0 Bedömningar
ID

46134

Beskrivning

Principal Investigator: Andrew W. Bergen, PhD, SRI International, Menlo Park, CA, USA; Oregon Research Institute, Eugene, OR, USA MeSH: Nicotine,Pharmacokinetics,Smoking Cessation,Cigarette Smoking,Smoking Cessation Agents,Bupropion,Tobacco Use Cessation Devices,Lung Neoplasms https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000931 This study (DA033813; PI: Andrew W Bergen; PMID:26132489) includes samples from two laboratory studies of nicotine metabolism. The Pharmacokinetics of Nicotine Metabolism in Twins study (PKTWIN; PI: Gary E Swan; PMID: 15527659) was based on recruitment from a twin registry (PMID: 23084148). The Integrated Research Project on Tobacco Use and Dependence (IRP; PI: Gary E Swan; PMID: 14578134) was based on recruitment from a pedigree-based longitudinal study of risk factors for substance use, the Smoking in Families study (SMOFAM; DA03706; PI: Hy Hops). These two laboratory studies (PKTWIN and IRP/SMOFAM) served as the Stage I dataset to interrogate Drug Metabolizing Enzyme and Transporter genes with a targeted SNP array for association with the Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine), an established biomarker of nicotine metabolism. In addition to the laboratory studies, samples from eight RCTs (PMID: 23249876) with the NMR and smoking-related measures used to test SNPs identified in Stage I (PMID: 26132489). In a third stage, a lung cancer meta-analysis database (PMID: 24880342) was used to assess association of SNPs identified in Stage II with lung cancer. The objectives of the study were to identify novel genes and SNPs contributing to nicotine metabolism (Stage I), and to validate PK SNPs associated with the NMR from individuals participating in a clinical laboratory protocol with the NMR obtained from treatment-seeking smokers, and then to investigate association with prospective smoking cessation (Stage II). This study built upon existing studies of nicotine metabolism and randomized trials of smoking cessation therapies. Enhanced knowledge of the genes influencing nicotine metabolism and prospective abstinence may help personalize smoking cessation treatment and risk assessment for smoking-related diseases. For Stage I, both subject [fixed-dose NMR, covariates (age, BMI, ethnicity, sex, smoking status, and hormone use), and pedigree relationships] and sample (common DMET SNP genotype, genotyping quality control) data are available in this accession. The analysis protocol, quality control summaries, summary genotype, summary phenotype, and analysis results are available for Stage I, II and III samples (PMID: 26132489). Extensive discussion of the prior *CYP2A6* association literature with the NMR, abstinence, smoking heaviness and lung cancer risk is available (PMID: 26132489). The NMR has previously been associated with *CYP2A6* activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; *CYP2A6* and two *CYP2A6* SNPs attained experiment-wide significance adjusted for correlated SNPs (*CYP2A6* PsubACT/sub=4.1E-7, rs4803381 PsubACT/sub=4.5E-5, rs1137115, PsubACT/sub=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In *post-hoc* analyses of *CYP2A6* SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. *CYP2A6* minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that *CYP2A6* plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.br

Länk

dbGaP study id = phs000931

Nyckelord

Versioner (1)
  1. 2024-11-27 2024-11-27 - Dr. Christian Niklas
Rättsinnehavare

Andrew W. Bergen, PhD, SRI International, Menlo Park, CA, USA; Oregon Research Institute, Eugene, OR, USA

Uppladdad den

27 november 2024

DOI

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Licens

Creative Commons BY 4.0
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    dbGaP phs000931 DMET Genes, Nicotine Metabolism and Prospective Abstinence

    Engelsk

    Eligibility Criteria

    7 Formulär  
    Inclusion and exclusion criteria
    Beskrivning

    Inclusion and exclusion criteria

    Alias
    UMLS CUI [1,1]
    C1512693
    UMLS CUI [1,2]
    C0680251
    **PKTWIN**
    Beskrivning

    Elig.phs000931.v1.p1.1

    Datatyp

    boolean

    Alias
    UMLS CUI [1,1]
    C3274381
    Existing data (the fixed-dose NMR and covariates) and DNA samples were selected from a twin registry based study of nicotine metabolism and the impact of genetics and environment on nicotine metabolism (PMID:15527659). Twins from the Registry were recruited into the laboratory study of nicotine metabolism if both twins (monozygotic or dizygotic) were interested and eligible based on a three-stage screening procedure consisting of initial telephone-based screening, secondary in-person screening, and tertiary in-hospital review by the project physician. Exclusion criteria consisted of the following criteria: age &lt;18 years or &gt;65 years; weight &gt;130% ideal height-adjusted weight; pregnancy; use of drug metabolism-altering medications such as anticonvulsants and barbiturates; uncontrolled hypertension; diabetes; history of heart disease; Raynaud's disease; cancer, chronic liver or kidney disease, and/or asthma that was not stable or in remission for at least one year; migraine; anemia; abnormal blood-sugar levels; substance abuse or dependence, excluding nicotine dependence; psychiatric disorders that could limit study compliance or require use of metabolism altering psychotropic medication; HIV<sup>+</sup> status; Hepatitis B or Hepatitis C; history of vasovagal reactions; discomfort with venipuncture procedures or history of difficult veins.
    Beskrivning

    Elig.phs000931.v1.p1.2

    Datatyp

    boolean

    Alias
    UMLS CUI [1,1]
    C0041427
    UMLS CUI [1,2]
    C2348585
    UMLS CUI [1,3]
    C0030761
    Verbal consent was obtained from participants prior to collection of possible exclusion criteria, description of study procedures and distribution of a health and smoking history questionnaire (first screen). Written informed consent, which explained study procedures, risks and benefits, was obtained from each co-twin in turn prior to collection of concomitant medications, vital status, and biospecimens (blood and urine). At each of these stages, screening of collected data was performed by a medical doctor to judge whether the co-twin was eligible and medically approved, prior to repeating the process for the co-twin. Prior to the in hospital nicotine infusion, an electrocardiogram, vital status, and a brief physical exam were conducted before final medical approval.
    Beskrivning

    Elig.phs000931.v1.p1.3

    Datatyp

    boolean

    Alias
    UMLS CUI [1,1]
    C0021430
    UMLS CUI [1,2]
    C0449438
    Recruitment incentives include monetary compensation for full participation and the opportunity to participate in the laboratory study portion simultaneously with the participant's co-twin.
    Beskrivning

    Elig.phs000931.v1.p1.4

    Datatyp

    boolean

    Alias
    UMLS CUI [1,1]
    C5418626
    UMLS CUI [1,2]
    C0871819
    **IRP/SMOFAM**
    Beskrivning

    Elig.phs000931.v1.p1.5

    Datatyp

    boolean

    Alias
    UMLS CUI [1,1]
    C3274381
    For an integrated research project studying the environmental, genetic and metabolic determinants of tobacco use (PMID:14578134), probands and family members were recruited from those SMOFAM families in which the proband had completed at least seven of the first ten assessments on tobacco use and elected to provide a blood sample for DNA analysis. Probands and each first degree relative completed a family history of tobacco use including sex, age, relationship to proband (biological or nonbiological; full-, half-, or nonbiological sibling), vital status, lifetime &#8220;ever&#8221; smoking of 100 cigarettes, ever regular use of cigars, pipes, or smokeless tobacco, age at initiation of daily cigarette smoking, average number of cigarettes smoked per day when smoking, ever tried to quit, and success in permanent quitting.
    Beskrivning

    Elig.phs000931.v1.p1.6

    Datatyp

    boolean

    Alias
    UMLS CUI [1,1]
    C3669174
    Informed consent was obtained from all participants for each the questionnaire, blood collection, and laboratory study components of the study. Permission to store biospecimens and to conduct additional genetic analyses was obtained. Participants agreed to the provision that genetic test results would not be made available to participants. A United States Department of Health and Human Services certificate of confidentiality was obtained for the study.
    Beskrivning

    Elig.phs000931.v1.p1.7

    Datatyp

    boolean

    Alias
    UMLS CUI [1,1]
    C0021430
    UMLS CUI [1,2]
    C3846676
    Tillbaka till toppen

    Similar models

    Eligibility Criteria

    7 Formulär
    Name
    Typ
    Description | Question | Decode (Coded Value)
    Datatyp
    Alias
    Item Group
    Inclusion and exclusion criteria
    C1512693 (UMLS CUI [1,1])
    C0680251 (UMLS CUI [1,2])
    Elig.phs000931.v1.p1.1
    Item
    **PKTWIN**
    boolean
    C3274381 (UMLS CUI [1,1])
    Elig.phs000931.v1.p1.2
    Item
    Existing data (the fixed-dose NMR and covariates) and DNA samples were selected from a twin registry based study of nicotine metabolism and the impact of genetics and environment on nicotine metabolism (PMID:15527659). Twins from the Registry were recruited into the laboratory study of nicotine metabolism if both twins (monozygotic or dizygotic) were interested and eligible based on a three-stage screening procedure consisting of initial telephone-based screening, secondary in-person screening, and tertiary in-hospital review by the project physician. Exclusion criteria consisted of the following criteria: age &lt;18 years or &gt;65 years; weight &gt;130% ideal height-adjusted weight; pregnancy; use of drug metabolism-altering medications such as anticonvulsants and barbiturates; uncontrolled hypertension; diabetes; history of heart disease; Raynaud's disease; cancer, chronic liver or kidney disease, and/or asthma that was not stable or in remission for at least one year; migraine; anemia; abnormal blood-sugar levels; substance abuse or dependence, excluding nicotine dependence; psychiatric disorders that could limit study compliance or require use of metabolism altering psychotropic medication; HIV<sup>+</sup> status; Hepatitis B or Hepatitis C; history of vasovagal reactions; discomfort with venipuncture procedures or history of difficult veins.
    boolean
    C0041427 (UMLS CUI [1,1])
    C2348585 (UMLS CUI [1,2])
    C0030761 (UMLS CUI [1,3])
    Elig.phs000931.v1.p1.3
    Item
    Verbal consent was obtained from participants prior to collection of possible exclusion criteria, description of study procedures and distribution of a health and smoking history questionnaire (first screen). Written informed consent, which explained study procedures, risks and benefits, was obtained from each co-twin in turn prior to collection of concomitant medications, vital status, and biospecimens (blood and urine). At each of these stages, screening of collected data was performed by a medical doctor to judge whether the co-twin was eligible and medically approved, prior to repeating the process for the co-twin. Prior to the in hospital nicotine infusion, an electrocardiogram, vital status, and a brief physical exam were conducted before final medical approval.
    boolean
    C0021430 (UMLS CUI [1,1])
    C0449438 (UMLS CUI [1,2])
    Elig.phs000931.v1.p1.4
    Item
    Recruitment incentives include monetary compensation for full participation and the opportunity to participate in the laboratory study portion simultaneously with the participant's co-twin.
    boolean
    C5418626 (UMLS CUI [1,1])
    C0871819 (UMLS CUI [1,2])
    Elig.phs000931.v1.p1.5
    Item
    **IRP/SMOFAM**
    boolean
    C3274381 (UMLS CUI [1,1])
    Elig.phs000931.v1.p1.6
    Item
    For an integrated research project studying the environmental, genetic and metabolic determinants of tobacco use (PMID:14578134), probands and family members were recruited from those SMOFAM families in which the proband had completed at least seven of the first ten assessments on tobacco use and elected to provide a blood sample for DNA analysis. Probands and each first degree relative completed a family history of tobacco use including sex, age, relationship to proband (biological or nonbiological; full-, half-, or nonbiological sibling), vital status, lifetime &#8220;ever&#8221; smoking of 100 cigarettes, ever regular use of cigars, pipes, or smokeless tobacco, age at initiation of daily cigarette smoking, average number of cigarettes smoked per day when smoking, ever tried to quit, and success in permanent quitting.
    boolean
    C3669174 (UMLS CUI [1,1])
    Elig.phs000931.v1.p1.7
    Item
    Informed consent was obtained from all participants for each the questionnaire, blood collection, and laboratory study components of the study. Permission to store biospecimens and to conduct additional genetic analyses was obtained. Participants agreed to the provision that genetic test results would not be made available to participants. A United States Department of Health and Human Services certificate of confidentiality was obtained for the study.
    boolean
    C0021430 (UMLS CUI [1,1])
    C3846676 (UMLS CUI [1,2])
    Tillbaka till toppen 

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