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.

慢性肾脏疾病（CKD），影响超过2600万美国人，经常导致肾衰竭。每年有超过10万人患上终末期肾病（ESKD），近50万人接受肾脏移植或正在进行透析，每年花费300亿美元。在此之前，我们使用混合映射来定位22号染色体上与局灶节段性肾小球硬化（FSGS）和hiv相关肾病（HIVAN）相关的区域。随后，我们和其他人发现，该区域的APOL1编码变异体包括2个绝对连锁不平衡错义变异体（G1等位基因）和1个第6帧碱基对缺失（G2等位基因），与高血压ESKD、局灶节段性肾小球硬化（FSGS）和hiv相关肾病（HIVAN）的OR分别为7、19和27。ApoL1可保护人体免受布氏锥虫感染。APOL1风险等位基因最近在撒哈拉以南非洲出现，但由于非洲侨民，在世界其他地区也发现了apo1风险等位基因。非洲裔美国人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裔美国人患肾病的所有额外风险，从而为全球主要的健康差异提供了遗传基础。在与校内外研究者的合作研究中，我们继续对APOL1进行研究，以确定风险变异是否与其他显示种族差异的非肾脏或肾脏表型相关，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，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。1)非裔美国人（AA）镰状细胞特征（SCT）和终末期肾脏疾病（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，其中大部分可归因于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中具有独立的作用。我们评估了近10,000名参加中风地理和种族差异（REGARDS）研究的非裔美国人，并确定SCT携带者的发生率比非携带者高2倍（8.5 vs 4 /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。这些结果对慢性肾脏疾病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suar（可溶性尿激酶纤溶酶原激活物受体）、APOL1风险变异和整合素的三元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，这增加了整合素的激活，导致小鼠蛋白尿。人类APOL1高危基因型患者肾功能下降与suPAR水平呈正相关。3) APOL1风险变异在心血管疾病中的作用是相互矛盾的，一些研究显示有保护作用，而另一些研究报告有易感或无关联。我们发现APOL1高危基因型与CARDIA研究中肾功能保持的年轻成人的高血压无关，与慢性肾脏疾病（CKD）患者的心血管疾病（CVD）无关。另一方面，我们发现，在没有糖尿病或慢性肾脏疾病等心血管疾病危险因素的患者中，中风风险增加2倍，心肌梗死风险增加的趋势。在蛋白尿、慢性肾脏疾病或糖尿病患者中，我们没有发现APOL1与CVD事件之间的关联。先前报告APOL1与CVD呈正相关的研究是在普通人群中进行的，而报告阴性（保护性）或无关联的研究是在CKD或糖尿病人群中进行的，这掩盖了APOL1与CVD的独立关联。4)野生型和变异型APOL1在转基因小鼠中的组成性表达会导致幼崽的丧失和子痫前期以及母鼠的死亡。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，我们发现携带APOL1高危基因型的胎儿，而不是母亲，使子痫前期的风险增加了两倍。我们现在正在研究APOL1相关的先兆子痫的遗传修饰因子，以及来自有和没有子痫前期的母亲的APOL1高风险和低风险胎盘的RNA转录谱，以更好地了解致病机制和干扰途径。5)在与约翰霍普金斯大学的研究人员合作中，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。我们发现并复制了欧洲人和非裔美国人CKD进展时肾脏中表达的LINC00923 RNA基因的snp。5)血友病A是一种先天性出血性疾病，其特征是反复出血进入主要关节。我们进行了一项全基因组关联研究，以确定与血友病儿童主要关节活动范围（ROM）异常相关的遗传因素。我们发现了一些与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著性阈值。然而，这项研究支持了遗传变异增加血友病关节病风险的可能性，并为未来的研究铺平了道路，以推进精确治疗，改善血友病人群的预后。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多年前在墨西哥瓦哈卡偏远村庄收集的中美洲样本已被用于一系列研究，以了解西班牙裔人哮喘的遗传结构。同样的样本被用于西蒙斯基因组多样性项目，该项目对代表142个不同种群的300个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，非非洲人与非洲人分化以来的突变积累率，以及土著澳大利亚人、新几内亚人和安达曼人与其他非非洲人的祖先是共同的，表明这些群体不是来自非洲以外的早期分散。这些见解不仅对理解现代人类的历史很重要，而且对理解环境因素在塑造人类基因组、促进遗传多样性和特定人群对疾病的易感性方面的作用也很重要。