Publications by authors named "Shiva Krishnan"

15 Publications

  • Page 1 of 1

Stromal PTEN determines mammary epithelial response to radiotherapy.

Nat Commun 2018 07 17;9(1):2783. Epub 2018 Jul 17.

Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.

The importance of the tumor-associated stroma in cancer progression is clear. However, it remains uncertain whether early events in the stroma are capable of initiating breast tumorigenesis. Here, we show that in the mammary glands of non-tumor bearing mice, stromal-specific phosphatase and tensin homolog (Pten) deletion invokes radiation-induced genomic instability in neighboring epithelium. In these animals, a single dose of whole-body radiation causes focal mammary lobuloalveolar hyperplasia through paracrine epidermal growth factor receptor (EGFR) activation, and EGFR inhibition abrogates these cellular changes. By analyzing human tissue, we discover that stromal PTEN is lost in a subset of normal breast samples obtained from reduction mammoplasty, and is predictive of recurrence in breast cancer patients. Combined, these data indicate that diagnostic or therapeutic chest radiation may predispose patients with decreased stromal PTEN expression to secondary breast cancer, and that prophylactic EGFR inhibition may reduce this risk.
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http://dx.doi.org/10.1038/s41467-018-05266-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050339PMC
July 2018

Discovery and replication of microRNAs for breast cancer risk using genome-wide profiling.

Oncotarget 2016 Dec;7(52):86457-86468

Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

Background: Genome-wide miRNA expression may be useful for predicting breast cancer risk and/or for the early detection of breast cancer.

Results: A 41-miRNA model distinguished breast cancer risk in the discovery study (accuracy of 83.3%), which was replicated in the independent study (accuracy = 63.4%, P=0.09). Among the 41 miRNA, 20 miRNAs were detectable in serum, and predicted breast cancer occurrence within 18 months of blood draw (accuracy 53%, P=0.06). These risk-related miRNAs were enriched for HER-2 and estrogen-dependent breast cancer signaling.

Materials And Methods: MiRNAs were assessed in two cross-sectional studies of women without breast cancer and a nested case-control study of breast cancer. Using breast tissues, a multivariate analysis was used to model women with high and low breast cancer risk (based upon Gail risk model) in a discovery study of women without breast cancer (n=90), and applied to an independent replication study (n=71). The model was then assessed using serum samples from the nested case-control study (n=410).

Conclusions: Studying breast tissues of women without breast cancer revealed miRNAs correlated with breast cancer risk, which were then found to be altered in the serum of women who later developed breast cancer. These results serve as proof-of-principle that miRNAs in women without breast cancer may be useful for predicting breast cancer risk and/or as an adjunct for breast cancer early detection. The miRNAs identified herein may be involved in breast carcinogenic pathways because they were first identified in the breast tissues of healthy women.
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http://dx.doi.org/10.18632/oncotarget.13241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349926PMC
December 2016

Single-Nucleotide Polymorphisms and Markers of Oxidative Stress in Healthy Women.

PLoS One 2016 7;11(6):e0156450. Epub 2016 Jun 7.

Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York, United States of America.

Purpose: There is accumulating evidence that oxidative stress is an important contributor to carcinogenesis. We hypothesized that genetic variation in genes involved in maintaining antioxidant/oxidant balance would be associated with overall oxidative stress.

Methods: We examined associations between single nucleotide polymorphisms (SNPs) in MnSOD, GSTP1, GSTM1, GPX1, GPX3, and CAT genes and thiobarbituric acid-reactive substances (TBARS), a blood biomarker of oxidative damage, in healthy white women randomly selected from Western New York (n = 1402). We used general linear models to calculate age-adjusted geometric means of TBARS across the variants. We also examined the associations within strata of menopausal status.

Results: For MnSOD, being heterozygous was associated with lower geometric means of TBARS (less oxidative stress), 1.28 mg/dL, compared to homozygous T-allele or homozygous C-allele,1.35 mg/dL, and 1.31 mg/dL correspondingly (p for trend = 0.01). This difference remained among postmenopausal women, 1.40 mg/dL for TT, 1.32 mg/dL for TC, and 1.34mg/dL for CC (p for trend 0.015); it was attenuated among premenopausal women. SNPs in the other genes examined (GSTP1, GSTM1, GPX1, GPX3, and CAT) were not associated with TBARS.

Conclusions: Our findings suggest that genetic variation in MnSOD gene may be associated with oxidative status, particularly among postmenopausal women.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156450PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896456PMC
July 2017

Associations of erythrocyte ω-3 fatty acids with biomarkers of ω-3 fatty acids and inflammation in breast tissue.

Int J Cancer 2015 Dec 28;137(12):2934-46. Epub 2015 Jul 28.

Department of Internal Medicine, Division of Cancer Prevention and Control, The Ohio State University College of Medicine, Columbus, OH.

There is increasing evidence that chronic inflammation is associated with increased breast cancer risk. Long-chain omega-3 polyunsaturated fatty acids (LCω-3PUFA) may reduce circulating biomarkers of inflammation; however associations of blood LCω-3PUFA with breast tissue LCω-3PUFA and breast tissue biomarkers of inflammation are not well understood. We conducted a cross-sectional analysis of breast tissue and blood samples from n = 85 women with no history of breast cancer, who underwent breast reduction surgery. Fatty acids of erythrocytes and undissected breast tissues were analyzed by gas chromatography; C-reactive protein (CRP), interleukin (IL)-6 and IL-8 in plasma and tissue were measured by ELISA. Multivariable-adjusted regression models were used to estimate associations between erythrocyte LCω-3PUFA and breast tissue biomarkers. Women in the highest erythrocyte LCω-3PUFA tertile had LCω-3PUFA concentrations in the breast 73% (95% CI: 31-128%; p trend < 0.0001) higher than women in the lowest tertile. Associations for each individual LCω-3PUFA were similar in magnitude. No significant association was found for the shorter ω-3 PUFA, α-linolenic acid. Although compatible with no association, women in the highest tertile of erythrocyte eicosapentaenoic acid had a nonsignificant 32% (95% CI: -23 to 62%) reduced breast tissue CRP. No correlation was observed between erythrocyte ω-3 PUFA and tissue IL-6 or IL-8 concentrations. Our findings provide evidence that erythrocyte ω-3 fatty acids are valid measures of breast tissue concentrations, and limited evidence that inverse associations from prospective epidemiologic studies of blood LCω-3PUFA and breast cancer risk may be partly explained by reductions in breast tissue inflammation; however, these findings require replication.
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http://dx.doi.org/10.1002/ijc.29675DOI Listing
December 2015

Promoter methylation of E-cadherin, p16, and RAR-β(2) genes in breast tumors and dietary intake of nutrients important in one-carbon metabolism.

Nutr Cancer 2011 14;63(7):1143-50. Epub 2011 Sep 14.

Department of Social and Preventive Medicine, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York 14214, USA.

Aberrant DNA methylation plays a critical role in carcinogenesis, and the availability of dietary factors involved in 1-carbon metabolism may contribute to aberrant DNA methylation. We investigated the association of intake of folate, vitamins B(2), B(6), B(12), and methionine with promoter methylation of E-cadherin, p16, and RAR-β(2) genes in archived tumor tissues from incident, primary breast cancer cases in a population-based case-control study. Real-time methylation-specific PCR was performed on 803 paraffin-embedded samples; usual dietary intake was queried from a food frequency questionnaire. Unconditional logistic regression was used to derive adjusted odds ratios and 95% confidence intervals for likelihood of promoter methylation for high compared to low intake of those 1-carbon nutrients. Overall, in case-case comparisons, dietary intakes of folate, vitamins B(2), B(6), B(12), and methionine were not associated with likelihood of promoter methylation of E- cadherin, p16, and RAR-β(2) for all cases combined or within strata defined by menopausal status and estrogen receptor status in this study. This finding, however, does not exclude the possibility that intake of such nutrients might have the ability to modulate promoter methylation in normal or premalignant (dysplastic) breast tissue.
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http://dx.doi.org/10.1080/01635581.2011.605982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834353PMC
February 2012

Body mass and DNA promoter methylation in breast tumors in the Western New York Exposures and Breast Cancer Study.

Am J Clin Nutr 2011 Sep 20;94(3):831-8. Epub 2011 Jul 20.

Department of Social and Preventive Medicine, School of Public Health and Health Professions, University at Buffalo, NY, USA.

Background: The mechanism of the observed association between body mass, particularly centralized body fat, and postmenopausal breast cancer risk is not well understood.

Objective: We hypothesized that body mass may affect DNA methylation through increased estrogen and chronic inflammation. The association between body mass and promoter methylation in breast tumors was investigated in a population-based, case-control study.

Design: The promoter methylation of E-cadherin, p16, and RAR-β(2) genes was assessed in breast tumor blocks from 803 pre- and postmenopausal cases by using real-time methylation-specific polymerase chain reaction. Unconditional logistic regression was used to derive the adjusted OR and 95% CI for case-case comparisons of tumors with and without promoter methylation of the genes.

Results: The frequency of promoter methylation was 20% for E-cadherin, 25.9% for p16, and 27.5% for RAR-β(2). There was no difference in the prevalence of the DNA methylation of individual genes by BMI, waist-to-hip ratio (WHR), or lifetime weight change between the age of 20 y and the present. However, in a case-case comparison of postmenopausal breast cancer, a greater WHR was associated with an increased likelihood of ≥1 of the 3 genes being methylated (OR: 1.85; 95% CI: 1.10, 3.11; P-trend < 0.02).

Conclusions: We showed that WHR was associated with DNA promoter methylation of ≥1 of 3 genes in postmenopausal breast tumors. It may be that the association of body fat composition and postmenopausal breast cancer is related to altered DNA methylation. However, future studies in other populations and with an examination of the methylation of more genes are needed.
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http://dx.doi.org/10.3945/ajcn.110.009365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155934PMC
September 2011

Single-nucleotide polymorphisms in DNA repair genes and association with breast cancer risk in the web study.

Carcinogenesis 2011 Aug 27;32(8):1223-30. Epub 2011 May 27.

Department of Social and Preventive Medicine, University at Buffalo, Buffalo, NY 14214, USA.

Base excision repair (BER) and nucleotide excision repair (NER) pathways repair damaged DNA, and polymorphisms in these genes might affect breast cancer susceptibility. We evaluated associations between seven single-nucleotide polymorphisms in four DNA repair genes (ERCC4 rs1799801, XPC rs2227998, rs2228001, rs2228000, OGG1 rs1052133 and XRCC1 rs25487 and rs25486) and breast cancer risk, examining modification by smoking and alcohol consumption, using data from the Western New York Exposures and Breast Cancer Study. Women aged 35-79 years with incident breast cancer (n = 1170) and age- and race-matched controls (n = 2115) were enrolled. Genotyping was performed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). No significant associations were observed in premenopausal women. Among postmenopausal women, rs25487 and rs25486 (OR = 1.24; 95% CI 1.01-1.51 and OR = 1.23; 95% CI 1.01-1.49, respectively, for combined heterozygous and homozygous variant compared with reference) were associated with increased risk of breast cancer. Postmenopausal women carrying the variant allele of the synonymous XPC polymorphism (rs2227998) were also at borderline significantly increased risk (OR = 1.24; 95% CI 1.01-1.52, heterozygous variant compared with reference; OR = 1.22; 95% CI 1.01-1.48, for combined heterozygous and homozygous variant compared with reference). There was no evidence of genotype-smoking and genotype-alcohol consumption interactions for pre- and postmenopausal women. These results indicate that some of the variants in BER and NER genes may influence risk of postmenopausal breast cancer.
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http://dx.doi.org/10.1093/carcin/bgr096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149207PMC
August 2011

Alcohol consumption in relation to aberrant DNA methylation in breast tumors.

Alcohol 2011 Nov 18;45(7):689-99. Epub 2010 Dec 18.

Department of Social and Preventive Medicine, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA.

The mechanism for the observed association of alcohol consumption breast cancer risk is not known; understanding that mechanism could improve understanding of breast carcinogenesis and optimize prevention strategies. Alcohol may impact breast malignancies or tumor progression by altering DNA methylation. We examined promoter methylation of three genes, the E-cadherin, p16, and retinoic acid-binding receptor-β2 (RAR-β2) genes in archived breast tumor tissues from participants in a population-based case-control study. Real time methylation-specific PCR was performed on 803 paraffin-embedded samples, and lifetime alcohol consumption was queried. Unordered polytomous and unconditional logistic regression were used to derive adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RAR-β2 methylation was not associated with drinking. Among premenopausal women, alcohol consumption was also not associated with promoter methylation for E-cadherin and p16 genes. In case-case comparisons of postmenopausal breast cancer, compared with lifetime never drinkers, promoter methylation likelihood was increased for higher alcohol intake for E-cadherin (OR=2.39; 95% CI, 1.15-4.96), in particular for those with estrogen receptor-negative tumors (OR=4.13; 95% CI, 1.16-14.72), and decreased for p16 (OR=0.52; 95% CI, 0.29-0.92). There were indications that the association with p16 was stronger for drinking at younger ages. Methylation was also associated with drinking intensity independent of total consumption for both genes. We found alcohol consumption was associated with DNA methylation in postmenopausal breast tumors, suggesting that the association of alcohol and breast cancer may be related, at least in part, to altered methylation, and may differ by drinking pattern.
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http://dx.doi.org/10.1016/j.alcohol.2010.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137700PMC
November 2011

DNA promoter methylation in breast tumors: no association with genetic polymorphisms in MTHFR and MTR.

Cancer Epidemiol Biomarkers Prev 2009 Mar 24;18(3):998-1002. Epub 2009 Feb 24.

Department of Social and Preventive Medicine, School of Public Health and Health Professions, 270 Farber Hall, University at Buffalo, Buffalo, NY 14214, USA.

Aberrant promoter methylation is recognized as an important feature of breast carcinogenesis. We hypothesized that genetic variation of genes for methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR), two critical enzymes in the one-carbon metabolism, may alter DNA methylation levels and thus influence DNA methylation in breast cancer. We evaluated case-control association of MTHFR C677T, A1298C, and MTR A2756G polymorphisms for cases strata-defined by promoter methylation status for each of three genes, E-cadherin, p16, and RAR-beta2 in breast cancer; in addition, we evaluated case-case comparisons of the likelihood of promoter methylation in relation to genotypes using a population-based case-control study conducted in Western New York State. Methylation was evaluated with real-time methylation-specific PCRs for 803 paraffin-embedded breast tumor tissues from women with primary, incident breast cancer. We applied unordered polytomous regression and unconditional logistic regression to derive adjusted odds ratios and 95% confidence intervals. We did not find any association of MTHFR and MTR polymorphisms with breast cancer risk stratified by methylation status nor between polymorphisms and likelihood of promoter methylation of any of the genes. There was no evidence of difference within strata defined by menopausal status, estrogen receptor status, folate intake, and lifetime alcohol consumption. Overall, we found no evidence that these common polymorphisms of the MTHFR and MTR genes are associated with promoter methylation of E-cadherin, p16, and RAR-beta2 genes in breast cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-08-0916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837294PMC
March 2009

DNA hypermethylation and clinicopathological features in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study.

Breast Cancer Res Treat 2009 Apr 8;114(3):559-68. Epub 2008 May 8.

Department of Social and Preventive Medicine, School of Public Health and Health Professions, University at Buffalo, 270 Farber Hall, Buffalo, NY 14214, USA.

Aberrant DNA hypermethylation of gene promoter regions has been increasingly recognized as a common molecular alteration in carcinogenesis. We evaluated the association between major clinicopathological features and hypermethylation of genes in tumors among 803 incidence breast cancer cases from a large population-based case-control study conducted in Western New York State. DNA samples were isolated from archive paraffin embedded tumor tissue and were analyzed for hypermethylation status of the E-cadherin, p16, and RAR-beta(2) genes using real time methylation-specific polymerase chain reaction. The frequencies of hypermethylation were 20.0% for E-cadherin, 25.9% for p16, and 27.5% for RAR-beta(2) genes. For postmenopausal women, hypermethylation of E-cadherin tended to be more likely in progesterone receptor (PR) negative than in PR-positive tumors (odds ratio (OR), 1.41; 95% confidence interval (CI), 0.91-2.18). Hypermethylation of p16 tended to be more frequent among estrogen receptor (ER) negative cases than ER-positive cases (OR, 1.51; 95% CI, 1.01-2.32). Hypermethylation of RAR-beta(2) gene was inversely associated with histological and nuclear grade of breast cancer.
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http://dx.doi.org/10.1007/s10549-008-0028-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408917PMC
April 2009

p53 Mutation analysis in breast tumors by a DNA microarray method.

Cancer Epidemiol Biomarkers Prev 2006 Jan;15(1):80-5

Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057-1465, USA.

The p53 gene acts as a regulator of cell growth and DNA repair in normal cells; inactivation of the gene seems to lead to cancer. It is the most commonly mutated gene in human cancers, and a high-throughput sequencing method is needed for cancer etiology studies using large sample sets. In our population-based case-control study of breast cancer, the p53 gene was amplified by PCR for 392 subjects from seven hospitals in Western New York using the Affymetrix GeneChip technology. One hundred thirty-eight (35%) of the breast tumors had p53 mutations, of which 88% were located in exons 5 to 8. New hotspots were identified at codons 179, 195, 196, 213, 217, 249, 254, 278, 281, and 298, and previously reported hotspots were found at codons 175, 248, and 273. Manual sequencing for exons 5 to 9 of the p53 gene was done for 139 tumors to validate the Affymetrix assay. The two methods had 100% concordance for mutations detectable by the Affymetrix assay. We also successfully assayed paraffin-embedded breast and lung tumors from as early as 1958 and employed a nested PCR strategy to improve weak PCR amplification. To have statistical power, the investigation of gene environment interactions and cancer requires a large number of tumor analyses, which are frequently only available from archived tissue from multiple sources. We have shown the utility of the Affymetrix GeneChip method under these challenging conditions and provided new data for the mutational spectra of breast cancer in a population-based study.
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http://dx.doi.org/10.1158/1055-9965.EPI-05-0444DOI Listing
January 2006

Diet and alcohol consumption in relation to p53 mutations in breast tumors.

Carcinogenesis 2004 Jun 23;25(6):931-9. Epub 2004 Jan 23.

Department of Social and Preventive Medicine, University at Buffalo, Buffalo, NY 14214, USA.

There is evidence linking alcohol consumption to p53 mutations in tumors, considerable evidence linking alcohol consumption with risk of breast cancer and some evidence that alcohol and folate consumption interact to affect risk. Further, while there is some indication that oxidation may play a role in breast cancer etiology, there has been little examination of an association of oxidative stress with p53 mutations. We examined several dietary components related to one-carbon metabolism and antioxidants to determine if these factors were related to the prevalence of p53 mutations in breast tumors. We conducted a case-control study of primary, histologically confirmed breast cancer in western New York. Controls <65 were selected from drivers license lists; those > or =65 were selected from Health Care Finance Administration lists. p53 mutations in archived tumor blocks were identified in exons 2-11 and flanking intron sequences. Usual dietary intake was assessed by interview regarding intake in the previous 2 years; alcohol consumption was queried for 2, 10 and 20 years in the past. Our data were consistent with increased likelihood of tumors with p53 mutations for premenopausal breast cancer with increased alcohol intake 10 or 20 years previous; for intake of 16 or more drinks per month in the period 20 years before the interview compared with non-drinkers, the OR was 5.25, 95% CI 1.48-18.58. For postmenopausal women, there was increased likelihood of tumors with p53 mutations among women with higher folate. Antioxidant nutrients were not differentially related to p53 mutations. These results indicate that there may be heterogeneity in breast tumors, as indicated by differences in associations for those with or without p53 mutations, and that causal pathways for these nutrients may vary for pre- and postmenopausal women. For premenopausal women, alcohol consumption in the past was associated with p53 mutations.
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http://dx.doi.org/10.1093/carcin/bgh088DOI Listing
June 2004

Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial.

Health Psychol 2003 Sep;22(5):541-8

University of Pennsylvania, Dept of Psychiatry, Abramson Cancer Ctr, Philadelphia, PA 19104, USA.

This study examined the role of dopaminergic genes in prospective smoking cessation and response to bupropion treatment in a placebo-controlled clinical trial. Smokers of European ancestry (N=418) provided blood samples for genetic analysis and received either bupropion or placebo (10 weeks) plus counseling. Assessments included the dopamine D2 receptor (DRD2) genotype, dopamine transporter (SLC6A3) genotype, demographic factors, and nicotine dependence. Smoking status was verified at the end of treatment (EOT) and at 6-month follow-up. The results provided evidence for a significant DRD2 * SLC6A3 interaction effect on prolonged smoking abstinence and time to relapse at EOT, independent of treatment condition. Such effects were no longer significant at 6-month follow-up, however. These results provide the first evidence from a prospective clinical trial that genes that alter dopamine function may influence smoking cessation and relapse during the treatment phase.
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http://dx.doi.org/10.1037/0278-6133.22.5.541DOI Listing
September 2003

Microsomal epoxide hydrolase variants are not associated with risk of breast cancer.

Cancer Epidemiol Biomarkers Prev 2002 Dec;11(12):1697-8

Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.

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December 2002

Pharmacogenetic investigation of smoking cessation treatment.

Pharmacogenetics 2002 Nov;12(8):627-34

Department of Psychiatry, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.

Despite the efficacy of bupropion for smoking cessation, smokers exhibit variability in treatment outcome. The CYP2B6 gene has been implicated in bupropion kinetics and nicotine metabolism, and is a plausible candidate for pharmacogenetic studies of treatment response. We investigated whether a functional genetic polymorphism in the CYP2B6 gene predicts smoking outcomes in a placebo-controlled randomized trial. Four hundred and twenty-six smokers of European Caucasian ancestry provided blood samples and received bupropion (300 mg/day for 10 weeks) or placebo, plus counseling. Smoking status, abstinence symptoms and side-effects were recorded weekly, and smoking status was verified at the end of treatment and at 6-month follow-up. Smokers with a decreased activity variant of CYP2B6 reported greater increases in cravings for cigarettes following the target quit date and had higher relapse rates. These effects were modified by a significant gender x genotype x treatment interaction, suggesting that bupropion attenuated the effects of genotype among female smokers. We conclude that smokers with the CYP2B6 variant may be more vulnerable to abstinence symptoms and relapse. Bupropion may attenuate these effects, especially among females. Additional trials are warranted to confirm these results, as are studies to explore the neurobiological mechanisms. Such research could ultimately enable practitioners to select the optimal type and dose of medication for individual smokers.
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http://dx.doi.org/10.1097/00008571-200211000-00007DOI Listing
November 2002