GENES AND CHEMICAL EXPOSURE ASSOCIATED WITH SLE RISK

系统性红斑狼疮(SLE)是一种自身免疫性、致残、毁容的系统性风湿病，优先困扰女性和非裔美国人。迄今为止，已发现的易感遗传标记并不能完全解释非裔美国人中SLE的额外风险。性激素具有免疫调节作用。在月经初潮和更年期之间，与同龄男性相比，女性接触到的雌激素水平要高得多。这种雌激素暴露的性别差异可能解释了SLE风险的性别不平衡。同样，非裔美国人的性激素水平也高于高加索人。观察到的性激素水平种族差异的遗传决定因素可能有助于SLE易感性的种族差异。几个多态的细胞色素P-450基因编码雌激素和雄激素合成和降解的关键途径中的酶。这些基因之间的相互关系可能是激素水平的重要遗传决定因素，也可能影响激素对狼疮易感性的影响。基因-激素的相互作用影响激素功能的动态平衡，我们推测，这些会受到环境因素的影响。环境中的有机氯物质如2，2-双(若氯苯基)-1，1，1-三氯乙烷(DDT)及其长效代谢物DDE可能通过多种机制影响性激素的动态平衡。我们假设，影响性激素稳态和功能的基因(雄激素受体(AR)、雌激素受体(ER)和细胞色素P450基因)与内源性和/或外源性雌激素以及有机氯暴露的相互作用解释了SLE患者的性别和种族差异。这项建议的具体目的是：1.在一项大型的SLE病例/对照研究中，用基于聚合酶链式反应的方法检测SLE受试者和对照组的AR、ER和细胞色素P450基因；2.确定目标1中遗传标记与内源性和外源性雌激素以及接触有机氯在预测SLE风险中的相对重要性。

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.