Red blood cell transfusion: impact of an education program and a clinical guideline on transfusion practice.

BACKGROUND: Red blood cell (RBC) transfusion guidelines have been developed by professional societies. These guidelines recommend a restrictive RBC transfusion practice for most clinical populations. Despite the consistency of guidelines and limited evidence for RBC transfusion efficacy, there is variability in RBC transfusion practice. METHODS: A program was initiated in a tertiary medical center to align RBC transfusion practice with best-practice RBC transfusion guidelines. The program included an educational program, followed after 6 months by RBC transfusion decision support that included the approval of a best-practice RBC transfusion guideline by the hospital medical board and an RBC transfusion order form that included the guideline recommendations. RBC transfusion practice was followed over an 18-month period and compared with transfusion practice over the prior 18 months. The primary outcome variables were adult inpatient RBC units transfused, RBC units per admission, and RBC units per 100 patient-days. RESULTS: The mean RBC units transfused decreased with initiation of each component of the program: from 923 ± 68 units to 852 ± 40 (P = 0.025) with education and further to 690 ± 52 (P < 0.0001) with the RBC transfusion decision support. Similarly, RBC transfusions per 100 patient-days fell from 10.56 ± 0.80 to 9.69 ± 0.49 (P = 0.02) and to 7.68 ± 0.63 (P = 0.0001) during the 3 time periods. CONCLUSION: An education program coupled with institutional adoption of a best-practice RBC transfusion guideline and RBC transfusion order set resulted in a reduction in total RBC units transfused.

The differential effect of NAT2 variant alleles permits refinement in phenotype inference and identifies a very slow acetylation genotype.

Indirect evidences suggest that acetylation phenotype categories are heterogeneous and that subcategories, related to specific NAT2 variant alleles might exist. We analyzed the in vivo acetylation phenotype and genotype in 504 north-American subjects of Caucasian origin. The analyses of the SNPs rs1801280 and rs1799930 allowed the discrimination of five categories with different acetylation status within the study population. These categories are related to the distinct effect of NAT2 alleles on the acetylation status in vivo and to the occurrence of a gene-dose effect. These five phenotype categories, from higher to lower acetylation capacity, correspond to the genotypes NAT2*4/*4, NAT2*4/*5 or *4/*6, NAT2*5/*5, NAT2*5/*6 and NAT2*6/*6 (p ≤ 0.001 for all comparisons). The NAT2*6/*6 genotype correspond to a phenotype category of very-slow acetylators. The refinement in phenotype prediction may help to identify risks associated to phenotype subcategories, and warrants the re-analysis of previous studies that may have overlooked phenotype subcategory-specific risks.

The certifying examination of the american board of surgery: the effect of improving communication and professional competency: twenty-year results.

PURPOSE: In 1985, a small research group identified variables affecting applicant success on the oral Certifying Examination (CE) of the American Board of Surgery (ABS). This led to the design of an oral examination course first taught in 1991. The success of and need for this program led to its continuation. The results from the first 10 years were presented at the 2001 Association of Program Directors in Surgery annual meeting.(1) We now report the outcomes for the course of the second 10 years as measured by success on the CE. METHODS: Thirty-six courses were held over 20 years. There were 57 invited faculty from 27 general surgery programs throughout the United States and Canada. The participant-to-faculty ratio ranged from 16:7 to 5:1 in the newer 3-day format (2007). Courses were offered at sites that replicated the actual examination setting. Each course included (1) pretest and posttest examinations, (2) analysis of case presentation skills, (3) measurement of communication apprehension, (4) 1:1 faculty feedback, (5) small-group practice sessions, (6) individual videotaping, (7) didactic review of specific behaviors on examinations, (8) a debrief session with two faculty members, and (9) a written evaluative summary that included an improvement strategy. RESULTS: There were 36 courses with 326 participants (30-54 years). Follow-up data are available for 225 participants. Trends were analyzed between 1991-2001 and 2002-2011. As resident performance on the CE increased in importance, applicant profiles changed from those who had previously failed (1991-2001) to residents identified by program directors as needing assistance (52%). Since 2002, most course participants (69%) who had failed the CE had completed at least 1 other review course. Participants reported more significant stressors (2002-2011) 9%, but communication apprehension remained the same. As a result, individual counseling for anger and family stressors was integrated into the course. The perception of knowledge deficits was associated with those who enrolled in fellowship training and delayed their examination. The recent groups exhibited more professionalism and articulation issues related to performance. Five surgeons (2002-2011) were asked not to return to the course because of severe knowledge deficiencies or ethical/behavioral issues based on faculty evaluations. Although complete follow-up of all participants was not possible (only 225/326), the success rate among those providing follow-up was 97% for those who followed their remediation plan, giving 218/326, a worse-case pass rate of 67%. CONCLUSION: Communication and professionalism deficits are still common in those struggling with the CE, Early identification of those at risk of failing by program directors who are documenting the competencies may promote earlier interventions and thus lead to success. This program continues to be effective at identifying behaviors that interfere with success on the CE of the ABS.

Functional genetic variants in the 3'-untranslated region of sulfotransferase isoform 1A1 (SULT1A1) and their effect on enzymatic activity.

Sulfotransferase isoform 1A1 (SULT1A1) is the most highly expressed hepatic sulfotransferase and is involved in the biotransformation of a wide variety of endo- and xenobiotics. A common single nucleotide polymorphism (SNP) in the coding region of SULT1A1, several proximal promoter SNPs, and copy number variation (CNV) are associated with altered enzymatic activity, but these variants do not fully account for the observed variation of SULT1A1 activity in human populations. In order to identify additional SNPs modulating SULT1A1 activity, we examined the 3'-untranslated region (UTR) of SULT1A1 in 97 liver samples. Direct sequencing revealed that two SNPs in the 3'-UTR (902A > G [rs6839] and 973C > T [rs1042157]) and one SNP in the 3'-flanking region (1307G > A [rs4788068]) were common. These SNPs are in absolute linkage disequilibrium with each other and in tight linkage with SULT1A1 1/2 (linkage coefficient D' 0.83) and are significantly associated with SULT1A1 messenger RNA (p = 0.001, 0.029, 0.021) and enzymatic activity (p = 0.022, 0.012, 0.027). We then examined the collective effects of 3'-UTR SNPs, SULT1A1 1/2, and CNV on SULT1A1 activity in 498 Caucasian and 127 African-American subjects by haplotype analysis. This analysis revealed that SULT1A1 1/2 does not contribute to the variation in SULT1A1 enzymatic activity when the 3'-UTR SNPs are included in the statistical model. Two major haplotypes (ACG and GTA) were significantly correlated with SULT1A1 activity, and when stratified by copy number, the SULT1A1 3'-UTR SNPs remain significantly associated with SULT1A1 enzymatic activity in Caucasians, but not in African-Americans. Subsequent functional characterization revealed that a microRNA, miR-631, regulates SULT1A1 expression in a genotype-specific manner.

Polymorphisms in inflammatory genes, plasma antioxidants, and prostate cancer risk.

BACKGROUND: Presence of xenotropic murine leukemia virus-related virus and chronic inflammation in prostate tumor suggests that inflammation plays a role in prostate cancer etiology. This study investigated whether variants in inflammatory genes act alone or interact with plasma antioxidants to influence prostate cancer risk in a population-based case-control study in Central Arkansas. METHODS: Cases (n = 193) were men, aged 40-80, diagnosed with prostate cancer in three major hospitals in 1998-2003, and controls (n = 197) were matched to cases by age, race, and county of residence. RESULTS: After adjustment for confounders, polymorphisms in COX-2 (rs689466) and IL-8 (rs4073) were not significantly associated with prostate cancer risk. However, apparent interactions were observed between these genetic variants and plasma antioxidants on the risk of this malignancy. The protective effect of the mutant allele of the COX-2 polymorphism was more pronounced among subjects with high plasma levels of beta-cryptoxanthin, lycopene, beta-carotene, or selenium (>or=median) [e.g., OR (95% CI): 0.37 (0.15, 0.86) (AG/GG vs. AA) for beta-cryptoxanthin]. Conversely, the promoting effect of the variant allele of the IL-8 polymorphism was more remarkable in subjects with low plasma levels of Lutein/zeaxanthin, beta-cryptoxanthin, and beta-carotene (

Polymorphisms in hOGG1 and XRCC1 and risk of prostate cancer: effects modified by plasma antioxidants.

OBJECTIVES: To investigate whether polymorphisms in genes involved in the repair of oxidative DNA damage, modulate, and/or interact with antioxidants to influence prostate cancer risk in a population-based case-control study in Central Arkansas. Accumulating evidence indicates that oxidative stress plays a role in prostate carcinogenesis. METHODS: Cases (n = 193) included men aged 40-80 years, diagnosed with prostate cancer in 3 major hospitals in 1998-2003, and controls (n = 197) were matched to cases by age, race, and county of residence. RESULTS: After adjustment for confounders, subjects who were heterozygous or homozygous for the variant allele of the hOGG1 Ser326Cys polymorphism appeared to experience a lower risk of prostate cancer than those who were homozygous for the wild-type allele (odds ratio [OR] (95% confidence interval [CI]): 0.72 (0.46-1.10)]. Conversely, a significant increased risk was observed for individuals who carried 1 or 2 copies of the variant allele of the XRCC1 Arg399Gln polymorphism, compared with those who only harbored the wild-type allele (OR [95% CI]: 1.56 [1.01-2.45]). The above-mentioned associations were generally more pronounced among subjects with low plasma carotenoids or alpha-tocopherol (

Physical activity, diet, and pancreatic cancer: a population-based, case-control study in Minnesota.

Although mounting evidence suggests that insulin resistance is involved in pancreatic carcinogenesis, few epidemiologic studies have comprehensively investigated the role of lifestyle factors influencing this metabolic disorder in the etiology of pancreatic cancer. We sought to examine this problem in a case-control study conducted in 1994-1998 in Minnesota. Cases (n = 186), aged 20 yr or older, were ascertained from all hospitals in the metropolitan area of the Twin Cities and the Mayo Clinic; from the latter, only cases residing in the Upper Midwest of the United States were recruited. Controls (n = 554) were randomly selected from the general population and frequency matched to cases by age (within 5 yr) and sex. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. After adjustment for confounders, physical activity was associated with a reduced risk, but this protective effect was confined to light activity and moderate activity only (OR = 0.55, 95% CI = 0.30-0.97, P(trend) = 0.038 and OR = 0.51, 95% CI = 0.28-0.93, P(trend) = 0.07, for highest vs. lowest quartile, respectively). An increased risk was found for dietary intakes of energy and fat but was statistically significant for saturated and polyunsaturated fat only. Of note, no appreciable difference in the magnitude of the associations existed between saturated, monounsaturated, and polyunsaturated fat. Compared with individuals in the lowest quartile of fiber intake, the risk was approximately halved for those in the third (OR = 0.49, 95% CI = 0.26-0.94) and the highest quartile (OR = 0.52, 95% CI = 0.21-1.30). Our study lends support to the hypothesis that dietary and other lifestyle factors influencing insulin resistance modulate pancreatic cancer risk.

Phenotypic CYP2A6 variation and the risk of pancreatic cancer.

OBJECTIVE: Cytochrome P450 2A6 (CYP2A6) is an important metabolic enzyme capable of activating several procarcinogens, including dietary and tobacco-specific nitrosamines, which have been linked to pancreatic cancer. Positive associations between high CYP2A6 activity and lung and colorectal cancers have been reported. This is the first investigation of CYP2A6 activity and pancreatic cancer. DESIGN: In this case-control study of cancer of the exocrine pancreas, phenotypic CYP2A6 activity was measured using a ratio of urinary caffeine metabolites. Demographic, smoking, dietary and medical information were obtained by questionnaire. CYP2A6 phenotype, which is not influenced by smoking status, was measured for 90 cases and 470 controls. RESULTS: When modeled as a continuous variable, and adjusted for age, sex, race, education, current smoking status and chronic pancreatitis, the odds ratio (OR) per one unit of the natural log of the CYP2A6 ratio was 1.52 (95% confidence interval, CI: 1.09-2.12). In an adjusted categorical analysis, subjects in the uppermost quartile (based on controls) of CYP2A6 activity, when compared to the lower three quartiles, carried an 80% greater risk of pancreatic cancer (OR=1.80; 95% CI: 1.07-3.02). CONCLUSIONS: High levels of CYP2A6 activity, as measured by a caffeine phenotyping assay, were positively associated with pancreatic cancer in this casecontrol study among a Midwestern U.S. population.

Association of demographic and treatment variables in long-term colon cancer survival.

The purpose of this study is to examine demographic and treatment variables because they relate to 5-year survival in colon cancer. The study design is analysis of 174 471 patients with colon and rectosigmoid cancer as reported to the American College of Surgeons National Cancer Data Base. Factors associated with a reduced risk of mortality included female gender (hazard ratio = 0.89; 95% confidence interval, 0.87-0.90), education status (hazard ratio = 0.87; 95% confidence interval, 0.85-0.89), increased number of lymph nodes resected (compared with <8, 8-12: hazard ratio = 0.90; 95% confidence interval, 0.89-0.92; >12: hazard ratio = 0.79; 95% confidence interval, 0.77-0.80), and addition of chemotherapy (hazard ratio = 0.69; 95% CI, 0.68-0.71). African American race (hazard ratio = 1.14; 95% confidence interval, 1.11-1.18) and increasing age correlated with an increased hazard risk (61-75 years: hazard ratio = 1.26; 95% confidence interval, 1.23-1.29; >or=76 years: hazard ratio = 2.15; 95% confidence interval, 2.09-2.21, compared with age <60 years). Survival in colon cancer is significantly impacted by patient's age, race, gender, and education status but not by income or area of residence.

The UGT2B17 gene deletion polymorphism and risk of prostate cancer. A case-control study in Caucasians.

BACKGROUND: UDP-glucuronosyltransferase (UGT) 2B17 is a phase II metabolizing enzyme that mediates the glucuronidation of C(19) steroids. A deletion polymorphism in the UGT2B17 gene is associated with a substantial reduction in glucuronidation activity in vitro. METHODS: We examined the association between the UGT2B17 deletion polymorphism and the risk of incident prostate cancer in a population-based study from central Arkansas that included 411 Caucasian cases and 397 Caucasian controls. We developed a novel high-throughput procedure that uses real-time PCR and allelic discrimination for genotyping analysis. RESULTS: The prevalence of the UGT2B17 deletion [(0/0)] was 12% in the controls, which was consistent with previous population estimates and with Hardy Weinberg equilibrium. There was no association between the UGT2B17 deletion polymorphism and prostate cancer risk in unconditional logistic regression analysis. Compared to the wild-type group (+/+), the adjusted odds ratio (OR) was 0.89 (95% CI=0.55-1.45) for the homozygous deletion (0/0), and the OR was 0.99 (95% CI=0.73-1.35) for the heterozygote group (+/0). CONCLUSION: These findings show that the UGT2B17 deletion polymorphism is not associated with prostate cancer risk in Caucasians.

Plasma carotenoids and prostate cancer: a population-based case-control study in Arkansas.

Carotenoids possess antioxidant properties and thus may protect against prostate cancer. Epidemiological studies of dietary carotenoids and this malignancy were inconsistent, partially due to dietary assessment error. In this study, we aimed to investigate the relation between plasma concentrations of carotenoids and the risk of prostate cancer in a population-based case-control study in Arkansas. Cases (n = 193) were men with prostate cancer diagnosed in 3 major hospitals, and controls (n = 197) were matched to cases by age, race, and county of residence. After adjustment for confounders, plasma levels of lycopene, lutein/zeaxanthin, and beta-cryptoxanthin were inversely associated with prostate cancer risk. Subjects in the highest quartile of plasma lycopene (513.7 microg/l) had a 55% lower risk of prostate cancer than those in the lowest quartile (140.5 microg/l; P trend = 0.042). No apparent association was observed for plasma alpha-carotene and beta-carotene. Further adjustment for the other 4 carotenoids did not materially alter the risk estimates for plasma lycopene, lutein/zeaxanthin, and beta-cryptoxanthin but appeared to result in an elevated risk with high levels of plasma alpha-carotene and beta-carotene. The results of all analyses did not vary substantially by age, race, and smoking status. This study added to the emerging evidence that high circulating levels of lycopene, lutein/zeaxanthin, and beta-cryptoxanthin are associated with a low risk of prostate cancer.

Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes.

PURPOSE: Peroxisome proliferator-activated receptor gamma (PPARgamma) mediates cell cycle arrest and adipocyte differentiation; has tumor suppressor activity in liposarcoma, lung, and prostate cancers; and suppresses colonic polyp formation in adenomatous polyposis coli (APC)min/+ mice. To assess the influence of thiazolidinediones (TZDs), which are PPAR ligands used to treat diabetes mellitus, a retrospective analysis of a database from 10 Veteran Affairs medical centers was conducted. PATIENTS AND METHODS: Data on male patients 40 years and older diagnosed to have diabetes mellitus between 1997 and 2003 were obtained from the Veterans Integrated Services Network 16 (VISN 16) data warehouse. Subsequent diagnoses of colorectal, lung, and prostate cancer and use of TZD, other antidiabetic agents, and insulin were identified. Cox regression with time-dependent covariates was used to estimate the association between TZD use and cancer risk. Relative risks were adjusted for confounders (age, race/ethnicity, body mass index, use of insulin, and other oral antidiabetic agents). RESULTS: Of 87,678 individuals, 1,137 had colorectal cancer, 3,246 had prostate cancer, and 1,371 had lung cancer. We observed a 33% reduction in lung cancer risk among TZD users compared with nonusers after adjusting for confounder interactions (relative risk, 0.67; 95% CI, 0.51 to 0.87). The risk reduction for colorectal and prostate cancers did not reach statistical significance. CONCLUSION: TZD use was associated with reduced risk of lung cancer. Further studies are warranted to confirm our findings.

The urinary metabolite profile of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is predictive of colon DNA adducts after a low-dose exposure in humans.

Epidemiologic evidence indicates that exposure to heterocyclic amines in the diet is an important risk factor for the development of colon cancer. Well-done cooked meats contain significant levels of heterocyclic amines, which have been shown to cause cancer in laboratory animals. To better understand the mechanisms of heterocyclic amine bioactivation in humans, the most mass abundant heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was used to assess the relationship between PhIP metabolism and DNA adduct formation. Ten human volunteers where administered a dietary relevant dose of [(14)C]PhIP 48 to 72 hours before surgery to remove colon tumors. Urine was collected for 24 hours after dosing for metabolite analysis, and DNA was extracted from colon tissue and analyzed by accelerator mass spectrometry for DNA adducts. All 10 subjects were phenotyped for cytochrome P4501A2 (CYP1A2), N-acetyltransferase 2, and sulfotransferase 1A1 enzyme activity. Twelve PhIP metabolites were detected in the urine samples. The most abundant metabolite in all volunteers was N-hydroxy-PhIP-N(2)-glucuronide. Metabolite levels varied significantly between the volunteers. Interindividual differences in colon DNA adducts levels were observed between each individual. The data showed that individuals with a rapid CYP1A2 phenotype and high levels of urinary N-hydroxy-PhIP-N(2)-glucuronide had the lowest level of colon PhIP-DNA adducts. This suggests that glucuronidation plays a significant role in detoxifying N-hydroxy-PhIP. The levels of urinary N-hydroxy-PhIP-N(2)-glucuronide were negatively correlated to colon DNA adduct levels. Although it is difficult to make definite conclusions from a small data set, the results from this pilot study have encouraged further investigations using a much larger study group.

Discordance between N-acetyltransferase 2 phenotype and genotype in a population of Hmong subjects.

Polymorphisms of N-acetyltransferase 2 (NAT2) acetylation may influence drug toxicities and efficacy and are associated with a differential susceptibility to select cancers. Acetylation phenotype may have clinical implications. The purposes of this study were to determine the genetic basis of an apparent predominance of slow acetylation phenotype and to assess concordance with genotype in a population of Hmong residing in Minnesota. Urine and DNA obtained from unrelated Hmong 18 to 65 years of age were used to determine phenotype from caffeine metabolites, whereas direct nucleotide sequencing of the NAT2 coding region, followed by cloning, identified all known allelic variants. From 61 subjects (27 men, 30 +/- 11 years), analysis of 50 urine-DNA pairs identified 46 (92%) slow acetylators and 4 (8%) rapid acetylators by phenotype. Genotypic analysis inferred 5 (10%) slow acetylators and 45 (90%) rapid acetylators. There is 86% discordance between phenotype and genotype. A predominance of NAT2 slow acetylation phenotype in the Hmong is confirmed, and a significant discordance between NAT2 phenotype and genotype is identified. In this population, slow acetylation phenotype determined by a metabolic probe would not have been predicted by genotype alone. Environmental, genetic, or phenotypic anomalies that may contribute to this discordance should be considered and evaluated in future studies within this unique population.

Associations between catalase phenotype and genotype: modification by epidemiologic factors.

Catalase is an endogenous antioxidant enzyme that neutralizes hydrogen peroxide and is induced by oxidative challenge. A -262C --> T polymorphism in the promoter region of the gene (CAT) is associated with risk of several conditions related to oxidative stress. We sought to determine the functional effects of the CAT polymorphism on enzyme activity in erythrocytes and the potential modifying effects of demographic and lifestyle factors on genotype/phenotype relationships, using specimens and data from controls from breast and prostate cancer studies in Arkansas (n = 420). There was a dose-response reduction in catalase activity by genotype, with geometric means of 115.4 units/mg hemoglobin for those with CC genotypes, 82.1 units/mg for those with CT genotypes, and 73.5 units/mg for those with TT genotypes. Associations were only observed among Caucasians (P < 0.0001), with no effects among African Americans (P = 0.91), and were stronger among women than men, although numbers in stratified analyses were small. Differences in catalase activity by genotype were most pronounced among those in the highest tertiles of consumption of fruits and vegetables (-35%, P = 0.003), with weaker relationships among those who were lower consumers (-21.8%, P = 0.16). Among those with CC genotypes, there was no change in activity by consumption, but there were notable decreases in activity by tertiles of consumption for those with at least one T allele. These data indicate that the CAT -262C --> T polymorphism predicts a portion of catalase phenotype, which may be limited to Caucasians. Associations between genotype and phenotype were modified by dietary factors, illustrating the biochemical complexity of studies of genetic polymorphisms and disease risk.

Verified predominance of slow acetylator phenotype N-acetyltransferase 2 (NAT2) in a Hmong population residing in Minnesota.

Southeast Asians known as the Hmong have a high prevalence of tuberculosis and select cancers. The slow acetylation (SA) phenotype for N-acetyltransferase 2 (NAT2) has been associated with toxicity from the anti-tuberculosis drug, isoniazid and in increased risk of select cancers. Previous research indicates a 74.5% prevalence of SA in Hmong which differs from other Asian populations including the Japanese and Thai (range: 7%-45%). Given this contrast, the purpose of this study was to confirm or refute this unexpected predominance of the SA phenotype in Hmong. Unrelated, Minnesota Hmong between 18 and 65 years of age consented and participated by ingesting caffeine as the probe for NAT2. A urinary caffeine metabolic ratio AFMU/1X (<0.6) was used to classify subjects as slow acetylators. Among 51 analysable samples provided by 61 enrollees (27 male, 33 female, 1 sex unknown, age 30+/-11 years [mean+/-SD]) there were 47 (92.2%) slow and 4 (7.8%) rapid acetylators. The prevalence of the SA phenotype (92.2%) from this study exceeds the 74.5% (p<0.02 by chi-square test) previously noted in Minnesota Hmong (n=98). The predominance of the SA phenotype within Minnesota Hmong is confirmed. Further studies evaluating this unexpected prevalence, its genetic basis and potential clinical relevance to drug toxicity and disease are warranted.

Association of SULT2A1 allelic variants with plasma adrenal androgens and prostate cancer in African American men.

Dehydroepiandrosterone (DHEA) sulfate which is present at micromolar levels in the plasma, can be desulfated to supply free DHEA for metabolism to androgens or estrogens in peripheral tissues. Human cytosolic sulfotransferase (SULT) 2A1 catalyzes DHEA sulfation in the adrenal cortex. Three SULT2A1 nonsynonymous coding single nucleotide polymorphisms (SNPs), identified only in African Americans (AA), are associated with decreased levels of activity and expression as compared to wild-type cDNA when expressed in COS cells. To test whether the SNPs are associated with decreased plasma androgens, 124 normal AA men were genotyped and plasma DHEA, DHEA-sulfate and testosterone levels determined. The two SNPs identified in these participants occurred at allelic frequencies of 0.044 (G187C) and 0.101 (G781A). The G187C SNP was highly linked to the G781A SNP. Although no differences in hormone levels were associated with the individual SNPs, a significant increase in the DHEA:DHEA-sulfate ratio was observed in participants with a heterozygous G187C/G781A genotype. Increased free DHEA levels may result in increased testosterone synthesis and stimulation in the prostate, therefore a group of AA prostate cancer (PC) patients and controls were genotyped. No significant association of the presence of the different SULT2A1 alleles with the occurrence of PC was detected.

Dietary intake of heterocyclic amines and benzo(a)pyrene: associations with pancreatic cancer.

OBJECTIVE: Heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons, formed in temperature- and time-dependent manners during the cooking of meat, are mutagens and carcinogens. We sought to assess the association between dietary intake of HCA and benzo(a)pyrene [B(a)P] and exocrine pancreatic cancer in a population-based case-control study. METHODS: Subjects (193 cases and 674 controls) provided information on their usual meat intake and preparation method, e.g., stewed, fried, or grilled/barbecued, etc. Meat doneness preferences were measured using photographs that showed internal doneness and external brownness. We used a meat-derived HCA, B(a)P, and mutagen database with a questionnaire to estimate intake of PhIP, DiMeIQx, MeIQx, B(a)P, and mutagenic activity (revertants/g of daily meat intake). Data were analyzed with unconditional logistic regression. RESULTS: In analyses adjusted for age, sex, smoking, education, race, and diabetes, the odds ratio and 95% confidence interval for the highest compared with the lowest quintile were as follows: PhIP, 1.8 (1.0-3.1); DiMeIQx, 2.0 (1.2-3.5); MeIQx, 1.5 (0.9-2.7); B(a)P, 2.2 (1.2-4.0); and mutagenic activity, 2.4 (1.3-4.3). CONCLUSIONS: HCAs and B(a)P from well-done barbecued and pan-fried meats may be associated with increased risk for pancreatic cancer.

Common genetic polymorphisms in the 5'-flanking region of the SULT1A1 gene: haplotypes and their association with platelet enzymatic activity.

SULT1A1 is a phase II detoxification enzyme involved in the biotransformation of a wide variety of endogenous and exogenous phenolic compounds. Human platelet SULT1A1 enzymatic activity shows marked inter-individual variability and a common coding polymorphism, SULT1A1*1/*2, has been described that accounts for a proportion of this variability. We examined the 5'-flanking region of the SULT1A1 gene to determine if genetic variability in this portion of the gene influenced enzymatic activity. Direct sequencing revealed five common genetic polymorphisms (-624G>C, -396G>A, -358A>C, -341C>G and -294T>C) that were present at different allele frequencies in Caucasian, African-American and Chinese groups. Platelet SULT1A1 enzymatic activity was significantly correlated with individual promoter region polymorphisms and the associations were different between African-Americans and Caucasians. Haplotypes were constructed and platelet enzymatic activity according to haplotype was examined. The haplotypes were also significantly correlated with activity; haplotypes GAACT and GGACT (accounting for 13% and 5% of inter-individual variability in platelet activity, respectively) were important in Caucasians while haplotypes GAACC, GAACT and GGACC (accounting for 8%, 5% and 4% of variability) were significantly associated with activity in African-Americans. The coding region polymorphism, SULT1A1*1/*2 was in linkage disequilibrium with the promoter region polymorphisms and showed no effect on activity when examined in the context of the 5'-flanking region polymorphisms. These studies indicate that variation in the promoter region of the SULT1A1 gene exerts a significant influence on enzymatic activity.

CYP3A43 Pro(340)Ala polymorphism and prostate cancer risk in African Americans and Caucasians.

The human cytochrome P450 3A subfamily of enzymes is involved in the metabolism of steroid hormones, carcinogens, and many drugs. A cytosine-to-guanine polymorphism in CYP3A43 results in a proline-to-alanine substitution at codon 340. Although the functional significance of this polymorphism is unknown, we postulate that the substitution of proline, an alpha-imino acid, with alanine, an amino acid, could be of biochemical significance. In a case-control study with 490 incident prostate cancer cases (124 African Americans and 358 Caucasians) and 494 controls (167 African Americans and 319 Caucasians), we examined the association between CYP3A43 Pro(340)Ala polymorphism and prostate cancer risk. When all subjects were considered, there was a 3-fold increase in risk of prostate cancer among individuals with the CYP3A43-Ala/Ala genotype (odds ratio, 3.0; 95% confidence interval, 1.2-7.2) compared with those with the CYP3A43-Pro/Pro genotype after adjusting for age, race, and smoking. The prevalence of the polymorphism was significantly higher in African Americans than Caucasians (45% versus 13%). In African Americans, there was a 2.6-fold increase in prostate cancer risk among individuals with the CYP3A43-Ala/Ala genotype (odds ratio, 2.6; 95% confidence interval, 1.0-7.0) compared with those with the CYP3A43-Pro/Pro genotype. Among Caucasians, the small number of homozygotes precluded computing risk estimates; there were only three individuals with the CYP3A43-Ala/Ala genotype. Our results suggest that the CYP3A43-Pro(340)Ala polymorphism contributes to prostate cancer risk.