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
• 负责人: Thu H. Le
• 金额: $ 24.94万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763858
• 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.

慢性肾脏疾病（CKD）及其终末期肾脏疾病（ESRD）的后果是一个重要的公众