Genetic and environmental influences on SLE and lupus-related autoimmunity

遗传和环境对系统性红斑狼疮和狼疮相关自身免疫的影响

• 批准号: 8494004
• 负责人: DIANE L KAMEN
• 金额: $ 22.18万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494004
• 关键词: Admixture; Affect; Africa; African; African American; Age; Alleles; Autoimmunity; Biological Markers; Cohort Studies; Comparative Study; Cytomegalovirus; DNA; DNA Methylation; Data; Development; Diagnosis; Disease; Environmental Exposure; Environmental Pollution; Environmental Risk Factor; Epigenetic Process; Etiology; Exposure to; Family; Genes; Genetic; Genetic Drift; Genetic Predisposition to Disease; Home environment; Human Herpesvirus 4; Immune; Immune response; Individual; Infection; Inflammatory; Instruction; Island; Lead; Life; Link; Lupus; Malaria; Mercury; Morbidity - disease rate; Nitric Oxide; Parasites; Patients; Pattern; Pesticides; Population; Predisposition; Prevalence; Questionnaires; Rare Diseases; Reporting; Rheumatism; Risk; Sea; Serum; Severities; Sierra Leone; Silicon Dioxide; Simplexvirus; Societies; South Carolina; Sunlight; Systemic Lupus Erythematosus; Testing; United States; Virus; Vitamin D; Woman; base; caucasian American; child bearing; cohort; disease phenotype; enhancing factor; exome sequencing; gene environment interaction; insight; killings; microorganism; mortality; novel; pollutant; pressure

Systemic lupus erythematosus (SLE) affects a significant number of young African American women. The prevalence and severity of SLE in African American women is increasing despite recent advances in diagnosis and treatment. The etiology of the aggressive disease phenotype in African Americans is unknown. Development of SLE is believed to be due to a genetically susceptible individual being exposed to a triggering environmental factor(s). To what degree and how genetic/environmental interactions contribute to development and severity of SLE in African Americans is unclear. The prevalence of SLE in African Americans is in contradiction to the reported SLE prevalence in West Africa, where it is a rare disease. This prevalence difference led to the "gradient hypothesis" that environmental and genetic differences between West Africans and African Americans resulted in the increased prevalence of SLE in the United States. The prevalence gradient suggests that comparative studies of genetically related cohorts from the two continents may provide insight into the gene-environment interactions that result in the development of SLE and SLEr elated autoimmunity. The Sea Island Gullah population of South Carolina is unique in their genetic homogeneity and low levels of genetic admixture. They offer a unique opportunity to study genetic, environmental and epigenetic differences between themselves and individuals living in their ancestral home of Sierra Leone. Environmental exposures are clearly different in Sierra Leone and coastal South Carolina while genetics are similar. Based on prior studies by others and our collaborative group, we hypothesize that there are gene-environment interactions leading to the development SLE and that comparing the Gullah versus Sierra Leoneans will allow identification of key pathogenic factors in SLE. To test this hypothesis, we will pursue the following Specific Aims: Aim 1. Test the hypothesis that differences in certain environmental exposures between Sierra Leone and coastal South Carolina are associated with the presence of SLE and SLE-related autoimmunity. Aim 2. Test the hypothesis that certain environmental exposures induce epigenetic changes that differ between the Gullah patients and controls and Sierra Leone Africans, and that these differences correlate with the presence of SLE and SLE-related autoimmunity. Aim 3. Test the hypothesis that genetic factors influencing expression of nitric oxide and other reactive intermediate genes are involved in the development of SLE. Using two unique cohorts genetically and culturally linked in novel genetic/environmental studies will likely identify key factors associated with development of SLE in African Americans.

全身性红斑狼疮（SLE）会影响大量非裔美国妇女。尽管最近在诊断和治疗方面取得了进步，但非裔美国女性SLE的患病率和严重程度仍在增加。非洲裔美国人的侵略性疾病表型的病因尚不清楚。 SLE的发展被认为是由于遗传易感的个体暴露于触发环境因素。尚不清楚非洲裔美国人的遗传/环境相互作用如何促进SLE的发展和严重性。非裔美国人SLE的患病率与据报道的西非SLE患病率矛盾，这是一种罕见的疾病。这种普遍性差异导致了“梯度假设”，即西非人和非裔美国人之间的环境和遗传差异导致美国SLE的患病率增加。患病率梯度表明，来自两个大洲的遗传相关队列的比较研究可能会深入了解基因环境相互作用，从而导致SLE和SLER兴高采烈的自身免疫性的发展。南卡罗来纳州的海岛古拉人口在其遗传同质性和遗传混合水平较低方面是独一无二的。他们提供了一个独特的机会，可以研究自己与居住在塞拉利昂祖先家中的个人之间的遗传，环境和表观遗传差异。塞拉利昂和南卡罗来纳州沿海地区的环境暴露明显不同，而遗传学相似。基于他人和我们的协作小组的先前研究，我们假设存在基因环境相互作用导致SLE的发展，并且比较Gullah与Sierra Leoneans的相互作用将允许识别SLE中的关键致病因素。为了检验这一假设，我们将追求以下特定目的：目标1。检验以下假设：塞拉利昂和南卡罗来纳州塞拉利昂和南卡罗来纳州沿海地区某些环境暴露的差异与SLE和SLE相关的自身免疫的存在有关。 AIM 2。检验以下假设：某些环境暴露会诱导Gullah患者和对照组和塞拉利昂非洲人之间有所不同的表观遗传变化，并且这些差异与SLE和SLE相关的自身免疫的存在相关。目标3。检验以下假设：一氧化氮和其他反应性中间基因的遗传因子与SLE的发展有关。在新的遗传/环境研究中使用两个独特的人群在遗传和文化上联系，可能会发现与非裔美国人SLE发展相关的关键因素。