Angiotensin II type I receptor autoantibodies and prostate cancer: cross-sectional and longitudinal studies.

Autoantibodies against the angiotensin II type I receptor (AT1R) have been associated with multiple diseases (pre-eclampsia, malignant hypertension, transplant rejection, Huntington’s and Alzheimer’s disease, ovarian cancer) suggesting that while the autoantibodies are not necessarily causative they may promote disease progression. These autoantibodies (AT1RaAbs) bind and chronically activate the receptor increasing inflammatory burden. The prostate has a local renin angiotensin system that has been implicated in prostate cancer growth. Two distinct datasets were used to examine the associations between AT1RaAbs and prostate cancer. A cross-sectional set (n = 151) consisting of 101 serum specimens that were collected from patients with scheduled appointments for either elevated prostate specific antigen levels, a scheduled prostate biopsy or being seen as a newly diagnosed PCA patient in a Urology Outpatient Clinic. 80 of these patients were positive for PCA at biopsy, whereas 21 were biopsy benign (either atrophy, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia or inflammation). The remaining 50 specimens were collected from men visiting an offsite prostate cancer screening who were free of prostate disease. Comparisons of covariate values between groups were by Kruskal-Wallis ANOVA with Dunn’s multiple comparisons test. Pairwise correlations between AT1RaAb and clinical correlates or pathological measurements were assessed using Spearman rank correlations. The longitudinal set of pre-diagnosis serum samples from 109 men was obtained from the Baltimore Longitudinal Study of Aging. This prospective cohort study is run by the National Institute on Aging, National Institutes of Health. Clinical measures associated with each BLSA serum sample include age, BMI, blood pressure, PSA levels and, for subjects who later developed PCA, the diagnosis date. All serum is from subjects now deceased with known date of death and post-mortem pathological status of the prostate (disease-free or PCA present). Time to events (diagnosis or death) were modeled nonparametrically by Kaplan-Meier survival curves, dichotomizing samples into either low or high AT1RaAb levels and analyzing serum samples grouped as most proximal or distal to timed event. Accelerated failure estimates were used to assess the effects of other predictors on AT1RaAb association with disease-free and overall survival at most proximal or most distal time points. The datasets correspond to the a study described in the Journal of Translational Autoimmunity published online 13 August 2019, 10000. "Angiotensin receptor autoantibodies as exposures that modify disease progression: cross sectional, longitudinal and in vitro studies of prostate cancer." https://doi.org/10.1016/j.jtauto.2019.100008针对血管紧张素II 1型受体（angiotensin II type I receptor, AT1R）的自身抗体已与多种疾病相关联，包括子痫前期、恶性高血压、移植排斥反应、亨廷顿病、阿尔茨海默病以及卵巢癌，这提示尽管此类自身抗体未必具有致病性，但可能会促进疾病进展。这类自身抗体（AT1RaAbs）可结合并慢性激活该受体，从而加重炎症负荷。前列腺存在局部肾素-血管紧张素系统，该系统已被证实与前列腺癌的生长相关。本研究采用两套独立数据集，探究AT1RaAbs与前列腺癌之间的关联。 第一套为横截面数据集（n=151），其中包含101份血清样本，采集自泌尿外科门诊中因前列腺特异性抗原（prostate specific antigen, PSA）水平升高、计划接受前列腺活检，或初诊为前列腺癌（prostate cancer, PCA）的患者。其中80例患者经活检证实为PCA阳性，21例活检结果为良性（包括萎缩、良性前列腺增生、高级别前列腺上皮内瘤变或炎症）。剩余50份样本则采集自参与异地前列腺癌筛查且无前列腺疾病的男性。组间协变量值的比较采用克鲁斯卡尔-沃利斯方差分析结合邓恩多重比较检验；AT1RaAb水平与临床指标或病理检测结果之间的两两相关性则通过斯皮尔曼秩相关分析进行评估。 第二套为纵向数据集，包含109名男性的诊断前血清样本，均来自巴尔的摩纵向衰老研究（Baltimore Longitudinal Study of Aging, BLSA）。该项前瞻性队列研究由美国国立卫生研究院下属的美国国立衰老研究所开展。每份BLSA血清样本对应的临床指标包括年龄、体重指数（BMI）、血压、PSA水平，对于后续确诊PCA的受试者，还包含诊断日期。所有血清样本均来自已故受试者，其死亡日期已知，且具备前列腺的死后病理状态信息（无前列腺疾病或存在PCA）。事件发生时间（确诊或死亡）采用卡普兰-迈耶生存曲线进行非参数建模，将样本按AT1RaAb水平分为低、高两组，并按距目标事件（确诊或死亡）的时间远近将血清样本分为近端组与远端组分别进行分析。采用加速失效模型，评估在距目标事件最近或最远的时间点上，其他预测因素对AT1RaAb与无病生存期及总生存期关联的影响。 本数据集对应发表于《转化自身免疫学杂志（Journal of Translational Autoimmunity）》2019年8月13日在线版的研究，论文标题为《血管紧张素受体自身抗体作为疾病进展调节因素：前列腺癌的横断面、纵向及体外研究（Angiotensin receptor autoantibodies as exposures that modify disease progression: cross sectional, longitudinal and in vitro studies of prostate cancer）》，DOI为10.1016/j.jtauto.2019.100008。