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.
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