Genetic Features of Gender Differences in COPD

慢性阻塞性肺病性别差异的遗传特征

基本信息

批准号：
8102022
负责人：
DAWN L DEMEO
金额：
$ 77.77万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8102022
关键词：
Address African African American Autoimmune Diseases Autoimmune Process Biological Biological Aging Boston Case-Control Studies Caucasians Caucasoid Race Characteristics Chromosomes, Human, Pair 6 Chronic Obstructive Airway Disease Clinic DNA DNA Modification Process DNA Sequence Diagnosis Disease susceptibility Epidemiologic Studies Epidemiology Epigenetic Process Family Family member Female Gender Gene Expression Genes Genetic Genetic Determinism Genetic Predisposition to Disease Genetic Variation Genome Genotype Goals Gonadal Steroid Hormones Histocompatibility Hormonal Human Individual Investigation Major Histocompatibility Complex Major Histocompatibility Complex Gene Malignant neoplasm of lung Measures Mediating Methods Methylation Monozygotic Twinning Monozygotic twins Pathway interactions Pattern Predisposition Public Health Publishing Research Personnel Respiratory physiology Severities Sex Characteristics Siblings Site Smoke Testing Variant Woman Women&apos s Health anticancer research base case control cohort early onset epigenetic variation falls genetic association insight male member men proband programs sex sexual dimorphism trait trend

项目摘要

DESCRIPTION (provided by applicant): Epidemiologic observations in the Boston Early-Onset COPD Study suggest that women may be more susceptible to develop COPD at an earlier age, but the biological basis of gender-specific susceptibility is unknown. Recently, the number of women dying from COPD surpassed the number of men, highlighting the importance of understanding gender-specific factors that may be relevant for COPD susceptibility, diagnosis and treatment. To address a potential biologic explanation, we hypothesize that susceptibility to COPD shares features of susceptibility to autoimmune diseases, and that insight into the variable features of COPD in women versus men may be understood through genetic and epigenetic variation in genes in the human major histocompatibility (MHC) locus and sex-steroid pathway. We will perform extensive genotyping of 2,360 SNPs in 160 genes of the MHC locus in 1,000 family members of the Boston Early-Onset COPD Study, 400 Caucasian COPD cases/400 Caucasian controls and 200 African-American COPD cases/200 African-American controls. We will test for overall association of MHC locus genes with COPD and identify sex-specific associations that replicate between the family-based and case-control analyses. We will also evaluate 384 SNPs in 16 sex-steroid pathway genes for sex-specific associations with COPD in the family- based cohort and attempt replication of findings in the case-control studies. We will explore epistatic interactions between MHC and sex-steroid pathway genes. Although DMA sequence variation is the most common susceptibility factor investigated to understand COPD, epigenetic variation may be important in influencing gene expression. Epigenetic variation through gene methylation has been demonstrated to be important to the sexual dimorphism of common human traits, autoimmune diseases, and lung cancer, but research in COPD has been minimal. In this application, we will evaluate global and specific gene methylation patterns in 371 genes at 1,536 potential methylation sites. We will compare methylation patterns between male and female probands and siblings in the Boston Early-Onset COPD study and male and female COPD cases and controls, to identify genes that may be subject to differential methylation (and potentially sexually dimorphic gene expression in COPD). Thus, genetic and epigenetic hypotheses will be integrated to investigate sex-specific features of COPD.

描述（由申请人提供）：波士顿早期发作的COPD研究中的流行病学观察表明，女性可能更容易在更早的年龄发展COPD，但是性别特异性易感性的生物学基础尚不清楚。最近，死于COPD的妇女人数超过了男性的数量，强调了了解可能与COPD易感性，诊断和治疗有关的性别特异性因素的重要性。为了解决潜在的生物学解释，我们假设对COPD的敏感性分享了对自身免疫性疾病的易感性的特征，并且可以通过人类主要的组织相容性（MHC）locus locus locus和sexserside的基因中对女性与男性的COPD可变特征的见解。我们将在1000名波士顿早期发作的COPD研究，400例高加索COPD病例/400个高加索对照组和200名非裔美国人COPD/200个非裔美国人案例/200个非裔美国人对照组中，在1,000名波士顿早发COPD研究的1000个家庭成员中，将在160个MHC基因座中进行2,360个SNP的广泛基因分型。我们将测试MHC基因座基因与COPD的总体关联，并确定在基于家庭和病例对照分析之间复制性别特定的关联。我们还将评估16个性类固醇途径基因中的384个SNP，以在基于家庭的队列中与COPD的性别特异性关联，并尝试在病例对照研究中复制发现。我们将探索MHC和性类固醇途径基因之间的同义相互作用。尽管DMA序列变异是研究COPD的最常见易感因素，但表观遗传变异对于影响基因表达可能很重要。通过基因甲基化的表观遗传变异已被证明对人类常见的人类性状，自身免疫性疾病和肺癌的性二态性很重要，但是COPD的研究很少。在此应用中，我们将评估1,536个潜在甲基化位点的371个基因中的全球和特定基因甲基化模式。我们将比较波士顿早发的COPD研究和男性和女性COPD病例和对照组中男性和女性探针和兄弟姐妹之间的甲基化模式，以鉴定可能受到甲基化差异（COPD中潜在性二态基因表达）的基因。因此，将整合遗传和表观遗传假设以研究COPD的性别特异性特征。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sex-specific features of emphysema among current and former smokers with COPD.

DOI：
10.1183/13993003.00996-2015
发表时间：
2016-01
期刊：
The European respiratory journal
影响因子：
0
作者：
Hardin M;Foreman M;Dransfield MT;Hansel N;Han MK;Cho MH;Bhatt SP;Ramsdell J;Lynch D;Curtis JL;Silverman EK;Washko G;DeMeo D;COPDGene Investigators
通讯作者：
COPDGene Investigators

Gender differences in COPD: are women more susceptible to smoking effects than men?