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1.
Addict Neurosci ; 72023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38645895

RESUMO

The use of standard protocols in studies supports consistent data collection, improves data quality, and facilitates cross-study analyses. Funded by the National Institutes of Health, the PhenX (consensus measures for Phenotypes and eXposures) Toolkit is a catalog of recommended measurement protocols that address a wide range of research topics and are suitable for inclusion in a variety of study designs. In 2020, a PhenX Working Group of smoking cessation experts followed a well-established consensus process to identify and recommend measurement protocols suitable for inclusion in smoking cessation and smoking harm reduction studies. The broader scientific community was invited to review and provide feedback on the preliminary recommendation of the Working Group. Fourteen selected protocols for measuring smoking cessation, harm reduction, and biomarkers research associated with smoking cessation were released in the PhenX Toolkit ( https://www.phenxtoolkit.org) in February 2021. These protocols complement existing PhenX Toolkit content related to tobacco regulatory research, substance use and addiction research, and other measures of smoking-related health outcomes. Adopting well-established protocols enables consistent data collection and facilitates comparing and combining data across studies, potentially increasing the scientific impact of individual studies.

2.
Nicotine Tob Res ; 24(11): 1803-1810, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-35639828

RESUMO

INTRODUCTION: Negative reinforcement models posit that relapse to cigarette smoking is driven in part by changes in affect and craving during the quit attempt. Varenicline may aid cessation by attenuating these changes; however, this mediational pathway has not been formally evaluated in placebo-controlled trials. Thus, trajectories of negative affect (NA), positive affect (PA), and craving were tested as mediators of the effect of varenicline on smoking cessation. AIMS AND METHODS: Secondary data analysis was conducted on 828 adults assigned to either varenicline or placebo in a randomized controlled trial for smoking cessation (NCT01314001). Self-reported NA, PA, and craving were assessed 1-week pre-quit, on the target quit day (TQD), and 1 and 4 weeks post-TQD. RESULTS: Across time, NA peaked 1-week post-quit, PA did not change, and craving declined. Less steep rises in NA (indirect effect 95% CI: .01 to .30) and lower mean craving at 1-week post-quit (CI: .06 to .50) were mediators of the relationship between varenicline and higher cessation rates at the end of treatment. PA was associated with cessation but was not a significant mediator. CONCLUSIONS: These results partially support the hypothesis that varenicline improves smoking cessation rates by attenuating changes in specific psychological processes and supported NA and craving as plausible treatment mechanisms of varenicline. IMPLICATIONS: The present research provides the first evidence from a placebo-controlled randomized clinical trial that varenicline's efficacy is due, in part, to post-quit attenuation of NA and craving. Reducing NA across the quit attempt and craving early into the attempt may be important treatment mechanisms for effective interventions. Furthermore, post-quit NA, PA, and craving were all associated with relapse and represent treatment targets for future intervention development.


Assuntos
Fumar Cigarros , Abandono do Hábito de Fumar , Adulto , Humanos , Vareniclina/uso terapêutico , Fissura , Abandono do Hábito de Fumar/métodos , Recidiva , Quinoxalinas/uso terapêutico , Benzazepinas/uso terapêutico
5.
Am J Public Health ; 111(9): 1661-1672, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34410826

RESUMO

The topic of e-cigarettes is controversial. Opponents focus on e-cigarettes' risks for young people, while supporters emphasize the potential for e-cigarettes to assist smokers in quitting smoking. Most US health organizations, media coverage, and policymakers have focused primarily on risks to youths. Because of their messaging, much of the public-including most smokers-now consider e-cigarette use as dangerous as or more dangerous than smoking. By contrast, the National Academies of Science, Engineering, and Medicine concluded that e-cigarette use is likely far less hazardous than smoking. Policies intended to reduce adolescent vaping may also reduce adult smokers' use of e-cigarettes in quit attempts. Because evidence indicates that e-cigarette use can increase the odds of quitting smoking, many scientists, including this essay's authors, encourage the health community, media, and policymakers to more carefully weigh vaping's potential to reduce adult smoking-attributable mortality. We review the health risks of e-cigarette use, the likelihood that vaping increases smoking cessation, concerns about youth vaping, and the need to balance valid concerns about risks to youths with the potential benefits of increasing adult smoking cessation.


Assuntos
Fumar Cigarros/prevenção & controle , Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Prevenção do Hábito de Fumar/métodos , Fumar Tabaco/terapia , Vaping/prevenção & controle , Adolescente , Adulto , Humanos , Estados Unidos
6.
Tob Control ; 29(Suppl 1): s5-s12, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31992658

RESUMO

A working group (WG) of experts from diverse fields related to nicotine and tobacco addiction was convened to identify elements and measures from the Host: Social/Cognitive domain to include in the Tobacco Regulatory Research Collection in the PhenX Toolkit, a catalogue of measures for biomedical research. This paper describes the methods used to identify, select, approve and include measures in the toolkit with potential relevance to users of both conventional and newer tobacco products, such as electronic cigarettes (e-cigarettes). In addition to 25 complementary measures primarily focused on cigarette use already present in the PhenX Toolkit, the WG recommended 11 additional social/cognitive measures focused on children and adult users or potential users of tobacco products. Of these, 10 were self-administered measures: frequency of communication with parents about smoking, quality of communication with parents about smoking, susceptibility to tobacco use, behaviour economics/purchase behaviour, motivation to quit (both single and multi-item measures), hedonic tone or response to pleasurable situations, multigroup ethnic identity, peer and family influence on smoking, attentional control and house rules about tobacco use. The remaining selected measure was computer based (distress tolerance). Although validated tools for use in the Host: Social/Cognitive realm are available, much remains to be done to develop, standardise and validate the tools for application to users of e-cigarettes and other non-combusted tobacco products, non-English language speakers and adolescents.


Assuntos
Coleta de Dados/métodos , Coleta de Dados/normas , Guias como Assunto , Fumantes/psicologia , Fumar/epidemiologia , Fatores Sociais , Uso de Tabaco/epidemiologia , Adolescente , Adulto , Comitês Consultivos , Consenso , Humanos , Fenótipo , Projetos de Pesquisa , Dispositivos para Fumar , Uso de Tabaco/legislação & jurisprudência
7.
Tob Control ; 29(Suppl 1): s20-s26, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31992660

RESUMO

The current paper describes the PhenX (Phenotypes and eXposures) Toolkit Tobacco Regulatory Research Agent specialty area and the Agent Working Group's (WG's) 6-month consensus process to identify high-priority, scientifically supported measures for cross-study comparison and analysis. Eleven measures were selected for inclusion in the Toolkit. Eight of these are interviewer-administered or self-administered protocols: history of switching to lower tar and nicotine cigarettes, passive exposures to tobacco products, tobacco brand and variety (covering cigars, cigarettes and smokeless tobacco separately), tobacco product adulteration (vent-blocking or filter-blocking) and tobacco warning label exposure and recall. The remaining three protocols are either laboratory-based or visual inspection-based: measurement of nicotine content in smoked or smokeless tobacco products and the physical properties of these two classes of products. Supplemental protocols include a biomarker of exposure and smoking topography. The WG identified the lack of standard measurement protocols to assess subjective ratings of tobacco product flavours and their appeal to consumers as a major gap. As the characteristics of tobacco products that influence perception and use are tobacco regulatory research priorities, the reliable assessment of flavours remains an area requiring further development.


Assuntos
Coleta de Dados/normas , Monitoramento Epidemiológico , Dispositivos para Fumar/normas , Fumar/epidemiologia , Uso de Tabaco/epidemiologia , Comitês Consultivos , Consenso , Humanos , Exposição por Inalação , Rotulagem de Produtos , Projetos de Pesquisa , Fumar/legislação & jurisprudência , Software , Uso de Tabaco/legislação & jurisprudência
8.
Tob Control ; 29(Suppl 1): s13-s19, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31992659

RESUMO

A working group (WG) of experts from diverse fields related to nicotine and tobacco addiction was constituted to identify constructs and measures for the PhenX (Phenotypes and eXposures) Tobacco Regulatory Research (TRR) Host: Biobehavioral Collection with potential relevance to users of both conventional and newer tobacco products. This paper describes the methods and results the WG used to identify, select, approve and place measures in the PhenX TRR Collection. The WG recognised 13 constructs of importance to guide their categorisation of measures already in the PhenX Toolkit ('complementary measures') and to identify novel or improved measures of special relevance to tobacco regulatory science. In addition to the 22 complementary measures of relevance to tobacco use already in the PhenX Toolkit, the WG identified and recommended nine additional Host: Biobehavioral measures characterising the use, exposure and health outcomes of tobacco products for application to TRR. Of these, five were self-administered or interviewer-administered measures: amount, type and frequency of recent tobacco use; flavor preference in e-cigarette users (adult and youth); pregnancy status and tobacco use; pregnancy status-mother and baby health and withdrawal from tobacco use. The remaining four measures were laboratory-based: cotinine in serum, expired carbon monoxide, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in urine and cue reactivity. Although a number of validated tools are now available in the Host: Biobehavioral Collection, several gaps were identified, including a need to develop and test the identified measures in adolescent samples and to develop or identify measures of nicotine dependence, tolerance and withdrawal associated with newer non-combusted tobacco products.


Assuntos
Coleta de Dados/métodos , Coleta de Dados/normas , Projetos de Pesquisa/normas , Fumantes/psicologia , Fumar/epidemiologia , Uso de Tabaco/epidemiologia , Adolescente , Adulto , Comitês Consultivos , Dióxido de Carbono/análise , Consenso , Cotinina/sangue , Sinais (Psicologia) , Feminino , Humanos , Masculino , Nitrosaminas/urina , Fenótipo , Gravidez , Software , Síndrome de Abstinência a Substâncias/epidemiologia , Uso de Tabaco/legislação & jurisprudência
9.
Tob Control ; 29(Suppl 1): s27-s34, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31992661

RESUMO

The PhenX (Phenotypes and eXposures) Toolkit provides researchers with recommended standard consensus measures for use in epidemiological, biomedical, clinical and translational studies. To expand the depth and breadth of measures in the PhenX Toolkit, the National Institutes of Health and U.S. Food and Drug Administration have launched a project to identify 'Core' and 'Specialty' collections of measures recommended for human subjects studies in tobacco regulatory research (TRR). The current paper addresses the PhenX Toolkit TRR Vector specialty area and describes the 6-month process to identify high-priority, low-burden, scientifically supported consensus measures. Self-reported, interviewer-administered and observational measurements were considered, and input from the research community assisted in justifying the inclusion of 13 tobacco industry-relevant measures (mainly interviewer-administered or self-reported measures) in the PhenX Toolkit. Compared with measures of addiction or the use of tobacco products, assessments of many Vector factors are much newer and at an earlier stage of development. More work is needed to refine and validate measures of the spatial distribution of tobacco retailers, retail environment, price promotions and corporate social responsibility.


Assuntos
Coleta de Dados/normas , Indústria do Tabaco/economia , Produtos do Tabaco/economia , Uso de Tabaco/economia , Comitês Consultivos , Comércio , Consenso , Estudos Epidemiológicos , Humanos , Marketing , Projetos de Pesquisa , Autorrelato , Software , Indústria do Tabaco/legislação & jurisprudência , Produtos do Tabaco/legislação & jurisprudência , Uso de Tabaco/legislação & jurisprudência
10.
Tob Control ; 29(Suppl 1): s35-s42, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31992662

RESUMO

OBJECTIVE: A Working Group (WG) of tobacco regulatory science experts identified measures for the tobacco environment domain. METHODS: This article describes the methods by which measures were identified, selected, approved and placed in the PhenX Toolkit. FINDINGS: The WG identified 20 initial elements relevant to tobacco regulatory science and determined whether they were already in the PhenX Toolkit or whether novel or improved measures existed. In addition to the 10 complementary measures already in the Toolkit, the WG recommended 13 additional measures: aided and confirmed awareness of televised antitobacco advertising, interpersonal communication about tobacco advertising, media use, perceived effectiveness of antitobacco advertising, exposure to smoking on television and in the movies, social norms about tobacco (for adults and for youth), worksite policies, youth cigarette purchase behaviours and experiences, compliance with cigarette packaging and labelling policies, local and state tobacco control public policies, and neighbourhood-level racial/ethnic composition. Supplemental measures included youth social capital and compliance with smoke-free air laws and with point of sale and internet tobacco marketing restrictions. Gaps were identified in the areas of policy environment (public and private), communications environment, community environment and social environment (ie, the norms/acceptability of tobacco use). CONCLUSIONS: Consistent use of these tobacco environment measures will enhance rigor and reproducability of tobacco research.


Assuntos
Coleta de Dados/normas , Guias como Assunto , Políticas , Meio Social , Uso de Tabaco/epidemiologia , Publicidade , Comitês Consultivos , Consenso , Humanos , Meios de Comunicação de Massa , Projetos de Pesquisa , Normas Sociais , Software , Uso de Tabaco/legislação & jurisprudência
11.
Front Immunol ; 10: 2469, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708922

RESUMO

Pregnant women are particularly susceptible to complications of influenza A virus infection, which may result from pregnancy-induced changes in the function of immune cells, including natural killer (NK) cells. To better understand NK cell function during pregnancy, we assessed the ability of the two main subsets of NK cells, CD56dim, and CD56bright NK cells, to respond to influenza-virus infected cells and tumor cells. During pregnancy, CD56dim and CD56bright NK cells displayed enhanced functional responses to both infected and tumor cells, with increased expression of degranulation markers and elevated frequency of NK cells producing IFN-γ. To better understand the mechanisms driving this enhanced function, we profiled CD56dim and CD56bright NK cells from pregnant and non-pregnant women using mass cytometry. NK cells from pregnant women displayed significantly increased expression of several functional and activation markers such as CD38 on both subsets and NKp46 on CD56dim NK cells. NK cells also displayed diminished expression of the chemokine receptor CXCR3 during pregnancy. Overall, these data demonstrate that functional and phenotypic shifts occur in NK cells during pregnancy that can influence the magnitude of the immune response to both infections and tumors.


Assuntos
Células Matadoras Naturais/imunologia , Gravidez/imunologia , Adulto , Células Cultivadas , Estudos de Coortes , Feminino , Humanos , Complicações Infecciosas na Gravidez/imunologia , Complicações Neoplásicas na Gravidez/imunologia
12.
Twin Res Hum Genet ; 22(6): 757-760, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31354124

RESUMO

The National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry is one of the oldest, national population-based twin registries in the USA. It comprises 15,924 White male twin pairs born in the years 1917-1927 (N = 31.848), both of whom served in the armed forces, chiefly during World War II. This article updates activities in this registry since the most recent report in Twin Research and Human Genetics (Page, 2006). Records-based data include information from enlistment charts and Veterans Administration data linkages. There have been three major epidemiologic questionnaires and an education and earnings survey. Separate data collection efforts with the NAS-NRC registry include the National Heart, Lung, and Blood Institute (NHLBI) subsample, the Duke Twins Study of Memory in Aging and a clinically based study of Parkinson's disease. Progress has been made on consolidating the various data holdings of the NAS-NRC Twin Registry. Data that had been available through the National Academy of Sciences are now freely available through National Archive of Computerized Data on Aging (NACDA).


Assuntos
Envelhecimento/genética , Sistemas Computadorizados de Registros Médicos , Memória , Sistema de Registros , Gêmeos/genética , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division , Estados Unidos , United States Department of Veterans Affairs
14.
Biol Sex Differ ; 8: 14, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28465822

RESUMO

BACKGROUND: The comparison of traits in twins from opposite-sex (OS) and same-sex (SS) dizygotic twin pairs is considered a proxy measure of prenatal hormone exposure. To examine possible prenatal hormonal influences on anthropometric traits, we compared mean height, body mass index (BMI), and the prevalence of being overweight or obese between men and women from OS and SS dizygotic twin pairs. METHODS: The data were derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) database, and included 68,494 SS and 53,808 OS dizygotic twin individuals above the age of 20 years from 31 twin cohorts representing 19 countries. Zygosity was determined by questionnaires or DNA genotyping depending on the study. Multiple regression and logistic regression models adjusted for cohort, age, and birth year with the twin type as a predictor were carried out to compare height and BMI in twins from OS pairs with those from SS pairs and to calculate the adjusted odds ratios and 95% confidence intervals for being overweight or obese. RESULTS: OS females were, on average, 0.31 cm (95% confidence interval (CI) 0.20, 0.41) taller than SS females. OS males were also, on average, taller than SS males, but this difference was only 0.14 cm (95% CI 0.02, 0.27). Mean BMI and the prevalence of overweight or obesity did not differ between males and females from SS and OS twin pairs. The statistically significant differences between OS and SS twins for height were small and appeared to reflect our large sample size rather than meaningful differences of public health relevance. CONCLUSIONS: We found no evidence to support the hypothesis that prenatal hormonal exposure or postnatal socialization (i.e., having grown up with a twin of the opposite sex) has a major impact on height and BMI in adulthood.


Assuntos
Estatura , Índice de Massa Corporal , Gêmeos Dizigóticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
PLoS Pathog ; 12(10): e1005892, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27764254

RESUMO

Vaccination with attenuated live varicella zoster virus (VZV) can prevent zoster reactivation, but protection is incomplete especially in an older population. To decipher the molecular mechanisms underlying variable vaccine responses, T- and B-cell responses to VZV vaccination were examined in individuals of different ages including identical twin pairs. Contrary to the induction of VZV-specific antibodies, antigen-specific T cell responses were significantly influenced by inherited factors. Diminished generation of long-lived memory T cells in older individuals was mainly caused by increased T cell loss after the peak response while the expansion of antigen-specific T cells was not affected by age. Gene expression in activated CD4 T cells at the time of the peak response identified gene modules related to cell cycle regulation and DNA repair that correlated with the contraction phase of the T cell response and consequently the generation of long-lived memory cells. These data identify cell cycle regulatory mechanisms as targets to reduce T cell attrition in a vaccine response and to improve the generation of antigen-specific T cell memory, in particular in an older population.


Assuntos
Vacina contra Herpes Zoster/imunologia , Herpes Zoster/imunologia , Memória Imunológica/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Idoso , Diferenciação Celular/imunologia , Ensaio de Imunoadsorção Enzimática , ELISPOT , Feminino , Herpes Zoster/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos
17.
J Infect Dis ; 214(11): 1666-1671, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27655870

RESUMO

Pregnancy-induced alterations in immunity may contribute to the increased morbidity associated with influenza A virus infection during pregnancy. We characterized the immune response of monocytes and plasmacytoid dendritic cells (pDCs) to influenza A virus infection in 21 pregnant and 21 nonpregnant women. In pregnant women, monocytes and pDCs exhibit an exaggerated proinflammatory immune response to 2 strains of influenza A virus, compared with nonpregnant women, characterized by increased expression of major histocompatibility complex class II (approximately 2.0-fold), CD69 (approximately 2.2-fold), interferon γ-induced protein 10 (approximately 2.0-fold), and macrophage inflammatory protein 1ß (approximately 1.5-fold). This enhanced innate inflammatory response during pregnancy could contribute to pulmonary inflammation following influenza A virus infection.


Assuntos
Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/virologia , Vírus da Influenza A/imunologia , Monócitos/imunologia , Monócitos/virologia , Adulto , Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Quimiocina CCL4/análise , Quimiocina CXCL10/análise , Feminino , Antígenos de Histocompatibilidade Classe II/análise , Humanos , Lectinas Tipo C/análise , Gravidez , Adulto Jovem
18.
Elife ; 52016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27481325

RESUMO

Antibody class switching is a feature of the adaptive immune system which enables diversification of the effector properties of antibodies. Even though class switching is essential for mounting a protective response to pathogens, the in vivo patterns and lineage characteristics of antibody class switching have remained uncharacterized in living humans. Here we comprehensively measured the landscape of antibody class switching in human adult twins using antibody repertoire sequencing. The map identifies how antibodies of every class are created and delineates a two-tiered hierarchy of class switch pathways. Using somatic hypermutations as a molecular clock, we discovered that closely related B cells often switch to the same class, but lose coherence as somatic mutations accumulate. Such correlations between closely related cells exist when purified B cells class switch in vitro, suggesting that class switch recombination is directed toward specific isotypes by a cell-autonomous imprinted state.


Assuntos
Linfócitos B/imunologia , Switching de Imunoglobulina , Isotipos de Imunoglobulinas/genética , Fatores Imunológicos/genética , Humanos , Recombinação Genética , Análise de Sequência de DNA , Hipermutação Somática de Imunoglobulina
19.
Sci Transl Med ; 8(332): 332ra46, 2016 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-27030598

RESUMO

Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood can escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-reactive CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. Although all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly. A genetic influence was seen for the sharing of individual TCR sequences from antigen-reactive cells but not for repertoire richness or the selection of dominant clones. VZV vaccination favored the expansion of infrequent VZV antigen-reactive TCRs, including those from naïve T cells with lesser boosting of dominant T cell clones. Thus, vaccination does not reinforce the in vivo selection that occurred during chronic infection but leads to a diversification of the VZV-reactive T cell repertoire. However, a single-booster immunization seems insufficient to establish new clonal dominance. Our results suggest that repertoire analysis of antigen-specific TCRs can be an important readout to assess whether a vaccination was able to generate memory cells in clonal sizes that are necessary for immune protection.


Assuntos
Antígenos Virais/imunologia , Vacina contra Varicela/imunologia , Herpesvirus Humano 3/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Vacinação , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Células Clonais , Humanos , Memória Imunológica
20.
Nicotine Tob Res ; 18(9): 1837-1844, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27113016

RESUMO

INTRODUCTION: Metabolic enzyme variation and other patient and environmental characteristics influence smoking behaviors, treatment success, and risk of related disease. Population-specific variation in metabolic genes contributes to challenges in developing and optimizing pharmacogenetic interventions. We applied a custom genome-wide genotyping array for addiction research (Smokescreen), to three laboratory-based studies of nicotine metabolism with oral or venous administration of labeled nicotine and cotinine, to model nicotine metabolism in multiple populations. The trans-3'-hydroxycotinine/cotinine ratio, the nicotine metabolite ratio (NMR), was the nicotine metabolism measure analyzed. METHODS: Three hundred twelve individuals of self-identified European, African, and Asian American ancestry were genotyped and included in ancestry-specific genome-wide association scans (GWAS) and a meta-GWAS analysis of the NMR. We modeled natural-log transformed NMR with covariates: principal components of genetic ancestry, age, sex, body mass index, and smoking status. RESULTS: African and Asian American NMRs were statistically significantly (P values ≤ 5E-5) lower than European American NMRs. Meta-GWAS analysis identified 36 genome-wide significant variants over a 43 kilobase pair region at CYP2A6 with minimum P = 2.46E-18 at rs12459249, proximal to CYP2A6. Additional minima were located in intron 4 (rs56113850, P = 6.61E-18) and in the CYP2A6-CYP2A7 intergenic region (rs34226463, P = 1.45E-12). Most (34/36) genome-wide significant variants suggested reduced CYP2A6 activity; functional mechanisms were identified and tested in knowledge-bases. Conditional analysis resulted in intergenic variants of possible interest (P values < 5E-5). CONCLUSIONS: This meta-GWAS of the NMR identifies CYP2A6 variants, replicates the top-ranked single nucleotide polymorphism from a recent Finnish meta-GWAS of the NMR, identifies functional mechanisms, and provides pan-continental population biomarkers for nicotine metabolism. IMPLICATIONS: This multiple ancestry meta-GWAS of the laboratory study-based NMR provides novel evidence and replication for genome-wide association of CYP2A6 single nucleotide and insertion-deletion polymorphisms. We identify three regions of genome-wide significance: proximal, intronic, and distal to CYP2A6. We replicate the top-ranking single nucleotide polymorphism from a recent GWAS of the NMR in Finnish smokers, identify a functional mechanism for this intronic variant from in silico analyses of RNA-seq data that is consistent with CYP2A6 expression measured in postmortem lung and liver, and provide additional support for the intergenic region between CYP2A6 and CYP2A7.


Assuntos
Citocromo P-450 CYP2A6/genética , Nicotina/genética , Nicotina/metabolismo , Fumar/genética , Tabagismo/genética , Adulto , Povo Asiático/genética , População Negra/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , População Branca/genética , Adulto Jovem
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