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.

系统性红斑狼疮(SLE)影响了相当数量的年轻非裔美国女性。尽管最近在诊断和治疗方面取得了进展，但非裔美国妇女中系统性红斑狼疮的患病率和严重程度仍在增加。非裔美国人侵袭性疾病表型的病因尚不清楚。系统性红斑狼疮的发生被认为是由于一个遗传易感个体暴露在触发环境因素中(S)。目前尚不清楚遗传/环境相互作用在多大程度上以及如何对非裔美国人的系统性红斑狼疮的发展和严重性做出贡献。非裔美国人中系统性红斑狼疮的患病率与西非报道的系统性红斑狼疮患病率相矛盾，在西非，系统性红斑狼疮是一种罕见的疾病。这种患病率差异导致了“梯度假说”，即西非人和非裔美国人之间的环境和基因差异导致美国系统性红斑狼疮患病率增加。流行梯度表明，对两大洲遗传相关队列的比较研究可能有助于深入了解导致SLE和SLE相关自身免疫发展的基因-环境相互作用。南卡罗来纳州的海岛古拉种群在遗传同质性和低水平的遗传混合方面是独一无二的。他们提供了一个独特的机会来研究他们自己与生活在其祖籍塞拉利昂的个人之间的遗传、环境和表观遗传学差异。塞拉利昂和南卡罗来纳州沿海地区的环境暴露明显不同，而遗传因素是相似的。根据其他人和我们的合作小组之前的研究，我们假设存在基因-环境相互作用导致SLE的发展，比较古拉人和塞拉利昂人将有助于确定SLE的关键致病因素。为了检验这一假说，我们将追求以下具体目标：目的1.检验这一假说，即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系统性红斑狼疮和系统性红斑狼疮相关自身免疫的存在有关。目的2.验证这样一种假设，即某些环境暴露引起的表观遗传学变化在古拉族患者和对照组以及塞拉利昂非洲人之间存在差异，并且这些差异与SLE和SLE相关自身免疫的存在有关。目的3.验证影响一氧化氮等活性中间基因表达的遗传因素参与系统性红斑狼疮发生发展的假说。在新的遗传/环境研究中使用两个在遗传和文化上有联系的独特队列，可能会确定与非裔美国人系统性红斑狼疮发展相关的关键因素。