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Association of Androgen Receptor Polymorphisms with Damage in SLE

雄激素受体多态性与 SLE 损伤的关联

基本信息

批准号：
8619113
负责人：
BETTY P TSAO
金额：
$ 19.64万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-23 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8619113
关键词：
Address Affect African Age Androgen Receptor Androgens Binding Biological Markers Biopsy CAG repeat Categories Cell Line Clinic Data Data Set Databases Development Disease Disease Progression Disease susceptibility Dose Environmental Risk Factor Ethnic Origin European Exhibits Explosion Female Gender Gene Expression Gene Targeting Genes Genetic Genetic Markers Genetic Polymorphism Genetic Variation Goals Gonadal Steroid Hormones Haplotypes Health Health Sciences Human Hypertension In Vitro Institutes Interferons International Intervention Kidney Length Link Logistic Regressions Lung Lupus Lupus Nephritis Measures Mediating Medical Research Morbidity - disease rate Multivariate Analysis Oklahoma Organ Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Physical Function Play Predisposing Factor Predisposition Prednisone Process Prognostic Marker Quality of life Receptor Gene Regression Analysis Risk Risk Assessment Risk Factors Role Sample Size Severities Sex Characteristics Sex Chromosomes Signal Transduction Smoking Status Staging Susceptibility Gene Systemic Lupus Erythematosus TGFB1 gene Testing Testosterone Therapeutic Intervention Transactivation Transfection Universities Update Woman X Chromosome X Inactivation cohort dehydroepiandrosterone disease diagnosis dosage gene function genetic profiling genetic risk factor high risk hypercholesterolemia illness length improved indexing insight instrument kidney cell male men mortality novel polyglycine prevent public health relevance response selective androgen receptor modulator

项目摘要

Project Summary Multiple genes and environmental factors likely contribute to disease susceptibility and expression in systemic lupus erythematosus (SLE). While an understanding of the genes that contribute to the pathogenesis is far from complete, significant progress has been made in identifying more than 40 susceptibility genes or loci. However, much less is known about genetic factors predisposing to good outcomes in SLE. Damage in SLE, defined by irreversible changes either as result of disease activity, therapeutic interventions or co-morbid conditions occurring after the disease diagnosis, is measured by an instrument developed by the Systemic Lupus International Collaborating Clinics as the SLICC/ACR damage index. Since male SLE patients tend to develop damage earlier in the course of the illness, it is plausible that gender differences including sex hormones, sex chromosome-linked genes and/or X chromosome inactivation (XCI) in women may play a role in disease progression in SLE. We selected the androgen receptor gene (AR) located on the X chromosome and tested whether shorter polyGLN polymorphisms (d17) conferring higher androgen transactivation activity were associated with accelerated damage in SLE. Our preliminary results of 129 men and 418 women affected with SLE showed 1) accelerated damage in men during the first 5 years of disease especially in risk for developing renal damage, and 2) significant associations of increased damage (SDI e 2) with shorter CAG repeat length of AR, higher cumulative prednisone dosage, and longer disease duration. These data suggested a heightened response to testosterone and dehydroepiandrosterone (DHEA) binding mediated by enhanced androgen transactivation activity of short CAG repeat in AR might be a prognostic marker for SLE damage in both genders. Although DHEA has previously shown beneficial in treating SLE manifestations, recent studies have yielded inconsistent results, highlighting the need for further studies. We hypothesize that one or more X-linked AR variants predispose to damage accrual in SLE, and propose to assemble a multiethnic dataset of >5,000 clinically well-characterized SLE patients containing > 500 male patients to address whether 1) men with SLE are at risk for overall or renal damage, 2) AR variants help identify at risk patients of both gender for damage accrual, and 3) differential levels of AR responsive gene expression contribute to damage in SLE. Results from these studies are likely to illuminate disease mechanisms, improve risk assessment of damage accrual, and promote consideration of selective androgen receptor modulators in therapeutic interventions of SLE.

项目总结