Genetics of Complex Diseases and Health Disparities

复杂疾病的遗传学和健康差异

• 批准号: 9343577
• 负责人: Cheryl Winkler
• 金额: $ 69.37万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9343577
• 关键词: AIDS-Associated Nephropathy; Adult; Affect; Africa South of the Sahara; African; African American; Age; Albuminuria; Alleles; American; Attenuated; Autopsy; Base Pairing; Biopsy; Cardiovascular Diseases; Cessation of life; Child; Childhood; Chromosomes, Human, Pair 22; Chronic; Chronic Kidney Failure; Clinical; Clinical Trials; Code; Complex; Coronary Artery Risk Development in Young Adults Study; Cytolysis; Data; Diagnosis; Dialysis patients; Disease; Disease Progression; Drug Targeting; Early Diagnosis; End stage renal failure; Enrollment; Environmental Risk Factor; Extramural Activities; Focal Segmental Glomerulosclerosis; Frequencies; GSTM1 gene; Genes; Genetic; Genetic Predisposition to Disease; Genetic Screening; Genotype; Glomerular Filtration Rate; Hypertension; Impairment; Incidence; Individual; Infection; International; Journals; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knowledge; Life; Linkage Disequilibrium; Manuscripts; Measures; Mississippi; Mutation; NPHS2 protein; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrology; Nephrons; Nephrotic Syndrome; Odds Ratio; Other Genetics; Oxidative Stress; Papillary; Participant; Patients; Persons; Phenotype; Population; Predisposition; Publishing; Regression Analysis; Renal carcinoma; Renal function; Research Personnel; Risk; Risk Factors; Role; Societies; Socioeconomic Status; South Africa; Steroid Resistance; Steroid therapy; Steroid-resistant idiopathic nephrotic syndrome; Sudden Death; Testing; Trypanosoma; Trypanosoma brucei brucei; Universities; Variant; Virginia; admixture mapping; age related; base; case control; cohort; cost; experience; follow-up; gene product; genetic association; genetic variant; global health; health disparity; high risk; modifiable risk; personalized medicine; racial disparity; rare variant; risk variant; young adult

Project Summary: Chronic kidney disease (CKD), affecting over 26 million Americans, frequently leads to kidney failure. More than 100,000 individuals develop end stage kidney disease (ESKD) annually and nearly 500,000 receive kidney transplants or are ongoing dialysis patients at an annual cost of $30 billion dollars. Previously, we used admixture mapping to localize a region on chromosome 22 associated with focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy (HIVAN). Subsequently, we and others showed that APOL1 coding variants within this region comprising 2 missense variants in absolute linkage disequilibrium (G1 allele) and an in frame 6 base pair deletion (G2 allele) were responsible for the association, with OR of 7, 19, and 27 for hypertensive ESKD, focal segmental glomerulosclerosis (FSGS), and HIV-associated nephropathy (HIVAN), respectively. ApoL1 provides protection against infection with Trypanosoma brucei brucei. The APOL1 risk alleles emerged recently in sub-Saharan Africa, but are found in other regions of the world as a result of the African Diaspora. The combined frequencies of G1 and G2 alleles are approximately 35% in African Americans. These alleles explain nearly all the excess risk of kidney disease in African Americans, thus providing a genetic basis for a major global health disparity. We have continued our studies of APOL1 to determine if the risk variants are associated with other non-renal or renal phenotypes that show racial disparities, such as papillary renal cancer and cardiovascular disease, in collaborative studies with intramural and extramural investigators. Accomplishments 1) About 20% of patients with primary FSGS or HIV-associated nephropathy carry 1 or 0 copies of APOL1 G1 or G2, suggesting that additional factors in APOL1 might contribute to disease. In an exhaustive study of more than 2000 people world-wide, including over a 1000 case and controls for FSGS and HIV-associated nephropathy (HIVAN), we showed that no other common variants lysed trypanosomes and no additional common or rare variants were associated with FSGS or HIVAN using association and burden tests. The immediate relevance of this study is that there is no clinical utility in sequencing APOL1 in patients with FSGS or HIVAN who do not carrying G1 or G2 renal risk variants. This data was published in Kidney International. 3) In a international study with researchers in South Africa we have shown that APOL1 variants are strongly associated with HIVAN, a rapidly progressive kidney disease (OR 89).This manuscript was published in the Journal of the American Society of Nephrology. 2) We are now investigating the role of genetic role of childhood-onset nephrotic syndrome in Indian and Black children in in South Africa. We find that APOL1 does not contribute to childhood nephrotic syndrome; however, we did find that sporadic steroid resistant nephrotic syndrome (SRNS) in Durban, South Africa, nearly a third are homozygous for a single mutation in the podocin gene (NPHS2). This study indicates that for the 30% of children with nephrotic syndrome carrying two copies of the NPHS2 variant, a precision diagnosis of steroid resistant focal segmental glomerulosclerosis can be made, abrogating the need for a renal biopsy or ineffective and potentially harmful steroid therapy. This study as been submitted for review. 3) We investigated the role of APOL1 on kidney function and albuminuria, a predictor of chronic kidney disease and cardiovascular disease in the Coronary Artery Risk Development in Young Adults study. We examined associations of APOL1 with incident albuminuria and kidney function decline among 3030 young adults with preserved glomerular filtration rate. The incidence rate per 1000 person-years for albuminuria, a predictor of chronic kidney disease and cardiovascular disease over 15 years follow-up was 15.6 for APOL1 high-risk genotypes, 7.8 for low-risk blacks, and 3.9 for whites. Compared withwhites, the odds ratio for incident albuminuria was 5.71 ) for high-risk blacks and 2.32 for low-risk blacks. Adjustment for risk factors attenuated the difference between low-risk blacks and whites. APOL1 low-risk blacks also had a faster yearly decline in kidney function compared with whites, but this difference was attenuated after adjustment for risk factors and socioeconomic position. We found that blacks with two APOL1 risk alleles had the highest risk for albuminuria and kidney decline in young adulthood, whereas disparities between low-risk blacks and whites were related to differences in traditional risk factors. This study was published in Journal of the American Society of Nephrology. 4) 6) We assessed correlations between APOL1 profiles and renal histological features in a of individuals who experienced sudden death. Glomerular number and mean glomerular volume were measured by our collaborators in kidneys of blacks and whites without renal disease, undergoing autopsies in Jackson, Mississippi. We found that carriage of APOL1 variants was associated with significant reductions in glomerular number and increases in glomerular volume with increasing age. Regression analysis predicted an annual average loss of 8834 glomeruli per single kidney over the first 38 years of adult life in African Americans with two risk alleles. These findings indicate that APOL1 risk alleles are associated with exaggerated age-related nephron loss, probably decaying from a larger pool of smaller glomeruli in early adult life, along with enlargement of the remaining glomeruli. The observations suggest a mechanism of accentuated susceptibility to kidney disease in APOL1-positive blacks. This study was published in the Journal of the American Society of Nephrologists. 5) Only 15% of carriers of two APOL1 high risk genotypes develop chronic kidney disease or progress to kidney failure, suggesting that other genetic or environmental factor is required for disease initiation and progression. In a collaborative study with investigators at NIDDK and the University of Virginia, we found that the GSTM1 null allele, which previously has been shown to associate with CKD progression to kidney failure or death, potentiates progression to ESRD in APOL1 high-risk participants. The GSTM1 gene product modulates oxidative stress. Having 0 or only 1 copy of the GSTM1 gene amplified the effect of the high-risk APOL1 genotypes in black patients with chronic kidney disease attributed to hypertension enrolled in the AASK clinical trial. We were unable to determine if carriage of 2 GSTM1 alleles would be protective because of limited numbers of individuals. Larger cohorts are needed to further explore the interactions between GSTM1 null and APOL1 high-risk genotypes (published in Journal of the American Society of Nephrology).

项目摘要：慢性肾病 (CKD) 影响着超过 2600 万美国人，经常导致肾衰竭。每年有超过 100,000 人患上终末期肾病 (ESKD)，近 500,000 人接受肾移植或正在进行透析，每年费用达 300 亿美元。此前，我们使用混合作图来定位 22 号染色体上与局灶节段性肾小球硬化症 (FSGS) 和 HIV 相关肾病 (HIVAN) 相关的区域。随后，我们和其他人表明，该区域内的 APOL1 编码变体（包括绝对连锁不平衡中的 2 个错义变体（G1 等位基因）和框内 6 碱基对缺失（G2 等位基因））是造成这种关联的原因，OR 为 7, 19,高血压 ESKD、局灶节段性肾小球硬化症 (FSGS) 和 HIV 相关肾病 (HIVAN) 分别为 27 和 27。 ApoL1 可提供针对布氏锥虫感染的保护作用。 APOL1 风险等位基因最近在撒哈拉以南非洲地区出现，但由于非洲人散居海外，在世界其他地区也发现了这种基因。非裔美国人中 G1 和 G2 等位基因的组合频率约为 35%。这些等位基因几乎解释了非裔美国人患肾病的所有过高风险，从而为全球主要的健康差异提供了遗传基础。在与校内和校外研究人员的合作研究中，我们继续对 APOL1 进行研究，以确定风险变异是否与显示种族差异的其他非肾或肾表型相关，例如乳头状肾癌和心血管疾病。成就 1) 约 20% 的原发性 FSGS 或 HIV 相关肾病患者携带 1 或 0 个 APOL1 G1 或 G2 拷贝，表明 APOL1 中的其他因素可能导致疾病。在一项对全世界 2000 多人进行的详尽研究中，包括 1000 多名 FSGS 和 HIV 相关肾病 (HIVAN) 的病例和对照，我们发现没有其他常见变异会裂解锥虫，也没有其他常见或罕见变异与锥虫相关。使用关联和负担测试的 FSGS 或 HIVAN。这项研究的直接意义在于，对不携带 G1 或 G2 肾脏风险变异的 FSGS 或 HIVAN 患者进行 APOL1 测序没有临床实用性。该数据发表在《国际肾脏病杂志》上。 3) 在与南非研究人员进行的一项国际研究中，我们发现 APOL1 变异与 HIVAN（一种快速进展的肾脏疾病 (OR 89)）密切相关。这篇手稿发表在《美国肾病学会杂志》上。 2) 我们现在正在研究南非印第安人和黑人儿童儿童期发病肾病综合征的遗传作用。我们发现 APOL1 不会导致儿童肾病综合征；然而，我们确实发现，在南非德班的散发性类固醇抵抗性肾病综合征（SRNS）中，近三分之一的人具有 podocin 基因（NPHS2）单一突变的纯合子。这项研究表明，对于 30% 携带两个 NPHS2 变异拷贝的肾病综合征儿童，可以对类固醇抵抗性局灶节段性肾小球硬化症进行精确诊断，从而无需进行肾活检或无效且可能有害的类固醇治疗。本研究已提交审查。 3) 我们在年轻人冠状动脉风险发展研究中研究了 APOL1 对肾功能和蛋白尿的作用，蛋白尿是慢性肾脏疾病和心血管疾病的预测因子。我们在 3030 名肾小球滤过率保持不变的年轻人中检查了 APOL1 与蛋白尿和肾功能下降的关联。蛋白尿（15 年随访期间慢性肾病和心血管疾病的预测因子）的每 1000 人年发病率，APOL1 高风险基因型为 15.6，低风险黑人为 7.8，白人为 3.9。与白人相比，高风险黑人发生蛋白尿的比值比为 5.71，低风险黑人的比值比为 2.32。对风险因素的调整削弱了低风险黑人和白人之间的差异。与白人相比，APOL1 低风险黑人的肾功能每年下降速度更快，但在调整风险因素和社会经济地位后，这种差异有所减弱。我们发现，具有两个 APOL1 风险等位基因的黑人在成年早期出现蛋白尿和肾功能衰退的风险最高，而低风险黑人和白人之间的差异与传统风险因素的差异有关。这项研究发表在《美国肾脏病学会杂志》上。 4) 6) 我们评估了经历猝死的个体的 APOL1 谱与肾脏组织学特征之间的相关性。我们的合作者在密西西比州杰克逊进行尸检，测量了没有肾病的黑人和白人的肾脏的肾小球数量和平均肾小球体积。我们发现，随着年龄的增长，APOL1 变异体的携带与肾小球数量的显着减少和肾小球体积的增加有关。回归分析预测，携带两个风险等位基因的非裔美国人在成年后的前 38 年中，每个肾脏每年平均损失 8834 个肾小球。这些发现表明，APOL1 风险等位基因与与年龄相关的肾单位过度丧失有关，可能是在成年早期因大量较小的肾小球而腐烂，同时剩余肾小球增大。这些观察结果表明，APOL1 阳性黑人更容易患肾脏疾病。这项研究发表在《美国肾脏病学家协会杂志》上。 5) 只有 15% 的两种 APOL1 高危基因型携带者会患上慢性肾病或进展为肾衰竭，这表明疾病的发生和进展需要其他遗传或环境因素。在与 NIDDK 和弗吉尼亚大学的研究人员进行的一项合作研究中，我们发现 GSTM1 无效等位基因（之前已被证明与 CKD 进展为肾衰竭或死亡相关）可增强 APOL1 高危参与者进展为 ESRD。 GSTM1 基因产物调节氧化应激。在参加 AASK 临床试验的患有高血压慢性肾病的黑人患者中，0 或仅 1 个 GSTM1 基因拷贝放大了高风险 APOL1 基因型的影响。由于个体数量有限，我们无法确定携带 2 个 GSTM1 等位基因是否具有保护作用。需要更大的队列来进一步探索 GSTM1 无效基因型和 APOL1 高风险基因型之间的相互作用（发表在美国肾脏病学会杂志）。