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，女性可能更容易在较早的年龄患上COPD，但性别易感性的生物学基础尚不清楚。最近，死于COPD的女性人数超过了男性，这突显了了解可能与COPD易感性、诊断和治疗相关的性别特定因素的重要性。为了解决可能的生物学解释，我们假设COPD的易感性与自身免疫性疾病的易感性相同，并且可以通过人类主要组织相容性(MHC)基因和性激素途径中的基因的遗传和表观遗传变异来了解COPD在女性和男性中的不同特征。我们将在波士顿早发性COPD研究的1000名家庭成员、400名高加索人COPD病例/400名高加索人对照和200名非裔美国人COPD病例/200名非裔美国人对照中，对MHC基因座160个基因的2360个SNP进行广泛的基因分型。我们将测试MHC基因与COPD的总体关联，并确定在基于家庭的分析和病例对照分析之间复制的性别特定关联。我们还将评估16个性激素途径基因中的384个SNPs与基于家庭的队列中COPD的性别特异性关联，并尝试复制病例对照研究的结果。我们将探索MHC和性类固醇途径基因之间的上位性相互作用。虽然DMA序列变异是了解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型性很重要，但对COPD的研究一直很少。在这项应用中，我们将评估位于1,536个潜在甲基化位点的371个基因的全局和特定的基因甲基化模式。我们将比较波士顿早发性COPD研究中男性和女性先证者和兄弟姐妹之间的甲基化模式，以及男性和女性COPD病例和对照之间的甲基化模式，以确定可能受到差异甲基化的基因(以及在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来研究COPD的性别特征。

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.