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

基本信息

  • 批准号:
    10176256
  • 负责人:
  • 金额:
    $ 23.59万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
慢性肾脏疾病(CKD)及其最终阶段肾病(ESRD)的后果是重要的公众 美国的健康伯恩(Health Burnen)在美国最近提出了令人兴奋的发现,即高度普遍的GSTM1总基因 删除多态性(GSTM1 NULL等位基因:0)与非洲的CKD进展更快有关 美国对肾脏疾病(AASK)试验参与者的研究,使一名无效(0/1)或两名无效的患者 (0/0)GSTM1等位基因分别具有1.7或2倍的综合结果风险增加 与具有两个全基因的肾小球滤过率(EGFR)或透析或死亡相比 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 以及非洲祖先特异性的载脂蛋白L1基因(APOL1)G1和G2风险编码变体,以介导 AASK的总体风险,而Active GSTM1(1/1)基因型抵消了APOL1高风险患者的CKD风险 等位基因。最近在社区(ARIC)研究的动脉粥样硬化风险中复制了这种关联 在非裔美国人(AA)和欧洲美国人(EA)中。使用诱导的高血压(血管紧张素II)或 GSTM1敲除小鼠中的CKD(残留肾脏)模型,我们表明GSTM1缺乏会导致增加 肾脏氧化应激水平,ER应激,感染,纤维化途径的激活,凋亡和肾脏 受伤。此外,缺乏GSTM1并表达人apol1 g2转基因的小鼠在足细胞中 CKD模型中最严重的高血压,表明肾脏疾病较差。这些证据与 需要表达第二个环境或遗传因素(例如GSTM1)的盛行的“两击”假设以表达 APOL1高风险基因型易感性是细胞损伤导致的肾功能渗透损失。 我们假设GSTM1通过其在控制氧化应激和炎症中的作用,相互作用 用APOL1影响高血压和肾脏损伤的敏感性。通过集成鼠标模型 通过人类队列遗传分析的慢性肾功能不全的遗传分析,为机械假设提供了信息 队列(CRIC);收缩压干预试验(SPRINT)队列; NHLBI Trans-中的3个队列 精密医学的OMICS计划:动脉粥样硬化的多种族研究(MESA),杰克逊 心脏学习(JHS),妇女健康计划(WHI) - 我们将:目标1:测试合并的假设 APOL1 G2变体的GSTM1缺乏和转基因表达增强了高血压和 CKD;并确定造血与实质GSTM1缺失在肾脏损伤中的贡献。 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 蛋白尿和/或通过对9717 AA的血压的影响,crin,Sprint,Sprint, JHS,梅萨,whi;在2682年,西班牙裔美国人(HA)在克里克,斯普林特,梅萨,whi。目标3:测试是否 GSTM1(0)和APOL1高风险等位基因通过氧化应激或凋亡分别起作用 通过测试其与诊断生物标志物水平的关联,损害了CRIC AA队列中的肾功能。

项目成果

期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
  • 影响因子:
    0
  • 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.
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:
  • 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.
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Thu H. Le其他文献

TMEM27 expression and clinical characteristics and survival in clear cell renal cell carcinoma
透明细胞肾细胞癌中 TMEM27 的表达、临床特征和生存
  • DOI:
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Rickinder Grewal;H. Choung;Lisa L Roberts;Timothy J. Beane;Luojing Chen;Daniel X. Gilroy;P. Rappold;Thu H. Le
  • 通讯作者:
    Thu H. Le
腸間膜血管内圧上昇に呼応した血管緊張におけるGDP/GTP交換因子p63RhoGEFの活性化
血管张力中 GDP/GTP 交换因子 p63RhoGEF 的激活响应肠系膜血管内压力增加
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Mykhaylo V. Artamonov;Swapnil K. Sonkusare;Miranda E. Good;Ko Momotani;Masumi Eto;Brant E. Isakson;Thu H. Le;Eric L. Cope;Zygmunt S. Derewenda;Urszula Derewenda;Avril V. Somlyo;坂井久美子 百渓江
  • 通讯作者:
    坂井久美子 百渓江
Ca2+感受性の亢進を通した平滑筋収縮制御におけるp63RhoGEFの機能解析
p63RhoGEF 通过增强 Ca2+ 敏感性控制平滑肌收缩的功能分析
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Mykhaylo V. Artamonov;Swapnil K. Sonkusare;Miranda E. Good;Ko Momotani;Masumi Eto;Brant E. Isakson;Thu H. Le;Eric L. Cope;Zygmunt S. Derewenda;Urszula Derewenda;Avril V. Somlyo;坂井久美子 百渓江;百渓江 坂井久美子
  • 通讯作者:
    百渓江 坂井久美子

Thu H. Le的其他文献

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{{ truncateString('Thu H. Le', 18)}}的其他基金

Safety, Feasibility and Efficacy of Sulforaphane in Chronic Kidney Disease
萝卜硫素治疗慢性肾脏病的安全性、可行性和有效性
  • 批准号:
    10196037
  • 财政年份:
    2021
  • 资助金额:
    $ 23.59万
  • 项目类别:
Safety, Feasibility and Efficacy of Sulforaphane in Chronic Kidney Disease
萝卜硫素治疗慢性肾脏病的安全性、可行性和有效性
  • 批准号:
    10478881
  • 财政年份:
    2021
  • 资助金额:
    $ 23.59万
  • 项目类别:
Safety, Feasibility and Efficacy of Sulforaphane in Chronic Kidney Disease
萝卜硫素治疗慢性肾脏病的安全性、可行性和有效性
  • 批准号:
    10676994
  • 财政年份:
    2021
  • 资助金额:
    $ 23.59万
  • 项目类别:
Institutional Career Development Core
机构职业发展核心
  • 批准号:
    10655332
  • 财政年份:
    2016
  • 资助金额:
    $ 23.59万
  • 项目类别:
Contribution of Gstm1 to the severity of hypertension and chronic kidney disease
Gstm1 对高血压和慢性肾脏病严重程度的影响
  • 批准号:
    8629733
  • 财政年份:
    2012
  • 资助金额:
    $ 23.59万
  • 项目类别:
Contribution of Gstm1 to the severity of hypertension and chronic kidney disease
Gstm1 对高血压和慢性肾脏病严重程度的影响
  • 批准号:
    8463524
  • 财政年份:
    2012
  • 资助金额:
    $ 23.59万
  • 项目类别:
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:
    9763858
  • 财政年份:
    2012
  • 资助金额:
    $ 23.59万
  • 项目类别:
Contribution of Gstm1 to the severity of hypertension and chronic kidney disease
Gstm1 对高血压和慢性肾脏病严重程度的影响
  • 批准号:
    8820806
  • 财政年份:
    2012
  • 资助金额:
    $ 23.59万
  • 项目类别:
Contribution of Gstm1 to the severity of hypertension and chronic kidney disease
Gstm1 对高血压和慢性肾脏病严重程度的影响
  • 批准号:
    8271475
  • 财政年份:
    2012
  • 资助金额:
    $ 23.59万
  • 项目类别:
Genes That Regulate Progression of Kidney Disease and Its Cardiovascular Effects
调节肾脏疾病进展及其心血管影响的基因
  • 批准号:
    8009985
  • 财政年份:
    2010
  • 资助金额:
    $ 23.59万
  • 项目类别:

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Hospice exposure and utilization among older African Americans with ADRD and their decisional support persons
患有 ADRD 的老年非洲裔美国人及其决策支持人员的临终关怀暴露和利用
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  • 财政年份:
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  • 批准号:
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