GSTM1, APOL1, and their joint contribution to severity of hypertension and chronic kidney disease

慢性肾病（CKD）及其终末期肾病（ESRD）的后果是一个重要的公众问题， 我们最近取得了令人兴奋的发现，高度流行的GSTM 1总基因 缺失多态性（GSTM 1无效等位基因：0）与非洲人CKD进展更快相关。 美国肾脏病研究（AASK）试验参与者，例如一个无效（0/1）或两个无效的患者 （0/0）GSTM 1等位基因分别有1.7或2倍的风险增加的复合结果下降， 估计肾小球滤过率（eGFR），或透析或死亡，与两个全基因 序列活性等位基因，GSTM 1（1/1）。此外，GSTM 1（0）等位基因间存在遗传互作 和非洲祖先特异性载脂蛋白L1基因（APOL 1）G1和G2风险编码变体介导 AASK的总体风险和活动性GSTM 1（1/1）基因型抵消了APOL 1高风险患者的CKD风险 等位基因这种关联最近在社区动脉粥样硬化风险（ARIC）研究中得到了复制 非裔美国人（AA）和欧洲裔美国人（EA）。使用诱导性高血压（血管紧张素II）或 在Gstm 1基因敲除小鼠的CKD（残肾）模型中，我们发现Gstm 1缺陷导致 肾氧化应激水平、ER应激、炎症、纤维化途径活化、细胞凋亡和肾 损伤此外，缺乏Gstm 1并在足细胞中表达人APOL 1 G2转基因的小鼠， CKD模型中最严重的高血压，表明肾脏疾病更严重。这一证据与 流行的“两击”假说，即需要第二个环境或遗传因素（如GSTM 1）来表达 APOL 1高风险基因型易感性作为细胞损伤导致的肾功能的渗透性丧失。 我们假设GSTM 1通过其在调节氧化应激和炎症中的作用， 与APOL 1一起影响对高血压和肾损伤的易感性。通过整合小鼠模型 通过慢性肾功能不全的人类队列遗传分析为机制假说提供信息 队列（CRIC）;收缩压干预试验（SPRINT）队列;以及NHLBI跨- 精准医学组学（TOPMed）计划：动脉粥样硬化的多种族研究（梅萨），杰克逊 心脏研究（JHS），妇女健康倡议（WHI）-我们将：目标1：测试假设，结合 GSTM 1缺陷和APOL 1 G2变异体的转基因表达增加高血压患者的肾损伤， CKD;并确定造血与实质GSTM 1缺失在肾损伤中的作用。 目的2：验证GSTM 1（0）等位基因与高危APOL 1基因型相互作用调节风险的假设。 CRIC、SPRINT、 JHS，梅萨，WHI; 2682年，CRIC，SPRINT，梅萨，WHI中的西班牙裔美国人（HA）。目标3：测试是否 GSTM 1（0）和APOL 1高危等位基因通过氧化应激或细胞凋亡单独或联合作用， 通过检测其与诊断生物标志物水平的相关性，在CRIC AA队列中检测肾功能损害。

Chronic kidney disease (CKD) and its end stage renal disease (ESRD) consequences are a significant public health burden in the U.S. We recently made the exciting discovery that the highly prevalent GSTM1 total gene deletion polymorphism (GSTM1 null allele: 0) was associated with more rapid CKD progression in the African American Study of Kidney Disease (AASK) trial participants, such that patients with one null (0/1) or two null (0/0) GSTM1 alleles respectively had a 1.7- or 2-fold increased risk for the composite outcome of decline in estimated glomerular filtration rate (eGFR), OR dialysis OR death, compared to those with two full-gene sequence active alleles, GSTM1(1/1). Furthermore, there was a genetic interaction between GSTM1(0) alleles and the African ancestry-specific apolipoprotein L1 gene (APOL1) G1 and G2 risk coding variants to mediate overall risk in AASK, and the active GSTM1(1/1) genotype offset the risk of CKD in those with APOL1 high risk alleles. This association was very recently replicated in the Atherosclerosis Risk in Communities (ARIC) study in African Americans (AA) and European Americans (EA). Using an induced hypertension (angiotensin-II) or CKD (remnant kidney) model in Gstm1 knockout mice, we show that Gstm1 deficiency results in increased levels of renal oxidative stress, ER stress, inflammation, activation of fibrotic pathway, apoptosis, and kidney injury. Furthermore, mice lacking Gstm1 and expressing the human APOL1 G2 transgene in podocytes had worst hypertension in the CKD model, suggesting worse kidney disease. This evidence is consistent with the prevailing 'two-hit' hypothesis that a second environmental or genetic (eg GSTM1) factor is needed to express the APOL1 high risk genotype susceptibility as a penetrant loss of kidney function resulting from cellular injury. We hypothesize that GSTM1, through its role in regulating oxidative stress and inflammation, interacts with APOL1 to influence susceptibility to hypertension and kidney injury. By integrating mouse models to inform mechanistic hypotheses with human cohort genetic analyses of the Chronic Renal Insufficiency Cohort (CRIC); Systolic Blood Pressure Intervention Trial (SPRINT) cohort; and 3 cohorts in the NHLBI Trans- Omics for Precision Medicine (TOPMed) program: Multi-Ethnic Study of Atherosclerosis (MESA), Jackson Heart Study (JHS), Women's Health Initiative (WHI) – we will: Aim 1: Test the hypothesis that combined GSTM1 deficiency and transgenic expression of APOL1 G2 variant augments renal injury in hypertension and CKD; and determine the contribution of hematopoietic versus parenchymal GSTM1 deletion in kidney injury. Aim 2: Test the hypothesis that the GSTM1(0) allele interacts with high risk APOL1 genotypes to modulate risk of proteinuria and/or loss of renal function through effects on blood pressure in 9717 AA in CRIC, SPRINT, JHS, MESA, WHI; and in 2682 Hispanic American (HA) in CRIC, SPRINT, MESA, WHI. Aim 3: Test whether the GSTM1(0) and APOL1 high risk alleles act separately or jointly through oxidative stress or apoptosis to impair renal function in the CRIC AA cohort by testing their association with levels of diagnostic biomarkers.