Genetics of Complex Diseases and Health Disparities

复杂疾病的遗传学和健康差异

• 批准号: 9556246
• 负责人: Cheryl Winkler
• 金额: $ 65.37万
• 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/9556246
• 关键词: AIDS-Associated Nephropathy; APOL1 gene; Affect; Affinity; Africa; Africa South of the Sahara; African; African American; African Trypanosomiasis; Albuminuria; Alleles; American; Architecture; Articular Range of Motion; Asthma; Base Pairing; Blood Coagulation Disorders; Cardiovascular Diseases; Cells; Cessation of life; Child; Chromosomes, Human, Pair 22; Chronic Kidney Failure; Code; Collaborations; Complex; Conflict (Psychology); DNA; Data; Diabetes Mellitus; Diagnosis; Dialysis patients; Disease; Disease Progression; Drug Targeting; Early Diagnosis; End stage renal failure; Enrollment; Environmental Risk Factor; European; Event; Extramural Activities; Fetal Death; Fetus; Focal Segmental Glomerulosclerosis; Frequencies; Functional disorder; Future; General Population; Genes; Genetic; Genetic Counseling; Genetic Risk; Genetic Transcription; Genetic Variation; Genetic study; Genome; Genotype; Glomerular Filtration Rate; HIV; Hemoglobin; Hemoglobin C; Hemophilia A; Hemorrhage; Hispanics; Human; Human Genome; Hypertension; Incidence; Indigenous; Individual; Infection; Integrins; International; Joints; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Laboratories; Linkage Disequilibrium; Longitudinal cohort study; Malaria; Masks; Mesoamerican; Mexico; Modern 1601-history; Mothers; Mus; Mutation; Myocardial Infarction; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrotic Syndrome; Papillary; Participant; Pathogenicity; Pathway interactions; Patients; Persons; Phenotype; Placenta; Population; Population Heterogeneity; Pre-Eclampsia; Precision therapeutics; Predisposition; Proteins; Proteinuria; Public Health; RNA; Recurrence; Renal carcinoma; Renal function; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Sampling; Series; Sickle Cell Trait; Steroids; Stroke; Transgenic Mice; Trypanosoma brucei brucei; Universities; Urine; Urokinase Plasminogen Activator Receptor; Variant; admixture mapping; arthropathies; cardiovascular disorder risk; cohort; cost; genetic variant; genome wide association study; genome-wide; geographic difference; global health; hazard; health disparity; high risk; improved; improved outcome; insight; liquid biopsy; policy implication; precision medicine; pup; racial difference; racial disparity; risk variant; sickling; trait; trend; 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. We have now extended our research to investigate the independent and interactive effects of sickle cell trait on cardiovascular and kidney diseases. Accomplishments 1) Sickle cell trait (SCT) and the risk of end stage renal disease (ESKD) in African Americans (AA). Compared to whites, African Americans have nearly 4-fold increased risk for ESKD, much of which is attributable to APOL1 renal risk variants. We sought to determine if SCT and hemoglobin C trait had an independent role in ESKD. We evaluated nearly 10,000 African Americans enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) and determined that incident rates for carries of SCT were 2-fold higher than for non-carriers (8.5 versus 4.0/1000 person years), with a hazards ratio (HR) for ESKD of 2.2, which is similar to the risk incurred by carriage of APOL1 renal risk variants. These results have important public health policy implications for genetic counseling of SCT carriers with chronic kidney disease. 2) Using genetic data provided by our laboratory, academic investigators found that a tripartite complex of suPAR (soluble urokinase plasminogen activator receptor), APOL1 risk variants, and integrin is responsible for decline in kidney function. Mechanistically, the APOL1 variant alleles have a higher affinity for suPAR, which augments integrin activation leading to proteinuria in mice. In humans decline in kidney function in patients with APOL1 high risk genotypes is positively correlated with suPAR levels. 3) The role of APOL1 risk variants in cardiovascular disease is conflicted with some studies showing a protective association and others reporting a susceptible or no association. We found that APOL1 high risk genotypes were not associated with hypertension in young adults with preserve kidney function enrolled in the CARDIA study and were not associated with cardiovascular disease (CVD) in persons with chronic kidney disease (CKD). On the other hand, we find a 2-fold increased risk of stroke and trend towards increased risk of myocardial infarction in patients without the well-established CVD risk factors of diabetes or chronic kidney disease. In participants with albuminuria, chronic kidney disease or diabetes, we found no association between APOL1 and CVD events. Previous studies reporting a positive association between APOL1 and CVD were performed in the general population whereas studies reporting a negative (protective) or no association were performed on cohorts with CKD or diabetes, which masked the independent association of APOL1 with CVD. 4) Constitutive expression of both wildtype and variant APOL1 in transgenic mice causes loss of pups and preeclampsia and death of the mothers. Incidence rates for preeclampsia are higher for African Americans and Africans compared to Europeans. In two cohorts, we found that carriage of APOL1 high risk genotypes by the fetus, but not the mother, increases the risk of preeclampsia by two-fold. We are now investigating genetic modifiers of APOL1-associated preeclampsia and RNA transcriptional profiles in APOL1 high and low risk placentas from mothers with and without preeclampsia to better understand the pathogenic mechanisms and perturbed pathways. 5) In a collaboration with researchers at John Hopkins University, we performed a genome wide association study to identify genetic factors associated with decline in glomerular filtration rate. We identified and replicated SNPs in the LINC00923 RNA gene expressed in the kidney with CKD progression in both European- and African Americans. 5) Hemophilia A is a congenital bleeding disorder that is characterized by recurrent hemorrhages into major joints. We performed a genome wide association study to identify genetic factors associated with abnormalities in range of motion (ROM) in the major joints in children with hemophillia enrolled in a longitudinal cohort study. We found a number of genetic variants that were associated with either increased or decreased ROM abnormalities but none that reached the genome-wide significance threshold. However, this study supports the likelihood that genetic variants contribute to risk for hemophilic arthropathy and paves the path for future studies to advance precision treatment to improve outcomes in the hemophilic population. 6) We have also contributed DNA samples, genotyping data, and expertise to several important genetic studies. Mesoamerican samples collected in remote villages in Oaxaca Mexico over 20 years ago have been used for a series of studies to understand the genetic architecture of asthma in Hispanics. The same samples were used in the Simons Genome Diversity project that sequenced genomes for 300 individuals representing 142 diverse populations. This study revealed key features of the landscape of human diversity, rate of the accumulation of mutations since the divergence of non-Africans compared to Africans, and that the ancestry of indigenous Australians, New Guineans, and Andamanese is shared with other non-Africans, indicating that these groups were not from an earlier dispersal out of Africa. These insights will be important not only for understanding the history of modern humans but also in understanding the role of environmental factors that shaped the human genome and contribute to genetic diversity and population-specific susceptibility to disease.

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，我们和其他人证明，该区域内的 APOL1 编码变体（包括绝对连锁不平衡（G1 等位基因）中的 2 个错义变体和一个框内 6 碱基对缺失（G2 等位基因））是造成这种关联的原因，高血压 ESKD、局灶节段性肾小球硬化症 (FSGS) 和 HIV 相关肾病的 OR 分别为 7、19 和 27 （HIVAN），分别。 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。我们现在已经扩展了我们的研究范围，以调查镰状细胞性状对心血管和肾脏疾病的独立和相互作用的影响。成就 1) 非裔美国人 (AA) 的镰状细胞性状 (SCT) 和终末期肾病 (ESKD) 的风险。与白人相比，非裔美国人患 ESKD 的风险增加了近 4 倍，其中大部分归因于 APOL1 肾脏风险变异。我们试图确定 SCT 和血红蛋白 C 特征是否在 ESKD 中具有独立作用。我们评估了参与卒中地理和种族差异原因 (REGARDS) 的近 10,000 名非裔美国人，并确定携带 SCT 的发病率是非携带者的 2 倍（8.5 比 4.0/1000 人年），ESKD 的风险比 (HR) 为 2.2，这与携带 APOL1 肾脏风险变异所产生的风险相似。这些结果对于患有慢性肾病的 SCT 携带者的遗传咨询具有重要的公共卫生政策意义。 2) 利用我们实验室提供的遗传数据，学术研究人员发现suPAR（可溶性尿激酶纤溶酶原激活剂受体）、APOL1风险变异和整合素的三方复合物是导致肾功能下降的原因。从机制上讲，APOL1 变异等位基因对 suPAR 具有更高的亲和力，从而增强整合素激活，导致小鼠出现蛋白尿。在人类中，APOL1 高危基因型患者的肾功能下降与 suPAR 水平呈正相关。 3) APOL1 风险变异在心血管疾病中的作用与一些研究显示保护性相关性和其他研究报告易感性相关或无相关性的研究相矛盾。我们发现，APOL1 高风险基因型与参加 CARDIA 研究的保留肾功能的年轻人的高血压无关，并且与慢性肾病 (CKD) 患者的心血管疾病 (CVD) 无关。另一方面，我们发现，在没有明确的糖尿病或慢性肾病等 CVD 危险因素的患者中，中风风险增加 2 倍，并且心肌梗塞风险有增加的趋势。在患有蛋白尿、慢性肾病或糖尿病的参与者中，我们发现 APOL1 与 CVD 事件之间没有关联。先前报告 APOL1 与 CVD 之间呈正相关的研究是在普通人群中进行的，而报告负相关（保护性）或无相关性的研究是在 CKD 或糖尿病队列中进行的，这掩盖了 APOL1 与 CVD 的独立相关性。 4) 转基因小鼠中野生型和变体 APOL1 的组成型表达会导致幼仔死亡和先兆子痫以及母亲死亡。与欧洲人相比，非裔美国人和非洲人的先兆子痫发病率更高。在两个队列中，我们发现胎儿（而非母亲）携带 APOL1 高风险基因型会使先兆子痫的风险增加两倍。我们现在正在研究 APOL1 相关先兆子痫的基因修饰因子以及患有和不患有先兆子痫的母亲的 APOL1 高风险和低风险胎盘中的 RNA 转录谱，以更好地了解致病机制和扰动途径。 5）与约翰·霍普金斯大学的研究人员合作，我们进行了一项全基因组关联研究，以确定与肾小球滤过率下降相关的遗传因素。我们在欧洲和非裔美国人的 CKD 进展肾脏中表达的 LINC00923 RNA 基因中鉴定并复制了 SNP。 5) A型血友病是一种先天性出血性疾病，其特征是主要关节反复出血。我们进行了一项全基因组关联研究，以确定与参与纵向队列研究的血友病儿童主要关节运动范围 (ROM) 异常相关的遗传因素。我们发现了许多与 ROM 异常增加或减少相关的遗传变异，但没有一个达到全基因组显着性阈值。然而，这项研究支持了遗传变异导致血友病关节病风险的可能性，并为未来研究推进精准治疗以改善血友病人群的预后铺平了道路。 6) 我们还为几项重要的基因研究贡献了 DNA 样本、基因分型数据和专业知识。 20多年前在墨西哥瓦哈卡州偏远村庄收集的中美洲样本已被用于一系列研究，以了解西班牙裔哮喘的遗传结构。西蒙斯基因组多样性项目使用了相同的样本，该项目对代表 142 个不同群体的 300 名个体进行了基因组测序。这项研究揭示了人类多样性景观的关键特征，自非非洲人与非洲人相比的分化以来突变积累的速度，以及澳大利亚土著人、新几内亚人和安达曼人与其他非非洲人共享的祖先，表明这些群体并非来自非洲较早的扩散。这些见解不仅对于理解现代人类的历史很重要，而且对于理解塑造人类基因组并有助于遗传多样性和特定人群对疾病的易感性的环境因素的作用也很重要。