Hormonal And Environmental Factors For Systemic Lupus Er

系统性狼疮的激素和环境因素

• 批准号: 6672970
• 负责人: Glinda S. Cooper
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6672970
• 关键词: clinical research; disease /disorder etiology; dust; environmental contamination; environmental exposure; epidemiology; estrogens; female; gene environment interaction; hormone regulation /control mechanism; human subject; immunopathology; occupational hazard; silicates; systemic lupus erythematosus

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.

全身性红斑狼疮（SLE）是一种自身免疫性疾病，可严重损害肾脏，关节和其他组织。遗传易感性在SLE中的作用已经进行了广泛的研究，但是对于可能与SLE病因有关的特定激素和环境影响的贡献相对较少。我们的研究重点是遗传因素和内源性激素暴露，雌激素的外源性来源以及可能影响SLE风险的职业暴露的量度。 我们检查了种族，性别和年龄的全身性红斑狼疮（SLE）的临床和免疫学特征的流行。遗传分析包括影响免疫功能的基因，例如免疫球蛋白γ（GM）和KAPPA（KM）同型，影响促炎性细胞因子介体介体（IL）-1和肿瘤坏死因子（TNF），DR3和DR2基因的多态性，DR3和DR2基因构成了2个基因，并构成了2个综合性，并构成了2概述（启动子多态性以及包括谷胱甘肽-S-转移酶（GST）GSTM1，GSTT1，GSTT1，GSTP1和N-乙酰基转移酶（NAT）NAT1和NAT2的代谢基因。我们还研究了C反应蛋白（CRP）基因内含子中的多态性GT重复是否有助于基线C反应蛋白（CRP）的变化，这是炎症的度量。检查的暴露包括吸烟和头发治疗（染料，永久物质），雌激素变异性和催乳素暴露的标记（初潮时代，年代年龄，生殖和泌乳病史，使用雌激素药物的使用），职业暴露于晶体硅胶，溶剂，溶剂，农药，汞和型号的特殊性和历史悠久的特殊性和历史悠久，并有特殊性和历史记录。在另一项暴露评估研究中，我们在北卡罗来纳州东部的农场工人的呼吸区测量了可呼吸的二氧化硅暴露。 与白人相比，黑人和其他少数族裔的SLE诊断年龄平均年龄小6岁。黑人中更常见的是盘状狼疮，蛋白尿，抗SM和抗RNP自身抗体。光敏性和粘膜溃疡的频率较低。与女性相比，蛋白尿，白细胞减少症，淋巴细胞减少和血小板减少症在男性中的常见大约三倍。随着年龄的增长，口腔或鼻腔溃疡的患病率和抗DNA自身抗体的患病率下降。 白人患者中KM表型的频率与对照组显着不同。 KM3,3与风险增加有关，而KM1,3与SLE相对风险较低有关。然而，在黑人中，与白人相关的关联模式不同，患者和对照组之间的总体差异在统计学上也不显着。 我们观察到IL-1α-889*1.1基因型的SLE风险增加了三倍，与在黑人和白人中的IL-1 Alpha -889*2等位基因相比。在黑人中，IL -1β -511*2等位基因的运输比IL -1β-511*1.1纯合子基因型的SLE风险更高。 IL -1 Alpha -889和IL -1β-511基因型与SLE与SLE独立相关，在控制所有五个基因座的多态性的模型中。这些结果表明，IL-1启动子多态性会影响发展SLE的风险，并支持了细胞因子脱离与SLE病因有关的假设。目前正在进行TNF和DR2/DR3分析。与对照组相比，黑人女性SLE患者的特异性NOS-2多态性更为常见。此外，黑人女性SLE患者的G-954C和CCTTT-8重复多态性在连锁不平。这些结果表明，NOS2转录的遗传控制改变是黑人女性中SLE的危险因素。我们发现，在正常个体和患有炎症性疾病全身性红斑狼疮的患者中，CRP多态性与基线CRP的差异有关。白人的GT（16）和GT（21）的频率比黑人高两个倍，但患者和对照组之间的等位基因分布没有差异。 SLE与纯合无效GSTM1或GSTT1基因型的存在之间没有独立的关联，纯合val/val/val或杂合的Val/Ile GSTP1基因型或职业阳光暴露。与GSTM1无效基因型的白人之间的24个月或更长时间相关的SLE风险增加了3倍，但阳光暴露与GSTM1阳性白人之间的风险无关。我们没有观察到任何GST基因，吸烟或使用头发治疗之间的任何相互作用。 SLE和NAT1或NAT 2基因型之间没有关联。 我们的结果表明，SLE风险与永久性染发剂或吸烟之间的关联最多。我们几乎没有证据表明雌激素或催乳素相关的暴露与狼疮的风险增加有关。母乳喂养与降低SLE的风险降低有关，母乳喂养的婴儿数量和总母乳喂养数周具有统计学意义的趋势。没有与怀孕或活产的数量相关。与对照组相比，与随后发育的女性更早发生了自然更年期（P小于0.001）。 SLE与激素替代疗法或口服避孕药的使用或使用时间之间没有关联，并且与先前使用生育药物没有关联。与二氧化硅，汞和与农业有关的农药（混合）的职业接触（混合），可以看到相当强的关联（4.5或更高）。在男女的单独分析中也看到了类似的模式。在诊断前的三年中，SLE风险随着带状疱疹的病史和经常发生的冷疮而增加。 在接触评估研究中，在各种农业活动中，从七个农场的27名工人收集了个人呼吸区样本（n = 37）。平均可呼吸二氧化硅浓度为0.77 mg/立方M，在红薯移植期间测量最高水平（3.91 +/- 2.07 mg/立方M）。这项研究表明，在特定的农业活动期间，存在暴露量高于0.05 mg/立方米的阈值限值的潜力。