PharmGKB submission update: V. PMT submissions of genetic variation in SLC22 family transporters.
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Genetic Variation↗
Biomedical subjects
Wendy Chan
Publications and source records attributed to Wendy Chan.
PharmGKB submission update: VI. PMT submissions of genetic variations in neurotransmitter transporters (SLC6, SLC17, and SLC18) to the PharmGKB network.
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Genetic Variation↗
The human organic anion transporter 3 (OAT3; SLC22A8): genetic variation and functional genomics.
The human organic anion transporter, OAT3 (SLC22A8), plays a critical role in renal drug elimination, by mediating the entry of a wide variety of organic anions, including a number of commonly used pharmaceuticals, into the renal proximal tubular cells. To understand the nature and extent of genetic variation in OAT3, and to determine whether such variation affects its function, we identified OAT3 variants in a large, ethnically diverse sample population and studied their transport activities in cellular assays. We identified a total of 10 distinct coding-region variants, which altered the encoded amino acid sequence, in DNA samples from 270 individuals (80 African-Americans, 80 European-Americans, 60 Asian-Americans, and 50 Mexican-Americans). The overall prevalence of these OAT3 variants was relatively low among the screened population, with only three variants having allele frequencies of >1% in a particular ethnic group. Clones of each variant were created by site-directed mutagenesis, expressed in HEK-293 cells, and tested for function using the model substrates, estrone sulfate (ES) and cimetidine (CIM). The results revealed a high degree of functional heterogeneity among OAT3 variants, with three variants (p. Arg149Ser, p. Gln239Stop, and p. Ile260Arg) that resulted in complete loss of function, and several others with significantly reduced function. One of the more common variants (p. Ile305Phe), found in 3.5% of Asian-Americans, appeared to have altered substrate specificity. This variant exhibited a reduced ability to transport ES, but a preserved ability to transport CIM. These data suggest that genetic variation in OAT3 may contribute to variation in the disposition of drugs.
Alleles↗
Egg consumption and endothelial function: a randomized controlled crossover trial.
BACKGROUND: Because of egg cholesterol content, reduction in egg consumption is generally recommended to reduce risk of cardiovascular disease. Recently, however, evidence has been accumulating to suggest that dietary cholesterol is less relevant to cardiovascular risk than dietary saturated fat. This randomized controlled crossover trial was conducted to determine the effects of egg ingestion on endothelial function, a reliable index of cardiovascular risk. METHODS: Forty-nine healthy adults (mean age 56 years, 40% females) underwent a baseline brachial artery reactivity study (BARS), and were assigned to two eggs or oats daily for 6 weeks in random sequence with a 4-week washout. A BARS was done at the end of each treatment phase, measuring flow-mediated vasodilation (FMD) in the brachial artery using a high-frequency ultrasound. RESULTS: FMD was stable in both egg and oat groups, and between-treatment differences were not significant (egg -0.96%, oatmeal -0.79%; p value >0.05). Six weeks of egg ingestion had no effect on total cholesterol (baseline: 203.8 mg/dl; post-treatment: 205.3) or LDL (baseline: 124.8 mg/dl; post-treatment: 129.1). In contrast, 6 weeks of oats lowered total cholesterol (to 194 mg/dl; p = 0.0017) and LDL (to 116.6 mg/dl; p = 0.012). There were no differences in body mass index (BMI), triglyceride, HDL or SBP levels between egg and oat treatment assignments. CONCLUSION: Short-term egg consumption does not adversely affect endothelial function in healthy adults, supporting the view that dietary cholesterol may be less detrimental to cardiovascular health than previously thought.
Cross-Over Studies↗
One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer.
Accumulating evidence from epidemiologic studies suggests that risk of breast cancer is reduced in relation to increased consumption of folate and related B vitamins. We investigated independent and joint effects of B vitamin intake as well as two polymorphisms of a key one-carbon metabolizing gene [i.e., methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C] on breast cancer risk. The study uses the resources of a population-based case-control study, which includes 1,481 cases and 1,518 controls. Significant inverse associations between B vitamin intake and breast cancer risk were observed among non-supplement users. The greatest reduction in breast cancer risk was observed among non-supplement users in the highest quintile of dietary folate intake [odds ratio (OR), 0.61; 95% confidence interval (95% CI), 0.41-0.93] as compared with non-supplement users in the lowest quintile of dietary folate intake (high-risk individuals). The MTHFR 677T variant allele was associated with increased risk of breast cancer (P, trend = 0.03) with a multivariate-adjusted OR of 1.37 (95% CI, 1.06-1.78) for the 677TT genotype. The 1298C variant allele was inversely associated with breast cancer risk (P, trend = 0.03), and was likely due to the linkage of this allele to the low-risk allele of 677C. The MTHFR-breast cancer associations were more prominent among women who did not use multivitamin supplements. Compared with 677CC individuals with high folate intake, elevation of breast cancer risk was most pronounced among 677TT women who consumed the lowest levels of dietary folate (OR, 1.83; 95% CI, 1.13-2.96) or total folate intake (OR, 1.71; 95% CI, 1.08-2.71). From a public heath perspective, it is important to identify risk factors, such as low B vitamin consumption, that may guide an effective prevention strategy against the disease.
Aged↗
Haplotype-phenotype relationships of paraoxonase-1.
Paraoxonase 1 (PON1) is an enzyme with multiple activities, including detoxification of organophosphates. It is believed to be important in preventing neurotoxic damage and has also been implicated in atherosclerosis. The PON1 gene contains five common polymorphisms, three in the promoter (-909G > C, -162A > G, -108C > T) and two in the coding region (M55L, Q192R) with varying but incomplete linkage disequilibrium. Our previous study showed that functional polymorphisms in PON1 were strongly associated with enzymatic activity in both pregnant women [26-30 weeks of gestation] and neonates. However, there was substantial overlapping of enzyme activities between genotypes. In this study, we investigated whether haplotype (genotype + phase) information would strengthen the genotype-phenotype relationship for PON1. The study consisted of a multiethnic population of 402 mothers and 229 neonates. Haplotypes were imputed by two widely used programs, PHASE and tagSNPs, which yielded very similar results. There were seven haplotypes with a frequency of 5% or higher in at least one ethnic group of the study population. Haplotype composition varied substantially with respect to ethnicity. Haplotypes in Caucasians and African-Americans showed the largest difference, and Caribbean Hispanics seemed to be a mixture of Caucasian and African ancestry. Collectively, the genetic (genotype or haplotype) contribution to PON1 enzymatic activity (measured as phenylacetate hydrolysis) was greater in neonates compared with mothers. Specifically, 16.6% of PON1 variability was explained by genotypes in mothers compared with 30.9% in neonates. Haplotype information offered a slightly increased power in predicting PON1 activity; they explained 35.5% and 19.3% of PON1 variability in neonates and mothers, respectively.
Adult↗
Polymorphisms in the one-carbon metabolic pathway, plasma folate levels and colorectal cancer in a prospective study.
One-carbon (e.g., folate) metabolism plays a pivotal role in the etiology of colorectal cancer (CRC). Cytosolic serine hydroxymethyltransferase (cSHMT), methylenetetrahydrofolate dehydrogenase (MTHFD1) and glutamate carboxypeptidase II (GCPII) are key genes involved in this pathway. Several new polymorphisms have been identified and there is evidence implicating their functionality. We examined whether polymorphisms in these genes, i.e., cSHMT L474F, MTHFD1 R653Q and GCPII H475Y, modify the risk of CRC in the prospective Physicians' Health Study. Among the 270 incident CRC cases and 453 controls, none of the one-carbon polymorphisms were associated with risk of CRC. Compared to the wild-type genotype, the multivariate-adjusted relative risks and 95% confidence intervals were 1.14 [0.68, 1.93] for cSHMT 474FF, 1.04 [0.67, 1.62] for MTHFD1 653QQ and 1.00 [0.55, 1.82] for GCPII 474HY. Furthermore, we examined the associations between one-carbon polymorphisms and folate status in terms of plasma folate and homocysteine levels in this population. No independent gene effect was observed. Although compound homozygous variants at cSHMT and MTHFD1 loci had the lowest plasma folate levels compared to other compound genotypes, no significant gene-gene interactions were observed. Findings from our prospective investigation indicate that these newly identified polymorphisms in one-carbon metabolizing genes have limited functionality in modifying folate status and related CRC risk.
Adult↗
Oats, antioxidants and endothelial function in overweight, dyslipidemic adults.
OBJECTIVE: To determine effects of oat and antioxidant vitamin (C 500 mg, E 400 IU) ingestion on endothelial function in overweight, dyslipidemic adults. DESIGN: Randomized, blinded, placebo-controlled, crossover trial Intervention(s): Subjects (16 males > or = age 35; 14 postmenopausal females) were assigned, in random order, to oats (60 g oatmeal), vitamin E (400 IU) plus vitamin C (500 mg), the combination of oats and vitamins, or placebo, and underwent brachial artery reactivity scans (BARS) following a single dose of each treatment, and again following 6 weeks of daily ingestion, with 2-week washout periods. At each test, a provocation high-fat meal (50 g, predominantly saturated) was administered and subjects were scanned pre, and 3 hours post-ingestion. RESULTS: Mean flow-mediated vasodilation (FMD; measured as percent diameter change before and after treatments) at baseline was 6.35 +/- 3.37. Oats increased FMD non-significantly (p > 0.05) with both single acute dose (from 6.07 +/- 6.25 to 9.22 +/- 8.82) and six weeks of sustained treatment (from 6.01 +/- 10.07 to 8.69 +/- 8.42). The direction of effect was negative for vitamins and the oat/vitamin combination with both acute and sustained treatment. There were no significant differences in FMD change among the treatments in either phase of the study, however when acute and sustained effects were pooled, oat treatment significantly augmented FMD (p < 0.05). CONCLUSIONS: This trial suggests but does not confirm a beneficial influence of oat ingestion on endothelial function in overweight, dyslipidemic adults. Further study of this potential association is warranted.
Adult↗
Functional and genetic diversity in the concentrative nucleoside transporter, CNT1, in human populations.
The concentrative nucleoside transporter, CNT1 (SLC28A1), mediates the cellular uptake of naturally occurring pyrimidine nucleosides and many structurally diverse anticancer and antiviral nucleoside analogs. As a first step toward understanding whether genetic variation in CNT1 contributes to variation in the uptake and disposition of clinically used nucleoside analogs, we determined the haplotype structure and functionally analyzed all coding region variants of CNT1 identified in ethnically diverse populations (100 African Americans, 100 European Americans, 30 Asians, 10 Mexican Americans, and 7 Pacific Islanders) (Leabman et al., 2003). A total of 58 coding region haplotypes were identified using PHASE analysis, 44 of which contained at least one amino acid variant. More than half of the coding region haplotypes were population-specific. Using site-directed mutagenesis, 15 protein-altering CNT1 variants, including one amino acid insertion and one base pair (bp) deletion, were constructed and expressed in Xenopus laevis oocytes. All variant transporters took up [3H]thymidine with the exception of CNT1-Ser546Pro, a rare variant, and CNT1-1153del, a single bp deletion found at a frequency of 3% in the African American population. The bp deletion results in a frame-shift followed by a stop-codon. The anticancer nucleoside analog gemcitabine had a reduced affinity for CNT1-Val189Ile (a common CNT1 variant found at a frequency of 26%) compared with reference CNT1 (IC50=13.8 +/- 0.60 microM for CNT1-reference and 23.3 +/- 1.5 microM for CNT1-Val189Ile, p<0.05). These data suggest that common genetic variants of CNT1 may contribute to variation in systemic and intracellular levels of anti-cancer nucleoside analogs.
Amino Acid Sequence↗
Smoking cessation for high school students. Impact evaluation of a novel program.
This pilot study was designed to evaluate the feasibility and the impact of a smoking-cessation program that would meet the specific needs of high school students. Feedback from focus groups conducted with adolescent smokers at a Connecticut high school was used to develop a tailored intervention. Intervention components included commonly used behavioral strategies, with additional options to assist students to quit smoking, including use of bupropion, concomitant support for parent smoking cessation, stress management, and physician counseling. On completion, 20 of the 22 enrolled students remained committed to quitting. Twenty-seven percent of students quit smoking and 69% of those who continued to smoke reduced the number of cigarettes smoked per day by an average of 13. Providing additional options to students and additional support for concomitant parental cessation may enhance the appeal of adolescent smoking-cessation programs. Further investigation into efficacy of bupropion use for adolescent cessation is warranted.
Adolescent↗
Polymorphism in the thymidylate synthase promoter enhancer region and risk of colorectal adenomas.
Thymidylate synthase (TS), a key one-carbon metabolizing gene, encodes an enzyme that converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. We recently reported that a promoter polymorphism in TS modified the risk of colorectal cancer as well as the survival rate after the disease. To explore whether TS may play an important role in colorectal carcinogenesis early in the multistaged pathogenic pathway, we investigated the relation between the TS promoter polymorphism and risk of colorectal adenoma in a nested case-control study within the prospective Health Professionals Follow-up Study. We ascertained the TS genotype from 373 incident colorectal adenoma cases and 720 control subjects. Although there was no overall association between the TS promoter polymorphism and adenoma risk, we observed a significant TS-alcohol interaction (P for interaction = 0.009); relative to low alcohol consumers with the 2R/2R genotype, those with high alcohol consumption (>30 g/d) were not at elevated risk if they had the 2R/2R genotype [relative risk (RR), 0.80; 95% confidence interval (95% CI), 0.34-1.90], but were at higher risk if they had the 2R/3R genotype (RR, 1.70; 95% CI, 0.87-3.31), and at the highest risk (RR, 3.16; 95% CI, 1.50-6.63) if they had the 3R/3R genotype. In addition, a significant interaction was observed between the TS promoter polymorphism and the 677C > T polymorphism of methylenetetrahydrofolate reductase (MTHFR; P for interaction = 0.007). These findings lend additional support that one-carbon metabolism is an important process in pathogenesis of colorectal cancer.
Adenoma↗
Raloxifene and endothelial function in healthy postmenopausal women.
OBJECTIVE: The purpose of this study was to determine the effects of raloxifene on endothelial function in healthy, postmenopausal women. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled crossover trial. Subjects (n = 19; mean age, 61 years) underwent endothelial function testing at baseline and after treatment with placebo or raloxifene (60 mg per day for 6 weeks). RESULTS: Brachial artery diameter change (flow-mediated dilation) increased 5.0% with placebo and 8.56% with raloxifene (SE = 1.83, P =.03) in response to a hyperemic stimulus; an adjustment of this response for a variation in stimulus intensity resulted in greater discrimination (P =.009). The ratio of area under the curve response to area under the curve reference with the use of laser Doppler measures was 1.18 for placebo and 1.28 for raloxifene (P =.05). Flow-mediated dilation and area under the curve ratio correlated significantly (r = 0.33, P =.04). CONCLUSION: Treatment with raloxifene enhanced endothelial-mediated dilation in brachial arteries and digital vessels in healthy, postmenopausal women. A potential mechanism for a cardioprotective effect of raloxifene is suggested and warrants further study.
Brachial Artery↗
Impediment profiling for smoking cessation. Preliminary experience.
INTRODUCTION: Cigarette smoking is a leading cause of preventable death. METHODS: Long and short "impediment profilers" (LIPs and SIPs, respectively) addressing nicotine addiction, depression, anxiety, stress, chemical dependency, weight control, and household smoking were developed and applied in a pilot smoking cessation study to tailor treatment. RESULTS: Quit rate 72 hours after the target quit date was 50%; at 8 and 12 weeks it was 61% and 39%, respectively. The LIP identified fewer impediments than the SIP. CONCLUSIONS: Impediment profiling for tailored smoking cessation intervention is associated with high initial quit rates and warrants further study.
Adult↗
Increased influence of genetic variation on PON1 activity in neonates.
PON1 (paraoxonase-1) detoxifies organophosphates by cleavage of active oxons before they have a chance to inhibit cholinesterases. The corresponding gene PON1 has common polymorphisms in both the promoter (-909, -162, -108) and the coding region (L55M, Q192R). The five PON1 genotypes were determined for maternal blood (n= 402) and cord blood (n= 229) as part of a study of the effects of organophosphate pesticide exposure on infant growth and neurodevelopment. PON1 enzymatic activities were determined for a majority of subjects. The population contained Caucasians, Caribbean Hispanics, and African Americans. PON1 activity was strongly dependent upon the promoter alleles in both maternal and cord blood. For example, PON1 activities for position -108CC, CT, and TT mothers were 146, 128, and 109 arylesterase U/mL (analysis of variance, p< 0.0001), whereas the same PON1 activities for the respective cord bloods were 49.0, 32.4, and 23.2 U/mL (p < 0.0001). Compared with adults, neonates had lower PON1 activity, implying reduced capacity to detoxify organophosphates. In addition there was a larger difference in activity between genotype groups in neonates than in adults. Because the five polymorphisms in PON1 occur in a short stretch of DNA, they were tested for linkage disequilibrium (LD). Significant LD was found among all three promoter polymorphisms as well as between promoter polymorphisms and L55M, with the strongest LD for Caucasians and the weakest for African Americans. The Caribbean Hispanics fall between these two groups. Surprisingly, significant LD also was observed between the promoter polymorphisms and C311S in PON2. LD between the promoter polymorphisms and Q192R was not significant.
Adult↗
Polymorphism in the thymidylate synthase promoter enhancer region modifies the risk and survival of colorectal cancer.
Thymidylate synthase (TS) converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. It is also the target for 5-flurorouracil, the most common chemotherapy agent for treatment of colorectal cancer (CRC). We designed a nested case-control study within the prospective Physicians' Health Study to investigate whether TS polymorphisms independently predict risk of CRC and simultaneously the overall survival after the disease in the same population. We also investigated influences of this polymorphism on plasma folate and homocysteine levels. The study consists of 270 incident CRC and 454 control subjects. Risk of CRC was estimated by use of conditional multiple logistic regression analysis. Survival was analyzed by Cox proportional hazards regression analysis. Compared with the TS 3R/3R genotype, the multivariate-adjusted risk ratio was 0.86 (0.59-1.25) for the 2R/3R genotype and 0.59 (0.36-0.98) for the 2R/2R genotype with P for trend of 0.03. The TS 2R/2R genotype was also associated with better survival, although the results were not significant. Compared with those with either the 3R/3R or 2R/3R genotypes, the age-adjusted hazard ratio for the 2R/2R genotype was 0.57 (0.30-1.07). Individuals with the 2R/2R genotype had significantly lower plasma folate levels than those with the 3R/3R genotype, whereas their plasma homocysteine levels were unaffected by the TS promoter polymorphism. The deletion polymorphism at the TS 3'-untranslated region did not influence the CRC risk and survival, nor did it modify the plasma folate and total homocysteine levels. Given that individuals with high plasma folate had a better survival outcome with a hazard ratio of 0.68 (0.45-1.03) compared with those with low plasma folate, we conclude that the TS promoter polymorphism may modify both the risk and the survival of CRC; however, these effects do not appear to be mediated through its modulation of biological folate levels.
Aged↗
Technical skills for weight loss: preliminary data from a randomized trial.
BACKGROUND: Optimal behavioral interventions for sustainable weight loss are uncertain. We therefore conducted a study among overweight/obese women comparing conventional dietary counseling of individuals (counseling-based intervention) to a novel, group-based skill-building intervention. METHODS: Eighty subjects were randomly assigned to either the counseling-based or to the skill-building intervention. Outcomes included weight loss, dietitian hours per group and per unit weight loss, and dollars spent per group and per unit weight lost. RESULTS: Weight loss at 6 months (follow-up rate 61.3%) in the counseling-based group was 8.8 lb (P = 0.0001), and in the skill-building group was 3.8 lb (P = 0.01). A total of 160 dietitian hours were required for the counseling-based group, and 131 for the skilled-building group. The counseling-based group cost an average of $21 per pound lost, while the skill-building cost an average of $48 per pound lost (P = 0.16). CONCLUSIONS: At 6 months, individualized office-based counseling produced more weight loss than a skill-building approach and cost less than half as much per pound of weight loss. Longer-term follow-up is required to determine if, as hypothesized, the skill-building intervention produces more sustainable weight loss.
Adult↗
T-cell rich B-cell lymphoma: clinical distinctiveness and response to treatment in 45 patients.
T-cell rich B-cell lymphoma (TCR-BCL) is a recently described pathologic diagnosis without a place among traditional lymphoma classification systems. In the past, TCR-BCL has been included among other diagnoses, in particular lymphocyte predominant Hodgkin's disease (LPHD). The study of TCR-BCL cohorts may elucidate clinical distinctiveness, response to therapy, and the effect of treatment regimen on outcome. Between 1992 and 1997, a hematopathologist at Memorial Sloan-Kettering Cancer Center (MSKCC) diagnosed 45 patients with TCR-BCL according to published criteria. Clinical data was collected through retrospective chart review and communication with other patient providers. Our patients presented most commonly as males in their fourth decade with advanced stage disease. Three-year overall survival (OS) and failure-free survival (FFS) were 73 and 37%, respectively. Conventional combination chemotherapy regimens were utilized for an aggressive non-Hodgkin's lymphoma (NHL) diagnosis in 26 and for a Hodgkin's disease (HD) diagnosis in 10. Disease-free survival (DFS) was significantly better for NHL (36%) vs. HD (10%) directed chemotherapy at 3 years (p = 0.003). Overall survival at 3 years was not statistically different (62 vs. 79%) due to successful salvage therapy in both groups. It is important to distinguish TCR-BCL from LPHD and classical HD. Advanced stage, extranodal disease, involvement of the mediastinum, mesentery and/or spleen are clinical clues to a TCR-BCL diagnosis. Chemotherapy directed to a NHL diagnosis rather than HD results in a significant improvement in disease-free survival. Initial Hodgkin's disease-directed (HD-directed) chemotherapy should be avoided, although salvage transplantation may result in prolonged survival.
Adolescent↗
Increasing the success of physician order entry through human factors engineering.
Even though the success of a physician order entry (POE) system depends on meeting physicians' needs, no studies of POE systems report using standard, formal methods for assessing physician needs and how to design the best technology to meet those needs. To increase the chance of a successful POE implementation, the article proposes that techniques from the field of human factors engineering (HFE) be used to enhance the interaction between technology and the physicians.
Attitude to Computers↗