Non-Hodgkin lymphoma in women: reproductive, hormonal and genetic factors

女性非霍奇金淋巴瘤：生殖、激素和遗传因素

• 批准号: 8144772
• 负责人: Paige M. Bracci
• 金额: $ 7.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144772
• 关键词: Adult; Affect; Age; Age at Menarche; Area; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Blood Circulation; Body mass index; Case-Control Studies; Catechol O-Methyltransferase; Celiac Disease; Cells; Classification; Complex; Cytochrome P450; DNA; Data; Data Set; Demographic Factors; Development; ESR1 gene; ESR2 gene; Epidemiologic Studies; Epidemiology; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Exogenous Hormone Therapy; Exposure to; Funding; Future; Genes; Genetic; Genetic Polymorphism; Goals; Gonadal Steroid Hormones; Hematologic Neoplasms; Hemolytic Anemia; Hereditary Disease; Hormonal; Hormones; Immune; Immunosuppression; Incidence; Infection; Inflammatory; Inherited; Interleukin-10; Interleukins; Interview; Life; Logistic Regressions; Lymphomagenesis; Measures; Menopause; Metabolism; Methods; Modeling; Modification; NF-kappa B; Non-Hodgkin' s Lymphoma; Odds Ratio; Oral Contraceptives; Pathway interactions; Persons; Predisposition; Pregnancy; Prevention; Prevention program; Preventive Intervention; Production; Psoriasis; Publishing; Recording of previous events; Relative Risks; Reproductive History; Risk; Risk Estimate; Risk Factors; Role; San Francisco; Screening procedure; Sex Characteristics; Sex Hormone-Binding Globulin; Single Nucleotide Polymorphism; Sjogren' s Syndrome; Source; Steroid biosynthesis; Syndrome; Systemic Lupus Erythematosus; TNF gene; Testing; Tumor Necrosis Factor-Beta; Tumor Necrosis Factor-alpha; Variant; Virus; Woman; abstracting; case control; cell type; epidemiologic data; gene environment interaction; gene function; granulocyte; hormone metabolism; immune function; improved; innovation; interest; men; parity; population based; programs; public health relevance; reproductive; reproductive hormone; response; sex; sex risk

DESCRIPTION (provided by applicant): Project Summary/Abstract Non-Hodgkin lymphoma in women: reproductive, hormonal and genetic factors Non-Hodgkin lymphoma (NHL) is the most common hematopoietic cancer in U.S. adults and has a higher incidence in men than in women (ratio of 1.4:1). Although several studies have investigated the association between reproductive factors and exogenous sex-hormone exposures to explain this sex differential, results have been varied and no comprehensive assessment of relevant epidemiologic and genetic factors related to risk of NHL and NHL subtypes has been conducted. Our innovative analyses will leverage NCI funding by using epidemiologic and genetic data already collected in our large population-based case-control NHL study (2055 cases, 2081 controls) to: Aim 1) determine whether endogenous and exogenous hormone exposures in women are associated with risk of NHL and common NHL subtypes and; Aim 2) determine whether single nucleotide polymorphisms (SNPs) in genes related to steroidogenesis or that function in the same immune- related biologic pathways as sex-hormones, alter the association between factors in Aim 1 and risk of NHL and NHL subtypes. SNPs in sex-hormone genes of interest include estrogen receptors (ESR), cytochrome P450 17A1 (CYP17A1), sex-hormone binding globulin (SHBG) and catechol-O-methyltransferase (COMT), and in immune/inflammatory pathways include interleukins (IL), nuclear factor kappa B (NF-:B), tumor necrosis factor alpha (TNF-1) and lymphotoxin alpha (LTA). Risk of NHL also has been associated with increased body mass index (BMI) and some autoimmune conditions with each in turn associated with levels and circulation of sex- hormones. Therefore, BMI and autoimmune conditions will be carefully assessed as potential confounders and effect modifiers of the association between hormonal effects and NHL risk. Parsimonious multivariable unconditional logistic regression models will be used to obtain odds ratios as estimates of relative risk. Gene- environment interactions will be evaluated for exposures and SNPs in genes that function in the same biologic pathways, e.g. pregnancy-related factors, and SNPs in IL-10, TNF-1, ESR1 and ESR2. False discovery rate methods will be used to control for multiple hypothesis testing. The study's major strengths are: 1) DNA already analyzed for SNPs in 146 genes in biologic pathways that may be relevant to the association between sex-hormone s and NHL susceptibility; 2) already collected rich epidemiologic dataset including extensive reproductive history, sex-steroid hormone use, autoimmune conditions and BMI available to evaluate main effects, confounding and effect modification; 5) pathological confirmation and NHL subtype classification using the WHO classification; 6) data will be pooled for future analyses within the InterLymph Consortium allowing analyses of rare subtypes and exposure. Clarifying the role of these sex-hormone related factors in NHL risk will improve our understanding of lymphomagenesis, generate hypotheses for future research and be directly applicable to screening and prevention programs to reduce NHL incidence. PUBLIC HEALTH RELEVANCE: Project Narrative Incidence of non-Hodgkin lymphoma (NHL) is higher in men than in women and few risk factors have been established other than those associated with severe immunosuppression and some rare genetic conditions. Given that sex-hormones impact immune function, it is plausible that hormonal-related exposures and conditions that differ between women and men may help explain the observed sex-difference in NHL. Analyses that clarify the association among reproductive factors, use of estrogen-related therapies and risk of NHL and NHL subtypes in women and whether the relationship between NHL risk and sex-related hormones is altered by variation in genes important in hormone metabolism/production and immune function will improve our understanding of NHL development, help to generate new hypotheses for future research and will be directly applicable to prevention, intervention and screening programs with a goal to reduce NHL incidence.

描述(由申请人提供)：项目摘要/摘要女性非霍奇金淋巴瘤：生殖、激素和遗传因素非霍奇金淋巴瘤(NHL)是美国成年人最常见的造血癌，男性的发病率高于女性(比率为1.4：1)。虽然已经有几项研究调查了生殖因素和外源性性激素暴露之间的关系，以解释这种性别差异，但结果各不相同，还没有对与NHL和NHL亚型风险相关的流行病学和遗传因素进行全面评估。我们的创新分析将利用NCI资金，使用我们的大型人群病例对照NHL研究(2055例，2081例对照)中已经收集的流行病学和遗传学数据来：目的1)确定女性内源性和外源性激素暴露是否与NHL和常见NHL亚型的风险有关；以及2)目的2)确定与类固醇生成相关的基因或与性激素具有相同免疫相关生物通路的单核苷酸多态(SNPs)是否改变目标1中的因素与NHL和NHL亚型的风险之间的关联。性激素相关基因中的SNP包括雌激素受体(ESR)、细胞色素P450 17A1(CYP17A1)、性激素结合球蛋白(SHBG)和儿茶酚-O-甲基转移酶(COMT)，免疫/炎症途径中的SNP包括白介素B(IL)、核因子-kappaB(NF-B)、肿瘤坏死因子α(TNF-1)和淋巴毒素α(LTA)。患非霍奇金淋巴瘤的风险还与身体质量指数(BMI)增加和一些自身免疫状况有关，每种情况都与性激素水平和循环有关。因此，BMI和自身免疫状况将被仔细评估为荷尔蒙效应和NHL风险之间关联的潜在混杂因素和效果修饰者。简约的多变量无条件Logistic回归模型将被用来获得相对风险估计的优势比。将评估基因与环境的相互作用，以了解在相同生物途径中发挥作用的基因的暴露情况和SNPs，例如与怀孕相关的因素，以及IL-10、TNF-1、ESR1和ESR2中的SNPs。将使用错误发现率方法对多重假设检验进行控制。这项研究的主要优势是：1)已经分析了146个基因中的SNPs，这些基因可能与性激素S和非霍奇金淋巴瘤易感性之间的关联有关；2)已经收集了丰富的流行病学数据，包括广泛的生殖史、性类固醇激素的使用、自身免疫状况和体重指数，可用于评估主要效果、混淆和影响修改；5)根据世界卫生组织的分类进行病理确认和非霍奇金淋巴瘤亚型划分；6)数据将汇集起来，用于国际淋巴联盟内的未来分析，以便分析稀有亚型和暴露情况。阐明这些性激素相关因素在NHL风险中的作用将提高我们对淋巴肿大的理解，为未来的研究产生假设，并直接适用于减少NHL发病率的筛查和预防计划。 公共卫生相关性：项目叙述非霍奇金淋巴瘤(NHL)在男性中的发病率高于女性，除了与严重免疫抑制和一些罕见的遗传疾病有关外，几乎没有其他危险因素被确定。鉴于性激素影响免疫功能，与荷尔蒙相关的暴露和情况在女性和男性之间的不同可能有助于解释观察到的非霍奇金淋巴瘤的性别差异。阐明生殖因素、雌激素相关疗法的使用与女性NHL和NHL亚型的风险之间的关系，以及NHL风险与性相关激素之间的关系是否因激素代谢/生产和免疫功能中重要基因的变化而改变，将有助于提高我们对NHL发展的理解，有助于为未来的研究产生新的假设，并将直接适用于旨在降低NHL发病率的预防、干预和筛查计划。