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：影响超过2600万美国人的慢性肾脏病（CKD）经常导致肾衰竭。每年有100,000多名患者患末期肾脏疾病（ESKD），近500,000人接受肾脏移植或正在进行的透析患者，年费用为300亿美元。以前，我们使用混合图映射将与局灶性节段性肾小球硬化（FSGS）和HIV相关肾病（Hivan）相关的22染色体上的区域定位。随后，我们和其他人表明，该区域内的APOL1编码变体包括2种绝对链接不平衡（G1等位基因）中的2个错义变体和一个In frame 6碱基对缺失（G2等位基因），负责该关联，与7、19和27的关联，用于高血压ESKD ESKD，局灶性分段性乳腺胶合症（FS），FS-GS-fs-romecrop and and Heiv（FS），以及HIV（FS），及其HIV（fs），及其HIV（FS）和HIV。 （Hivan）分别。 APOL1通过Brucei Brucei提供了防止感染的保护。 APOL1风险等位基因最近出现在撒哈拉以南非洲，但由于非洲侨民而在世界其他地区发现。在非裔美国人中，G1和G2等位基因的总频率约为35％。这些等位基因几乎解释了非洲裔美国人中肾脏疾病的所有过量风险，从而为全球重大健康差异提供了遗传基础。我们继续对APOL1进行研究，以确定风险变异是否与表现出种族差异的其他非肾脏或肾脏表型有关，例如乳头状肾脏癌和心血管疾病，在壁内和壁外研究人员的协作研究中。现在，我们扩展了研究，以研究镰状细胞性状对心血管疾病和肾脏疾病的独立和互动效果。成就1）非裔美国人（AA）中镰状细胞性状（SCT）和终阶段肾脏疾病（ESKD）的风险。与白人相比，非洲裔美国人的ESKD风险增加了近4倍，其中大部分归因于Apol1肾脏风险变体。我们试图确定SCT和血红蛋白C特征在ESKD中是否具有独立的作用。我们评估了近10,000名非洲裔美国人的中风的地理和种族差异的原因（有关），并确定SCT携带的事件率比非携带者高2倍（8.5对4.0/1000人年），危险比（HR）的ESKD为2.2，与2.2的危险率（HR）相似，这类似于风险风险的风险变化。这些结果对患有慢性肾脏疾病的SCT携带者的遗传咨询具有重要的公共卫生政策影响。 2）使用我们的实验室提供的遗传数据，学术研究人员发现，Supar的三方复合物（可溶性尿激酶纤溶酶原激活剂受体），APOL1风险变体和整合素造成肾功能下降。从机械上讲，APOL1变体等位基因对SUPAR具有更高的亲和力，从而增强了整联蛋白的活化，从而导致小鼠蛋白尿。在人类中，APOL1患者的肾功能下降，高风险基因型与SUPAR水平呈正相关。 3）APOL1风险变异在心血管疾病中的作用与某些研究表明保护性关联，而其他研究则报告了易感性或没有关联。我们发现，APOL1高风险基因型与患有CADCIA研究的肾脏功能的年轻人的高血压无关，并且与患有慢性肾脏疾病（CKD）患者的心血管疾病（CVD）无关。另一方面，我们发现中风的风险增加了2倍，并且在没有公认的糖尿病或慢性肾脏疾病的CVD危险因素的患者中增加了心肌梗塞风险的趋势。在蛋白尿，慢性肾脏疾病或糖尿病的参与者中，我们发现APOL1和CVD事件之间没有关联。先前报道APOL1和CVD之间呈正相关的研究在一般人群中进行了阳性，而报告的研究（保护性）或与CKD或糖尿病的队列进行了不存在的研究，该研究掩盖了APOL1与CVD的独立关联。 4）转基因小鼠中野生型和变异apol1的本构表达会导致幼犬的幼体和先兆子痫的丧失以及母亲的死亡。与欧洲人相比，非洲裔美国人和非洲人的子痫发病率更高。在两个队列中，我们发现胎儿（而不是母亲）将APOL1高风险基因型运输到胎儿的风险增加了两倍。现在，我们正在研究APOL1相关的先兆子痫和RNA转录谱的遗传修饰符，来自有或没有先兆子痫的母亲的APOL1高和低风险胎盘，以更好地了解致病机制和扰动途径。 5）在与约翰·霍普金斯大学（John Hopkins University）的研究人员的合作中，我们进行了一项基因组广泛的关联研究，以确定与肾小球滤过率下降有关的遗传因素。我们在肾脏和非裔美国人的CKD进展中鉴定了Linc00923 RNA基因中的SNP和复制的SNP。 5）血友病A是一种先天性出血疾病，其特征是反复出血成主要关节。我们进行了一项基因组广泛的关联研究，以鉴定与纵向队列研究的血液菌儿童的主要关节中与运动范围（ROM）异常相关的遗传因素。我们发现许多遗传变异与ROM异常增加或减少有关，但没有达到全基因组显着性阈值。然而，这项研究支持遗传变异有助于血友人关节炎的风险，并为未来的研究铺平了途径，以提高精度治疗以改善血友病人群的预后。 6）我们还为几项重要的遗传研究提供了DNA样本，基因分型数据和专业知识。 20年前，在墨西哥瓦哈卡岛的偏远村庄收集的中美洲样本已用于一系列研究，以了解西班牙裔哮喘的遗传结构。在Simons基因组多样性项目中使用了相同的样品，该项目对300名代表142个种群的个体进行了测序。这项研究揭示了人类多样性的景观的关键特征，与非洲人相比，非非洲人的分歧以来，突变的积累速率，以及与其他非非洲非洲非洲非洲非洲人的澳大利亚土著人，新几内亚人和安达曼人的祖先相同，表明这些群体不是从非洲的早期分配中。这些见解不仅对于理解现代人类的历史，而且对于理解塑造人类基因组并有助于遗传多样性和人群特异性疾病易感性的环境因素的作用而言至关重要。