Genetic Features of Gender Differences in COPD

描述（由申请人提供）：波士顿早发性COPD研究的流行病学观察表明，女性可能更容易在更早的年龄发展为COPD，但性别特异性易感性的生物学基础尚不清楚。最近，死于慢性阻塞性肺病的女性人数超过了男性人数，这凸显了了解可能与慢性阻塞性肺病易感性、诊断和治疗相关的性别因素的重要性。为了解决潜在的生物学解释，我们假设COPD易感性与自身免疫性疾病易感性具有相同的特征，并且通过人类主要组织相容性（MHC）位点和性类固醇途径中基因的遗传和表观遗传变异，可以了解女性与男性COPD的可变特征。我们将对波士顿早发性COPD研究的1000名家庭成员、400名白人COPD病例/400名白人对照和200名非裔美国人COPD病例/200名非裔美国对照中160个MHC位点基因的2360个snp进行广泛的基因分型。我们将测试MHC位点基因与COPD的总体关联，并确定在基于家庭和病例对照分析之间重复的性别特异性关联。我们还将在基于家庭的队列中评估16个性类固醇途径基因中的384个snp与COPD的性别特异性关联，并尝试复制病例对照研究中的结果。我们将探讨MHC和性类固醇途径基因之间的上位性相互作用。虽然DMA序列变异是研究COPD最常见的易感因素，但表观遗传变异在影响基因表达方面可能是重要的。通过基因甲基化的表观遗传变异已被证明对常见人类特征、自身免疫性疾病和肺癌的性别二态性很重要，但对慢性阻塞性肺病的研究很少。在这个应用中，我们将评估371个基因在1536个潜在甲基化位点的整体和特定基因甲基化模式。我们将比较波士顿早发性COPD研究中男性和女性先显子和兄弟姐妹以及男性和女性COPD病例和对照之间的甲基化模式，以确定可能受差异甲基化影响的基因（以及COPD中潜在的性别二态基因表达）。因此，遗传学和表观遗传学假说将被整合以研究COPD的性别特异性特征。

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.