GENES AND CHEMICAL EXPOSURE ASSOCIATED WITH SLE RISK

与系统性红斑狼疮风险相关的基因和化学物质暴露

• 批准号: 6078923
• 负责人: PATRICIA Ann FRASER
• 金额: $ 19.24万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6078923
• 关键词: African American; androgen receptor; caucasian American; clinical research; cytochrome P450; dichlorodiphenyltrichloroethane; disease /disorder proneness /risk; estrogen receptors; estrogens; female; gene environment interaction; genetic markers; genetic susceptibility; genotype; hormone biosynthesis; human subject; polymerase chain reaction; racial /ethnic difference; sex hormones; systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune, disabling, disfiguring systemic rheumatic disease that preferentially afflicts women and African-Americans. The excess risk of SLE in African-Americans is not entirely explained by the genetic markers of susceptibility that have been identified to date. Sex hormones are immunomodulatory. During the interval between menarche and menopause women are exposed to significantly higher estrogen levels when compared to men of similar age. This gender difference in estrogen exposure may explain the gender imbalance in SLE risk. Similarly, African-Americans have higher levels of sex hormones than Caucasians. Genetic determinants of the observed ethnic differences in sex hormone levels may contribute to the ethnic differences in predisposition to SLE. Several polymorphic cytochrome P-450 genes encode enzymes in critical pathways of estrogen and androgen synthesis and degradation. Inter-relationships among these genes may be important genetic determinants of hormone levels that may also influence the hormonal effects on lupus susceptibility. Gene-hormone interactions affect hormone homeostasis of function and these, we hypothesize, can be affected by environmental agents. Through a variety of mechanisms, organochlorines in the environment such as 2,2-bis(rho-chlorophenyl)-1,1,1- trichlorethane (DDT), and its long-lasting metabolite DDE may affect sex hormone homeostasis. We hypothesize that interactions of genes that affect sex hormone homeostasis and function (androgen receptor (AR) and estrogen receptors (ERs) and cytochrome P450 genes) with endogenous and/or exogenous estrogens and also with organochlorine exposures explain the gender and ethnic differences observed in SLE. The specific aims of this proposal are to: 1. Determine AR, ERs and cytochrome P450 genotypes in SLE subjects and controls by PCR based methodologies in a large SLE case/control study; 2. Determine the relative importance of genetic markers in Aim number 1 with endogenous and exogenous estrogens and with exposure to organochlorines in predicting risk of SLE.

全身性红斑狼疮（SLE）是一种自身免疫性，残疾，毁容的系统性风湿病，优先折磨妇女和非裔美国人。 迄今为止已经确定的易感性遗传标志物并未完全解释非裔美国人SLE的过多风险。 性激素是免疫调节的。 与年龄相似的男性相比，在初级和更年期之间的间隔期间，女性的雌激素水平明显更高。 雌激素暴露的性别差异可能解释了SLE风险的性别失衡。 同样，非裔美国人的性激素水平高于高加索人。 观察到的性激素水平中观察到的种族差异的遗传决定因素可能有助于SLE倾向的种族差异。 几种多态性细胞色素P-450基因在雌激素和雄激素合成和降解的关键途径中编码酶。这些基因之间的关系可能是激素水平的重要遗传决定因素，这也可能影响激素对狼疮易感性的影响。 基因激素相互作用会影响功能的激素稳态，我们认为这些相互作用可能受环境药物的影响。通过多种机制，环境中的有机氯，例如2,2-双（Rho-choloophenyl）-1,1,1-1-1-三氯乙烷（DDT）及其持久的代谢物DDE可能会影响性激素稳态。 我们假设影响性激素稳态和功能的基因相互作用（雄激素受体（AR）和雌激素受体（ERS）和细胞色素P450基因）与内源性和/或外源性雌激素，以及具有有机氯的外源性雌激素的相互作用，以及具有有机氯的外源性外观外观差异。 该提案的具体目的是：1。在大型SLE病例/对照研究中，在SLE受试者中确定SLE受试者中的AR，ER和细胞色素P450基因型； 2。确定遗传标志物在目标1中具有内源性和外源性雌激素的相对重要性，并在预测SLE风险中暴露于有机氯中的相对重要性。