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

慢性肾脏病(CKD)及其终末期肾病(ESRD)的后果是一个重要的公众 美国的健康负担。我们最近有一个令人兴奋的发现，高度流行的GSTM1总基因 缺失多态(GSTM1空等位基因：0)与非洲人CKD进展更快相关 美国肾脏疾病研究(AASK)试验参与者，即有一个零(0/1)或两个零的患者 (0/0)GSTM1等位基因的综合预后下降的风险分别增加1.7倍或2倍 估计肾小球滤过率(EGFR)，或透析或死亡，与有两个全基因的人比较 测序活性等位基因GSTM1(1/1)。此外，GSTM1(0)等位基因之间存在遗传互作 非洲血统特有的载脂蛋白L1基因(APOL1)G1和G2风险编码变体介导 AASK的总体风险和活跃的GSTM1(1/1)基因型抵消了APOL1高危人群中CKD的风险 等位基因。这种关联最近在社区动脉粥样硬化风险(ARIC)研究中得到了重复 在非裔美国人(AA)和欧洲裔美国人(EA)中。使用诱发性高血压(血管紧张素II)或 在GSTM1基因敲除小鼠的CKD(残肾)模型中，我们发现GSTM1缺乏导致 肾脏氧化应激、内质网应激、炎症、纤维化通路激活、细胞凋亡与肾脏 受伤。此外，缺乏GSTM1并在足细胞中表达人APOL1 G2转基因的小鼠有 CKD模型中最严重的高血压，提示更严重的肾脏疾病。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GSTM1)来表达 APOL1高危基因的易感性表现为细胞损伤导致的穿透性肾功能丧失。 我们假设GSTM1通过其在调节氧化应激和炎症中的作用相互作用 载脂蛋白1影响高血压和肾脏损伤的易感性。通过集成鼠标模型 慢性肾功能不全的人类队列遗传学分析为机械性假说提供依据 队列(CRIC)；收缩压干预试验(SPRINT)队列；以及NHLBI Transans中的3个队列。 精准医学组学(TOPMed)计划：动脉粥样硬化的多种族研究(MESA)，杰克逊 心脏研究(JHS)，女性健康倡议(WHI)-我们将：目标1：检验组合 GSTM1缺陷和APOL1 G2突变体的转基因表达增加高血压和高血压患者的肾脏损害 CKD；并确定造血GSTM1缺失与实质GSTM1缺失在肾脏损伤中的作用。 目的2：验证GSTM1(0)等位基因与高危APOL1基因相互作用以调节风险的假设 CRIC，Sprint，9717 AA患者的蛋白尿和/或肾功能丧失对血压的影响 JHS、梅萨、WHI；以及2682年西班牙裔美国人(HA)在CRIC、斯普林特、梅萨、WHI。目标3：测试是否 GSTM1(0)和APOL1高危等位基因通过氧化应激或细胞凋亡单独或联合作用于 在CRIC AA队列中，通过测试它们与诊断生物标记物水平的相关性来损害肾功能。

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.