes with F&V (P = 0.009). APAP glucuronidation was significantly influenced by the UGT2B15*2 polymorphism, supporting a role in vivo for UGT2B15 in APAP glucuronidation, whereas the contribution of UGT1A6*2 was modest. Selected F&V known to affect UGT activity led to greater glucuronidation and less sulfation.
Drug metabolism and disposition: the biological fate of chemicals 06/2011; 39(9):1650-7. · 3.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: Interindividual variation in aspirin (ASA) metabolism is attributed to concomitant use of drugs or alcohol, urine pH, ethnicity, sex, and genetic variants in UDP-glucuronosyltransferases (UGT). Little is known about the effects of diet.
We evaluated cross-sectionally whether urinary excretion of ASA and its metabolites [salicylic acid (SA), salicyluric acid (SUA) phenolic glucuronide (SUAPG), salicylic acid acyl glucuronide (SAAG) and salicylic acid phenolic glucuronide (SAPG)] differed by UGT1A6 genotype and dietary factors shown to induce UGT. Following oral treatment with 650 mg ASA, urine was collected over 8 h in 264 men and 264 women (21-45 years old).
There were statistically significant differences in metabolites excreted between sexes and ethnicities. Men excreted more SUA; women more ASA (p = 0.03), SA, SAAG and SAPG (p ≤ 0.001 for all). Compared to Caucasians, Asians excreted more ASA, SA and SAAG, and less SUA and SUAPG (p ≤ 0.03 for all); African-Americans excreted more SAAG and SAPG and less SUA (p ≤ 0.04). There was no effect of UGT1A6 genotypes. Increased ASA and decreased SUAPG excretion was observed with increased servings of vegetables (p = 0.008), specifically crucifers (p = 0.05).
Diet may influence the pharmacokinetics of ASA, but effects may be through modulation of glycine conjugation rather than glucuronidation.
Journal of Nutrigenetics and Nutrigenomics 05/2011; 4(2):110-8. · 1.31 Impact Factor
[show abstract][hide abstract] ABSTRACT: Epidemiologic studies have examined the association between fruit and vegetable (F&V) consumption and the risk of cancer. Several cancer-preventive mechanisms have been proposed, such as antioxidant properties and modulation of biotransformation enzyme activities; both may be associated with reducing DNA damage and hence the mutation rate. We investigated, in a randomized, controlled, crossover feeding trial, the effect of 10 servings/day of botanically defined F&V for 2 wk on endogenous DNA damage; resistance to gamma -irradiation damage; and DNA repair capacity in lymphocytes, measured by the Comet assay. We also explored the association between the UGT1A1*28 polymorphism and serum bilirubin concentrations and DNA damage and repair measures. Healthy men (n = 11) and women (n = 17), age 20 to 40 yr, provided blood samples at the end of each feeding period. Overall, F&V did not affect DNA damage and repair measures in lymphocytes. The number of UGT1A1*28 alleles was inversely associated with sensitivity to gamma -irradiation exposure and DNA repair capacity, but a biological mechanism to explain this association is unclear. A larger sample size is needed to investigate the association between bilirubin concentrations and endogenous DNA damage. With inconsistent findings in the literature, additional dietary intervention studies on the effect of F&V on DNA damage and repair are needed.
Nutrition and Cancer 04/2010; 62(3):329-35. · 2.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome colon cancers. Less understood is the risk of colon cancer associated with common polymorphisms in MMR genes and the potential interacting role of lifestyle factors known to damage DNA.
A study was conducted to examine whether MLH1 (-93G>A and Ile219Val) and MSH6 (Gly39Glu) polymorphisms were associated with risk of colon cancer in data from 1609 colon cancer cases and 1972 controls. Genotype data were further stratified by microsatellite instability status, smoking, alcohol, Western diet, alcohol and obesity, to investigate potential heterogeneity.
The MSH6 39Glu allele was associated with increased risk of colon cancer among men (Gly/Glu or Glu/Glu vs Gly/Gly, OR 1.27; 95% CI 1.04 to 1.54). Neither MLH1 polymorphism was associated with colon cancer risk overall. When stratified by microsatellite stability status, however, the MLH1 -93A allele was associated with a more than doubling in microsatellite instability (MSI)-positive colon cancer risk (AA vs GG, OR 2.47; 95% CI 1.48 to 4.11); no associations were observed between the MMR polymorphisms examined and MSI-negative colon cancer. Statistically significant interactions were observed between: MLH1 -93G>A and smoking (MSI-negative colon cancer only, p value interaction: 0.005); and MLH1 Ile219Val and Western diet (p value interaction: 0.03).
The MSH6 Gly39Glu and MLH1 -93G>A polymorphisms were associated with risk of overall colon and MSI-positive colon cancers, respectively. Risk for colon cancer, stratified by MMR genotype, was further modified by smoking and Western diet.
[show abstract][hide abstract] ABSTRACT: UDP-glucuronosyltransferase (UGT) 1A1 glucuronidates bilirubin, estrogens, and xenobiotic compounds. The UGT1A1*28 polymorphism results in lower promoter activity due to 7 thymine-adenine (TA) repeats rather than the more common 6 TA repeats. Previously, we showed that serum bilirubin, a marker of UGT1A1 activity, was lower among individuals homozygous for the UGT1A1*28 polymorphism (7/7) when randomized to a high fruit and vegetable (F&V) diet, whereas there was no effect in individuals with the wild-type (6/6) and heterozygous (6/7) genotypes. Our objective here was to determine if we could detect genotype x diet interactions on bilirubin concentrations in an observational study. Healthy nonsmoking men (n = 146) and women (n = 147), recruited from the Seattle area, provided blood samples for genotyping and bilirubin measurements. We used multiple linear regression to assess the relationships among UGT1A1 genotype, bilirubin concentrations, and consumption of specific F&V [cruciferous vegetables, citrus fruits, and soy foods (n = 268)] based on FFQ and F&V from 6 botanical families [Cruciferae, Rosaceae, Rutaceae, Umbelliferae, Solanaceae, and Leguminosae (n = 261)] based on 3-d food records. We observed a significant interaction of UGT1A1 genotype and citrus consumption among women. Women with the 7/7 genotype who consumed > or = 0.5 daily servings of citrus fruit or foods from the Rutaceae botanical family had approximately 30% lower serum bilirubin than those with the same genotype who consumed less, whereas 6/6 and 6/7 genotypes did not differ by consumption (P for interaction = 0.006 and 0.03, respectively). These results suggest that citrus consumption may increase UGT1A1 activity among women with the 7/7 genotype.
Journal of Nutrition 01/2009; 139(3):555-60. · 4.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: C-reactive protein (CRP) is a nonspecific marker of inflammation linked to cardiovascular disease and possibly colon cancer. Polymorphisms in CRP have been associated with differential CRP concentrations among healthy adults, with some evidence for functional effects on CRP expression.
A linkage disequilibrium-based tag single nucleotide polymorphism (SNP)-selection algorithm identified six tagSNPs for Europeans (-821A>G, -390C>T/A, 90A>T, 838G>C, 2043G>A, and 4363C>A), defining six haplotypes with more than 1% frequency. In a case-control study of adenomatous (n=491) or hyperplastic (n=184) polyps versus polyp-free controls (n=583) we investigated these SNPs in relation to colorectal polyp risk.
Individuals with 838 GC or CC genotypes had a modestly, although not statistically significantly, increased risk of adenomas (odds ratio: 1.4 95% confidence interval: 0.9-2.1) and a nearly 2-fold increased risk of concurrent adenomas and hyperplastic polyps (odds ratio: 2.0 95% confidence interval: 1.1-3.6). Increased risk for concurrent adenomas and hyperplastic polyps was also observed for haplotype ACACAC. No other main associations were detected. Risk of adenomas associated with 2043G>A differed with nonsteroidal anti-inflammatory drug (NSAID) use. Among NSAID nonusers, there was a suggestion that the GA or AA genotypes were associated with decreased risk of adenomas; this was not seen among NSAID users (P interaction=0.03). We also observed interactions between UGT1A1 [TA](7) promoter repeat polymorphism and CRP tagSNPs -390C>T/A and 90A>T, in which only the homozygous variant CRP genotype was associated with increased risk of adenoma among those with the UGT1A1 6rpt/6rpt genotype (P interaction=0.02 and 0.04 for -390C>T/A and 90A>T, respectively).
These results provide limited support for associations between genetic variation in CRP and colorectal polyp risk. The observed interactions should be evaluated further.
Pharmacogenetics and Genomics 12/2008; 19(2):113-20. · 3.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fruit and vegetable (F&V) intake may lower the risk of some cancers. One hypothesized, but understudied, chemopreventive mechanism is that plant food constituents inhibit beta-glucuronidase, an acid hydrolase that deconjugates glucuronides.
We conducted a crossover feeding trial in 63 healthy women and men ages 20 to 40 years to examine the effect of diet on serum beta-glucuronidase activity. Participants were randomized to two 2-week experimental diets with an intervening washout period: a diet high in selected citrus fruit, crucifers, and soy (F&V) and a diet devoid of fruits, vegetables, and soy (basal). Serum beta-glucuronidase activity was measured during the preintervention, F&V, and basal periods. Linear mixed models were used to obtain effect estimates and 95% confidence intervals (95% CI).
We observed statistically significantly higher beta-glucuronidase activity during the F&V than the basal diet (ratio, F&V versus basal diet, 1.09; 95% CI, 1.05-1.13; P < 0.01). These results were probably due to decreased beta-glucuronidase activity during the basal diet (ratio, basal period versus preintervention, 0.93; 95% CI, 0.87-0.98; P = 0.01) rather than increased enzyme activity during the F&V diet (ratio, F&V period versus preintervention, 1.01; 95% CI, 0.96-1.06; P = 0.64). Response to the experimental diet did not differ by sex (P(interaction) = 0.30), but there was a suggestion of a short-term diet effect at 8 versus 15 days (P(interaction) = 0.06).
This intervention of selected F&V did not lower beta-glucuronidase activity. Further investigation is needed regarding what other foods and phytochemicals may influence beta-glucuronidase activity and effect modifiers of this relation.
[show abstract][hide abstract] ABSTRACT: In vivo, aspirin (acetylsalicylic acid) is rapidly deacetylated to form salicylic acid, which then undergoes primary or secondary glucuronidation catalyzed by UDP-glucuronosyltransferases (UGTs). The variant UGT1A6*2 (T181A, R184S) is associated with altered enzyme function. Our objective was to compare salicylic acid glucuronidation in individuals with different UGT1A6 genotypes.
Following orally dosing with 650 mg aspirin, saliva and urine samples were collected over a period of 24 h from healthy individuals with homozygous wild-type UGT1A6 *1/*1 (n=19) and homozygous variant UGT1A6 *2/*2 (T181A, R184S) (n=9) genotypes.
No statistically significant differences were observed in salivary pharmacokinetic parameters. Urinary excretion of the sum of aspirin and its metabolites (salicyluric acid, salicyluric acid phenolic glucuronide, salicyl phenolic glucuronide, salicyl acyl glucuronide, salicylic acid) during the early period of 2-4 h of collection was significantly lower in UGT1A6 *1/*1 than in UGT1A6 *2/*2 individuals. Further, UGT1A6 *1/*1 individuals excreted a lower percentage of aspirin and its metabolites in the first 12 h and a greater percentage after 12 h than UGT1A6 *2/*2 individuals.
The variant UGT1A6*2 or polymorphisms in other UGTs that are in linkage disequilibrium with UGT1A6*2 may confer more rapid glucuronidation of salicylic acid than the wild-type UGT1A6 *1/*1.
Pharmacogenetics and Genomics 09/2007; 17(8):571-9. · 3.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study investigated associations between CpG island methylator phenotype (CIMP) colon cancer and genetic polymorphisms relevant to one-carbon metabolism and thus, potentially the provision of methyl groups and risk of colon cancer. Data from a large, population-based case-control study (916 incident colon cancer cases and 1,972 matched controls) were used. Candidate polymorphisms in methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), transcobalamin II (TCNII), methionine synthase (MTR), reduced folate carrier (RFC), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), dihydrofolate reductase (DHFR) and alcohol dehydrogenase 3 (ADH3) were evaluated. CIMP- or CIMP+ phenotype was based on five CpG island markers: MINT1, MINT2, MINT31, p16 and MLH1. The influence of specific dietary factors (folate, methionine, vitamin B(12) and alcohol) on these associations was also analyzed. We hypothesized that polymorphisms involved in the provision of methyl groups would be associated with CIMP+ tumors (two or more of five markers methylated), potentially modified by diet. Few associations specific to CIMP+ tumors were observed overall, which does not support the hypothesis that the provision of methyl groups is important in defining a methylator phenotype. However, our data suggest that genetic polymorphisms in MTHFR 1,298A > C, interacting with diet, may be involved in the development of highly CpG-methylated colon cancers. AC and CC genotypes in conjunction with a high-risk dietary pattern (low folate and methionine intake and high alcohol use) were associated with CIMP+ (OR = 2.1, 95% CI = 1.3-3.4 versus AA/high risk; P-interaction = 0.03). These results provide only limited support for a role of polymorphisms in one-carbon metabolism in the etiology of CIMP colon cancer.
[show abstract][hide abstract] ABSTRACT: Dietary polyunsaturated fatty acids (PUFAs) can be converted to prostaglandins and leukotrienes. Metabolism of omega-6 (n-6) PUFAs results in the production of pro-inflammatory mediators whereas downstream products of omega-3 (n-3) PUFAs have lower inflammatory activity. Elevated n-3 PUFA intake from dietary fish may be associated with lower risk of colorectal neoplasia among those with genetic variants resulting in higher levels of pro-inflammatory mediators. We investigated interactions between dietary fish intake and polymorphisms in cyclooxygenase (COX)-1, COX-2, ALOX5 and PGIS in a case-control study of adenomas (N = 522), hyperplastic polyps (N = 194) and polyp-free controls (N = 626). Polyp risk did not differ by fish intake. A suggested interaction with fish intake was observed for COX-1 P17L. Among those who were homozygous wild type, increasing fish intake was associated with a modestly reduced risk of adenoma, whereas among those with at least one variant allele, the reverse trend was observed (p-interaction = 0.08). The interaction was statistically significant when non-steroidal anti-inflammatory drug (NSAID) use was also taken into account: among those with COX-1 17PP genotypes, high fish intake and regular NSAID use was associated with a decreased risk compared with low fish intake and low NSAID use (odds ratio = 0.60, 95% confidence interval 0.33-1.09). The opposite association was observed among those with COX-1 17PL or LL genotypes (p-interaction = 0.04). Our results suggest that the effects of dietary n-3 PUFA intake and NSAID use may differ by genetic variation in COX-1.
[show abstract][hide abstract] ABSTRACT: Thymidylate synthase (TS) is a key enzyme in folate metabolism, a pathway that is important in colorectal carcinogenesis. We investigated the role of functional polymorphisms in the TS 5'-UTR promoter enhancer region (TSER, 3 or 2 repeats of a 28-bp sequence) and the 3'-UTR (1494delTTAAAG) and their association with colon tumor characteristics, including tumor stage and acquired mutations in p53, Ki-ras and microsatellite instability. Data from a population-based incident case-control colon cancer study in northern California, Utah and Minnesota (1,206 cases, 1,962 controls) was analyzed using unordered polytomous logistic regression models. In both men and women, individuals with variant TS alleles were at reduced risk of having an advanced stage tumor (metastatic disease: OR = 0.35, 95% CI: 0.2-0.6 vs. wildtype TSER and 3'-UTR). Stage-adjusted survival did not differ by genotype. Men with 1 or 2 variant alleles in both the TSER and 3'-UTR genotypes had a 50% reduced risk of a p53-positive tumor (OR = 0.5, 95% CI: 0.3-0.9 vs. homozygous wildtype TSER and 3'-UTR). Women with 1 or 2 variant alleles for either the TSER or 3'-UTR polymorphism had reduced risk of having any colon tumor that did not vary by mutation status. This study provides some support for associations between TS genotype and colon cancer tumor characteristics.
International Journal of Cancer 06/2007; 120(10):2226-32. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: UDP-glucuronosyltransferase (UGT) 1A1 glucuronidates bilirubin, estrogens, and exogenous compounds, including dietary carcinogens. The UGT1A1*28 polymorphism, characterized by variation in the number of thymine-adenine repeats in the promoter region, modulates UGT1A1 transcription. Observational and in vitro studies suggest that certain phytochemicals may increase UGT activity. We investigated, in a randomized, controlled, crossover feeding trial, whether approximately 10 servings/d (doses adjusted for body weight) of crucifers, soy, and citrus for 2 wk compared with a fruit- and vegetable-free basal diet affected UGT1A1 activity as measured by serum bilirubin concentrations and whether effects were modulated by the UGT1A1*28 polymorphism. Healthy men (n = 32) and women (n = 31), aged 20-40 y, enrolled based on UGT1A1 genotype, completed the study. We measured bilirubin in blood collected at d 8 and d 15 of each feeding period. Overall, fruit and vegetables (F&V) did not affect serum bilirubin; however, among 7/7 individuals, d 8 total (P = 0.057) and indirect (unconjugated) (P = 0.051) bilirubin tended to be lower when individuals consumed the F&V diet (28.97 +/- 2.36 micromol/L and 25.97 +/- 2.15 micromol/L) compared with the basal diet (32.46 +/- 2.63 micromol/L and 29.31 +/- 2.43 micromol/L). We no longer detected this difference at d 15, by which time bilirubin had also decreased when participants consumed the basal diet. Additionally, intervention effects on bilirubin were restricted to women with 7/7 genotype (P = 0.002). These results suggest that serum bilirubin glucuronidation is modulated by dietary intervention, but factors such as UGT1A1 genotype and sex may affect the response to diet.
Journal of Nutrition 05/2007; 137(4):890-7. · 4.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
Pharmacogenetics and Genomics 04/2007; 17(3):221-7. · 3.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Exposures such as cigarette smoke and meat contain a variety of procarcinogens, which are thought to play a role in elevation of risk for colorectal polyps and/or cancer. These procarcinogens (including heterocyclic amines and polycyclic aromatic hydrocarbons) are metabolized by a variety of polymorphic enzymes including N-acetyltransferases, sulfotransferases, cytochrome P450 enzymes and epoxide hydrolase. We hypothesized that genetic variation in the encoding genes NAT1, NAT2, SULT1A1, SULT1A2, CYP1A1 or EPHX1 is associated with risk of colorectal polyps and interacts with cigarette use or meat intake to modify risk of colorectal polyps. We examined the role of these genes in a clinic-based study of 651 Caucasian cases with hyperplastic polyps, adenomatous polyps or both types of polyps and 556 polyp-free controls. We found evidence for interaction between NAT acetylator status and SULT1A1 genotype in risk of hyperplastic polyps: individuals with SULT1A1 638AA genotype and NAT1 and NAT2 intermediate/fast phenotypes had 3.5-fold increased risk (95% CI 1.2-10.3) compared with individuals with SULT1A1 638GG genotype and NAT1 and NAT2 slow phenotypes. Data were also consistent with interactions between smoking and variation in SULT1A1, CYP1A1 and EPHX1 and between meat intake and variation in CYP1A1 and EPHX1. No interactions were statistically significant. Although results should be interpreted with caution considering sample size and the number of hypotheses examined, our study suggests future avenues of investigation in larger investigations of genetic and lifestyle factors in the pathway to colorectal cancer.
[show abstract][hide abstract] ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) play key roles in intracellular folate metabolism. Polymorphisms in these enzymes have been shown to modify toxicity of methotrexate (MTX) after hematopoietic cell transplantation. In this study, we evaluated the risk of acute graft-versus-host disease (GVHD) associated with genetic variation in recipient and donor MTHFR and TS genotypes to assess whether genotype alters the efficacy of MTX in acute GVHD prophylaxis. Data on the transplantation course were abstracted from medical records for 304 adults who received allogeneic hematopoietic cell transplants. MTHFR (C677T and A1298C) and TS (enhancer-region 28-base pair repeat, TSER, and 1494del6) genotypes were determined using polymerase chain reaction/restriction fragment length polymorphism and TaqMan assays. Multivariable logistic regression was used to assess the associations between genotypes and risk of acute GVHD. Compared with recipients with the wild-type MTHFR 677CC genotype, those with the variant 677T allele showed a decreased risk of detectable acute GVHD (677CT: odds ratio, 0.8; 95% confidence interval, 0.4-1.6; 677TT: odds ratio, 0.4; 95% confidence interval, 0.2-0.8; P for trend = .01). The variant MTHFR 1298C allele in recipients was associated with an increased risk of acute GVHD compared with the wild-type MTHFR 1298AA genotype (1298AC: odds ratio, 2.0; 95% confidence interval, 1.1-3.9; 1298CC: odds ratio, 3.6; 95% confidence interval, 1.0-12.7; P for trend < .01). No association with risk of acute GVHD was observed for donor MTHFR genotypes or for recipient or donor TS genotypes, with the exception of an increase in acute GVHD among recipients whose donors had the TSER 3R/2R genotype (odds ratio, 3.0; 95% confidence interval, 1.3-7.2). These findings indicate that host, but not donor, MTHFR genotypes modify the risk of acute GVHD in recipients receiving MTX, in a manner consistent with our previously reported associations between MTHFR genotypes and MTX toxicity. A direct trade-off between drug toxicity and drug efficacy may play a role. Alternatively, the systemic folate environment, regulated by host tissues, might influence donor T-cell growth and activity.
Biology of Blood and Marrow Transplantation 09/2006; 12(9):973-80. · 3.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: UDP-Glucuronosyltransferases (UGTs) are a superfamily of enzymes responsible for glucuronidation of xenobiotics and endobiotics. Genetic polymorphisms have been identified in the promoter and exonic regions of several UGT genes. The UGT1As on chromosome 2q37 have unique exons 1 but share the remainder of their coding sequence. We screened exon 1 of each of the nine functional UGT1As in Asians (n=46) and Caucasians (n=92) with the aim of determining linkage disequilibrium (LD) and haplotypes across the entire locus in both populations. For polymorphisms in UGT 1A3, 1A4, 1A5, 1A7, and 1A8, we observed significant differences in the allele frequency between the two populations. The haplotype block structure across the UGT1A locus was constructed using all 83 polymorphisms and showed four and five haplotype blocks in Caucasians and Asians, respectively. There was long-distance LD between UGT pairs: 1A8 and 1A10; 1A1 and 1A3; 1A1 and 1A6; 1A6 and 1A7; and 1A7 and 1A9. Whereas both ethnic groups shared some haplotype-tagging SNPs (htSNPs), Caucasians and Asians also had unique htSNPs. This was partly due to the fact that rare variants (<5% allele frequency) were included in our analyses. Haplotypes with frequencies >5% represented only 60% of Caucasian and 65% of Asian UGT1A haplotypes. Differences in haplotype distribution patterns suggest individual and ethnic differences in glucuronidation capacity.
Human Mutation 08/2006; 27(7):717. · 5.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: Smoking has been consistently associated with an increased risk of colorectal adenomas and hyperplastic polyps as well as colorectal cancer. Conversely, nonsteroidal anti-inflammatory drugs (NSAID) have been associated with reduced colorectal cancer risk. We conducted a population-based case-control study to evaluate the joint association between smoking and regular NSAID use with colorectal cancer risk; we also examined these associations stratified by tumor microsatellite instability (MSI). We analyzed 1,792 incident colorectal cancer cases and 1,501 population controls in the Seattle, Washington area from 1998-2002. MSI, defined as MSI high (MSI-H) or MSI-low/microsatellite stable (MSI-L/MSS), was assessed in tumors of 1,202 cases. Compared with nonsmokers, colorectal cancer risk was modestly increased among individuals who had ever smoked. Current NSAID use was associated with a 30% lower risk compared with nonusers. There was a statistically significant interaction between smoking duration and use of NSAIDs (P(interaction) = 0.05): relative to current NSAID users who never smoked, individuals who had both smoked for >40 years and had never used NSAIDs were at the highest risk for colorectal cancer (adjusted odds ratio, 2.8; 95% confidence intervals, 1.8-4.1). Compared with nonsmokers, there was a stronger association within MSI-H tumors with current smoking than there was within MSI-L/MSS tumors. Smokers of long duration were at elevated risk of MSI-H tumors even with NSAID use. The risk of MSI-L/MSS tumors was not elevated among long-duration smokers with long exposure to NSAIDs but was elevated among long-duration smokers who had never used NSAIDs. There seems to be a synergistic inverse association (implying protection) against colorectal cancer overall as a result of NSAID use and nonsmoking, but risk of MSI-H colorectal cancer remains elevated among smokers even when they have a history of NSAID use.
Cancer Research 07/2006; 66(13):6877-83. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mutations in the mismatch repair (MMR) enzymes hMLH1 and hMSH6 are known causes of hereditary nonpolyposis colorectal cancer and act by inducing a mutator phenotype characterized by microsatellite instability. The aim of our study was to determine if polymorphisms in the DNA MMR genes hMLH1 and hMSH6 are associated with an increased risk of colorectal polyps, and to evaluate interactions with exposures known to cause DNA damage.
In a Minnesota-based case-control study of individuals with adenomas (N=401), hyperplastic polyps (N=195), or both adenomas and hyperplastic polyps (N=123) versus polyp-free controls (N=624), we investigated the role of hMLH1-93G>A, hMLH1 I219V, and hMSH6 G39E polymorphisms in increasing the risk of colorectal polyps. Polytomous multivariate logistic regression analysis was used, adjusting for age, sex, body mass index, postmenopausal hormone use, aspirin use, and NSAID use.
Overall, no evidence of an association between any of the three polymorphisms or hMLH1 haplotypes and colorectal polyps was observed. However, risk associated with the hMLH1-93A variant differed by smoking: smoking-associated risks were stronger among those with variant -93AA or -93AG genotypes, showing a twofold greater risk of adenoma with >25 pack-years of smoking compared with nonsmokers, and a corresponding eightfold greater risk of hyperplastic polyps (genotype smoking: p-interaction=0.02 for hyperplastic polyps and p-interaction=0.08 for adenomas).
These data are consistent with the observation that smoking is associated with MMR in colorectal neoplasia and suggest that the risk increase with smoking may differ by hMLH1-93G>A genotype.
The American Journal of Gastroenterology 06/2006; 101(6):1313-9. · 7.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: It was shown that NSAIDs, such as aspirin or Celebrex, are effective cancer preventive agents when taken regularly. However, the long-term use of NSAIDs, the cyclooxygenase (COX) inhibitors, may have significant adverse effects - primarily on the gastrointestinal (inhibiting COX-1) and cardiovascular (inhibiting COX-2) systems. Genetic analysis of enzymes (including COX) involved in the prostaglandin synthesis should reveal and predict a person's benefits vs. toxicity resulting from the NSAID treatment.
Discovery medicine 05/2006; 6(32):71-4. · 2.97 Impact Factor