Systemic lupus erythematosus (SLE) is an autoimmune disease that can severely damage the kidneys, joints, and other tissues. The role of genetic susceptibility in SLE has been extensively examined, but relatively little is known about the contribution of specific hormonal and environmental influences that may be involved in the etiology of SLE. Our study focuses on genetic factors and on measures of endogenous hormone exposure, exogenous sources of estrogen, and occupational exposures that may affect the risk of SLE. We examined the prevalence of clinical and immunologic features of systemic lupus erythematosus (SLE) by race, sex, and age. Genetic analyses included genes affecting immune function such as immunoglobulin gamma (GM) and kappa (KM) allotypes, polymorphisms affecting the proinflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF), the DR3 and DR2 genes within the major histocompatibility complex, and nitric oxide synthase-2 (NOS2) promoter polymorphisms, and metabolism genes including glutathione-S-transferases (GST) GSTM1, GSTT1, GSTP1 and N-acetyl transferase (NAT) NAT1 and NAT2. We also investigated whether a polymorphic GT-repeat in the intron of the C-reactive protein (CRP) gene contributes to variation in baseline c-reactive protein (CRP), a measure of inflammation. Exposures examined included smoking and hair treatments (dyes, permanents), markers of variability in estrogen and prolactin exposure (age at menarche, age at menopause, reproductive and lactation history, use of estrogenic medications), occupational exposure to crystalline silica, solvents, pesticides, mercury, and ultraviolet radiation, and history of exposure to specific infectious agents. In a separate exposure assessment study, we measured respirable silica exposure in the breathing zone of farm workers in eastern North Carolina. Mean age at SLE diagnosis was 6 years younger among Blacks and other minorities compared with Whites. Discoid lupus, proteinuria, anti-Sm, and anti-RNP autoantibodies were more commonly seen in Blacks; photosensitivity and mucosal ulcers were noted less often. Proteinuria, leukopenia, lymphopenia, and thrombocytopenia were approximately three times more common in men compared with women. The prevalence of oral or nasal ulcers and anti-DNA autoantibodies declined with age. The frequency of KM phenotypes in White patients was significantly different from controls. KM3,3 was associated with an increased risk, whereas KM1,3 was associated with a lower relative risk of SLE. In Blacks, however, the pattern of associations with KM phenotypes differed from that in Whites, and the overall difference between patients and controls was not statistically significant. We observed a three-fold increased risk of SLE for the IL-1 alpha -889*1.1 genotype compared to carriage of the IL-1 alpha -889*2 allele among both Blacks and Whites. In blacks, carriage of the IL-1 beta -511*2 allele conferred a higher risk of SLE than the IL-1 beta -511*1.1 homozygous genotype. The IL-1 alpha -889 and IL-1 beta -511 genotypes were independently associated with SLE in models controlling for polymorphisms at all five loci. These results suggest that IL-1 promoter polymorphisms affect risk of developing SLE, and support the hypothesis that cytokine disregulation is involved in SLE etiology. The TNF and DR2/DR3 analyses are currently being conducted. Specific NOS-2 polymorphisms were more frequent among Black female SLE patients when compared with controls. Furthermore, the G-954C and CCTTT-8 repeat polymorphisms were in linkage disequilibrium among Black female SLE patients. These results suggest that altered genetic control of NOS2 transcription is a risk factor for SLE among Black females. We found that the CRP polymorphism was associated with differences in baseline CRP in both normal individuals and in patients with the inflammatory disease systemic lupus erythematosus. The frequency of GT(16) and GT(21) was two-fold higher in Whites than in Blacks, but there was no difference in allele distribution between patients and controls. There was no independent association between SLE and presence of the homozygous null GSTM1 or GSTT1 genotype, the homozygous Val/Val or heterozygous Val/Ile GSTP1 genotype, or occupational sunlight exposure. There was a three-fold increased risk of SLE associated with 24 or more months occupational sun exposure among whites with the GSTM1 null genotype, but sun exposure was not associated with risk among GSTM1 positive Whites. We did not observe any interaction between any of the GST genes, smoking, or use of hair treatments. There was no association between SLE and NAT1 or NAT 2 genotype. Our results suggested at most a weak association between SLE risk and permanent hair dyes or smoking. We found little evidence that estrogen- or prolactin-related exposures are associated with an increased risk of lupus. Breastfeeding was associated with a decreased risk of developing SLE with a statistically significant trend for number of babies breastfed and total weeks of breastfeeding. There were no associations with number of pregnancies or live births. Natural menopause occurred earlier for women with subsequent development of SLE compared with controls (p less than 0.001). There was no association between SLE and current use or duration of use of hormone replacement therapy or oral contraceptives, and no association with previous use of fertility drugs. Fairly strong associations (odds ratios 4.5 or higher) were seen with occupational exposure to silica, mercury, and farming-related pesticides (mixing). Similar patterns were seen in separate analyses for men and women. SLE risk increased with history of shingles and with frequent cold sores in the three years before diagnosis. In the exposure assessment study, personal breathing zone samples (n=37) were collected from 27 workers at seven farms during various agricultural activities. The mean respirable silica concentration was 0.77 mg/cubic-m and the highest levels were measured during sweet potato transplanting (3.91 +/- 2.07 mg/cubic-m). This study demonstrates that the potential for exposures above the Threshold Limit Value of 0.05 mg/cubic-m exists during particular agricultural activities.
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