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

GSTM1、APOL1 及其对高血压和慢性肾脏病严重程度的共同影响

• 批准号: 10176256
• 负责人: Thu H. Le
• 金额: $ 23.59万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-27 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176256
• 关键词: Affect; African; African American; Albuminuria; Alleles; American; Angiotensin II; Antihypertensive Agents; Apolipoproteins; Apoptosis; Atherosclerosis Risk in Communities; Biological Process; Blood Pressure; Bone Marrow; CASP3 gene; Cells; Cessation of life; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Code; Data; Development; Dialysis procedure; Disease Progression; Disease model; Dose; Drug Metabolic Detoxication; End stage renal failure; Enzymes; European; F2-Isoprostanes; Fibrosis; Flow Cytometry; Functional disorder; GSTM1 gene; Gene Deletion; Genes; Genetic; Genetic Polymorphism; Genotype; Glomerular Filtration Rate; Goals; Grant; Hematopoietic; Hispanic Americans; Human; Hypertension; Impaired Renal Function; Infiltration; Inflammation; Inflammatory; Injury; Injury to Kidney; Intervention Trial; Jackson Heart Study; Joints; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Link; Malondialdehyde; Mediating; Mediation; Modeling; Multi-Ethnic Study of Atherosclerosis; Mus; National Heart, Lung, and Blood Institute; Nephrosclerosis; Outcome; Oxidative Stress; Participant; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Plasma; Population; Predisposition; Process; Proteinuria; Public Health; Renal function; Risk; Role; Serum Markers; Severities; Testing; Time; Trans-Omics for Precision Medicine; Transgenes; Transgenic Organisms; Translating; Transplantation; Urine; Variant; Women' s Health; arm; blood pressure intervention; cell injury; chemokine; cohort; cytokine; diagnostic biomarker; drug metabolism; endoplasmic reticulum stress; genetic analysis; genetic association; genetic variant; high risk; mouse model; novel therapeutics; podocyte; programs; public health relevance; response; risk variant

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.

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 美国的健康负担 我们最近有了一个令人兴奋的发现，即高度流行的 GSTM1 总基因 缺失多态性（GSTM1 无效等位基因：0）与非洲人更快速的 CKD 进展相关 美国肾脏病研究 (AASK) 试验参与者，其中一项无效 (0/1) 或两项无效的患者 (0/0) GSTM1 等位基因的综合结果下降的风险分别增加 1.7 或 2 倍 与具有两个全基因的患者相比，估计肾小球滤过率（eGFR）、或透析或死亡 序列活性等位基因 GSTM1(1/1) 此外，GSTM1(0) 等位基因之间存在遗传相互作用。 以及非洲血统特异性载脂蛋白 L1 基因 (APOL1) G1 和 G2 风险编码变异来调节 AASK 的总体风险，并且活跃的 GSTM1(1/1) 基因型抵消了 APOL1 高风险人群的 CKD 风险 最近在社区动脉粥样硬化风险 (ARIC) 研究中复制了这种关联。 非裔美国人 (AA) 和欧洲美国人 (EA) 使用诱发高血压（血管紧张素-II）或 在 Gstm1 敲除小鼠的 CKD（残肾）模型中，我们发现 Gstm1 缺乏会导致 肾脏氧化应激、内质网应激、炎症、纤维化途径激活、细胞凋亡和肾脏的水平 此外，缺乏 Gstm1 并在足细胞中表达人 APOL1 G2 转基因的小鼠也出现了损伤。 CKD 模型中高血压最严重，表明肾脏疾病更严重，这一证据与 流行的“双重打击”假设，即需要第二个环境或遗传（例如 GSTM1）因子来表达 APOL1 高风险基因型易感性为细胞损伤导致的肾功能渗透性丧失。 我们发现 GSTM1 通过其调节氧化应激和炎症的作用，与 通过整合小鼠模型，APOL1 可以影响高血压和肾损伤的易感性。 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 Trans- 中的 3 个队列 精准医学组学 (TOPMed) 计划：动脉粥样硬化多种族研究 (MESA)，杰克逊 心脏研究 (JHS)、妇女健康倡议 (WHI) – 我们将： 目标 1：检验结合了这一假设的假设 GSTM1 缺陷和 APOL1 G2 变体的转基因表达会加重高血压和糖尿病患者的肾损伤 CKD；并确定造血与实质 GSTM1 缺失在肾损伤中的作用。 目标 2：检验 GSTM1(0) 等位基因与高风险 APOL1 基因型相互作用以调节风险的假设 CRIC、SPRINT 中的 9717 AA 中的血压影响导致蛋白尿和/或肾功能丧失 JHS、MESA、WHI；以及 CRIC、SPRINT、MESA、WHI 中的 2682 西班牙裔美国人 (HA) 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， 通过测试肾功能与诊断生物标志物水平的关联，损害 CRIC AA 队列中的肾功能。

项目成果

Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow-Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice.

• DOI: 10.4049/jimmunol.1601565
• 发表时间: 2017-04-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Sung SJ;Ge Y;Dai C;Wang H;Fu SM;Sharma R;Hahn YS;Yu J;Le TH;Okusa MD;Bolton WK;Lawler JR
• 通讯作者: Lawler JR

Testing the trajectory difference in a semi-parametric longitudinal model.

• DOI: 10.1177/0962280215584109
• 发表时间: 2017-06
• 期刊: Statistical methods in medical research
• 影响因子: 2.3
• 作者: Niu F;Zhou J;Le TH;Ma JZ
• 通讯作者: Ma JZ

Eat Your Broccoli: Oxidative Stress, NRF2, and Sulforaphane in Chronic Kidney Disease.

• DOI: 10.3390/nu13010266
• 发表时间: 2021-01-18
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Liebman SE;Le TH
• 通讯作者: Le TH

GSTM1 Gene, Diet, and Kidney Disease: Implication for Precision Medicine?: Recent Advances in Hypertension.

• DOI: 10.1161/hypertensionaha.121.16510
• 发表时间: 2021-09
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Le TH