Genetics of Complex Diseases and Health Disparities

复杂疾病的遗传学和健康差异

• 批准号: 8763052
• 负责人: Cheryl Winkler
• 金额: $ 48.11万
• 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/8763052
• 关键词: AIDS-Associated Nephropathy; Admixture; Adult; Affect; Africa South of the Sahara; African; African American; African Trypanosomiasis; Alleles; American; Antibodies; Apolipoproteins; Blood; Blood Pressure; Brothers; Candidate Disease Gene; Case-Control Studies; Cell Line; Child; Chromosomes, Human, Pair 22; Chronic; Chronic Kidney Failure; Clinical; Code; Coenzyme Q10; Complex; Cytolysis; Development; Dialysis procedure; Disease; Disease Association; Disease Attributes; Disease Progression; Drug Targeting; Early Diagnosis; End stage renal failure; Environmental Risk Factor; Ethnic group; European; Exposure to; Factor VIII; Focal Segmental Glomerulosclerosis; Frequencies; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Screening; Genotype; Graft Survival; HIV-1; Haplotypes; Hemophilia A; Heterozygote; Histology; Homozygote; Human; Human Genetics; Human Genome Diversity Project; Hypertension; Immune; Immune response; Impairment; Individual; Infection; International; Journals; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knowledge; Logistic Regressions; Maps; Medicine; Mitochondria; Modeling; Mus; Mutate; Mutation; Nephrons; Nephrotic Syndrome; Nigeria; Non-Insulin-Dependent Diabetes Mellitus; Nonmuscle Myosin Type IIA; Nucleotides; Odds Ratio; Outcome; Parasites; Participant; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Population; Population Control; Process; Proxy; Publishing; Randomized; Recording of previous events; Resistance; Risk; Risk Factors; Role; Sampling; Series; Serum; Signal Transduction; Single Nucleotide Polymorphism; Staging; Syndrome; Tail; Time; Trypanosoma; Trypanosoma brucei brucei; Variant; advanced disease; arm; base; case control; cohort; cost; design; genetic association; genetic inhibitor; genetic variant; global health; glomerulosclerosis; health disparity; inhibitor/antagonist; lymphoblastoid cell line; modifiable risk; mouse model; podocyte; risk variant

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 dialysis or kidney transplants at an annual cost of $30 billion dollars. The three leading causes of ESKD are type 2 diabetes, hypertension, and glomerulosclerosis. African Americans are 3-4 times more likely to develop end ESKD compared to their white counterparts. Focal segmental glomerulosclerosis (FSGS) is the leading cause of primary nephritic syndrome in adults and the leading cause of ESKD in children. FSGS represents a syndrome that includes idiopathic forms and forms associated with reduced nephron numbers, hypertension, and HIV-1 infection. Previously, we used admixture mapping to localize a region on chromosome 22 associated with FSGS and HIV-associated nephropathy (HIVAN). The strongest signal was centered on MYH9, encoding myosin IIA, a plausible candidate gene. Subsequently, coding variants comprising 2 missense variants (G1 allele) in absolute linkage disequlibrium and an inframe 6 basepair deletion (G2 allele) were identified in the APOL1 gene encoding apolipoprotein 1 (APOL1). The APOL1 coding variants were more strongly associated with FSGS than were the MYH9 variants. ApoL1 provides protection against infection with Trypanosoma brucei brucei; the APOL1 G1 and G2 risk alleles restore protection against T. b. rhodesiense, a cause of sleeping sickness in heterozygotes. APOL1 G1 and G2 alleles have been under recent positive selection resulting in haplotype homozygosity across the region comprising MYH9/APOL1. 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 frequencies of G1 and G2 alleles are approximately 35% in African Americans and 60% in Yoruba from Nigeria. 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 this genetic region to determine if these risk variants are associated with other non-renal or renal phenotypes. We are also determining if APOL1 variants in the donor or recipient are associated with donor graft survival. Accomplishments 1. FSGS and collapsing glomerulopathy are common causes of nephrotic syndrome. Variants in over 20 genes have been associated with podocyte glomerulopathies, including genes critical for mitochondrial function. PDSS2 is required for synthesis of the decaprenyl tail of coenzyme Q10 in humans. The mouse gene Pdss2 is mutated in the kd/kd mouse model of collapsing glomerulopathy, a histology seen in HIV-associated nephropathy in humans. We examined the hypothesis that human PDSS2 polymorphisms are associated with FSGS or collapsing glomerulopathy by genotyping 377 cases with primary FSGS or collapsing glomerulopathy and 900 controls, for nine single nucleotide polymorphisms (SNPs) in the PDSS2 gene in a case-control study. Among European Americans (EA), a pair of proxy SNPs was significantly associated with podocyte disease, and patients homozygous for one PDSS2 haplotype had a strongly increased risk for podocyte disease. By contrast, the distribution of PDSS2 genotypes and haplotypes were similar in AA cases and controls. Thus, a PDSS2 haplotype, which has a frequency of 13% in the EA control population and a homozygote frequency of 1.2%, is associated with a significantly increased risk for FSGS and collapsing glomerulopathy in EA. Lymphoblastoid cell lines (LCLs) from FSGS patients had significantly less coenzyme Q10 than cell lines from controls; unexpectedly this finding was independent of PDSS2 haplotype. These results suggest that FSGS patients have coenzyme Q10 deficiency, and that this deficiency is manifested in patient-derived LCLs. This study was published in the American Journal of Renal Physiological. 2. A series of studies have shown that the higher rates of the most common causes of chronic kidney disease in persons of African ancestry is due to APOL1 variants that under positive selection by Human African Trypanosomiasis (HAT). These variants are found in or near the serum-resistance-associated (SRA)-interacting-domain-encoding region of APOL1. To explore the distribution of potential functional variation at APOL1, we studied nucleotide variation in 187 individuals across ten geographically and genetically diverse African ethnic groups with exposure to two Trypanosoma brucei subspecies that cause HAT. We observed unusually high levels of nonsynonymous polymorphism in the regions encoding the functional domains that are required for lysing parasites. As we previously showed in African samples from the human genome diversity project allele frequencies of G2 were similar across all populations (3%-8%), the G1 allele was only common in the Yoruba (39%). We hypothesized that two new variants that showed signals of recent selection might be associated with HAT resistance as they occurred within domains required for lysis of trypanosomes. We are now exploring the association of these new variants with HAT resistance and CKD. This study was published in the American Journal of Human Genetics. 3) To examine the role of APOL1 risk variants in African Americans with kidney disease attributed to hypertension, we studied the association of APOL1 alleles on renal end points in in participants of the African American Study of Kidney Disease and Hypertension (AASK) cohort. In this cohort, randomized to two treatment arms and to two blood pressure targets there was relentless progression to end stage renal disease regardless of treatment arm. To better understand this, coding variants in the apolipoprotein L1 (APOL1) was evaluated for an association with hypertension-attributed nephropathy and clinical outcomes in a study comprising 675 AASK participant cases and 618 non-nephropathy control individuals. APOL1 G1 and G2, along with 44 ancestry informative markers, were genotyped and analyzed by logistic regression multivariable models. In recessive models, APOL1 risk variants were significantly associated with kidney disease in all cases compared to controls with an odds ratio of 2.57. In AASK cases with more advanced disease, the association was strengthened with odds ratios of 4.61-6.29. APOL1 risk variants were consistently associated with renal disease progression across medication classes and blood pressure targets. This study was published in Kidney International. 4) The development of inhibitory antibodies to factor VIII in people with hemophilia A is a complex process involving multiple genetic and environmental factors, including the type of F8 mutation that causes the deficiency. To investigate the genetic basis for inhibitor development we developed the The Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort comprising 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using the Illumina iSelect platform, we designed a panel of 13 331 single-nucleotide polymorphisms from 1081 immune response and immune modifier genes. After adjustment for potential confounders, 53 single-nucleotide polymorphisms were found to be significant predictors of inhibitor status. Of the 53 markers, 13 had meta P .001. Eight of the 53 were significant predictors among the discordant pairs. These results indicate that the genetic contribution to inhibitor development is complex and likely involves many genes or pathways. This study was published in Blood.

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 人接受透析或肾移植，每年费用达 300 亿美元。 ESKD 的三大主要原因是 2 型糖尿病、高血压和肾小球硬化症。与白人相比，非裔美国人患最终 ESKD 的可能性是白人的 3-4 倍。局灶节段性肾小球硬化症 (FSGS) 是成人原发性肾病综合征的主要原因，也是儿童 ESKD 的主要原因。 FSGS 代表一种综合征，包括特发性形式和与肾单位数量减少、高血压和 HIV-1 感染相关的形式。此前，我们使用混合作图来定位 22 号染色体上与 FSGS 和 HIV 相关肾病 (HIVAN) 相关的区域。最强的信号集中在 MYH9，它编码肌球蛋白 IIA，这是一个可能的候选基因。随后，在编码载脂蛋白 1 (APOL1) 的 APOL1 基因中鉴定出包含绝对连锁不平衡的 2 个错义变体（G1 等位基因）和一个框内 6 碱基对缺失（G2 等位基因）的编码变体。与 MYH9 变体相比，APOL1 编码变体与 FSGS 的相关性更强。 ApoL1 可防止布氏锥虫感染； APOL1 G1 和 G2 风险等位基因恢复针对结核杆菌的保护。罗得西亚，杂合子昏睡病的一个原因。 APOL1 G1 和 G2 等位基因最近受到正选择，导致包含 MYH9/APOL1 的区域出现单倍型纯合性。 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。 G1 和 G2 等位基因的频率在非裔美国人中约为 35%，在尼日利亚约鲁巴人中约为 60%。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。我们继续对该遗传区域进行研究，以确定这些风险变异是否与其他非肾脏或肾脏表型相关。我们还在确定供体或受体的 APOL1 变异是否与供体移植物的存活相关。成就 1. FSGS 和塌陷性肾小球病是肾病综合征的常见病因。超过 20 个基因的变异与足细胞肾小球病相关，其中包括对线粒体功能至关重要的基因。 PDSS2 是人体辅酶 Q10 十异戊二烯尾部合成所必需的。小鼠基因 Pdss2 在塌陷性肾小球病的 kd/kd 小鼠模型中发生突变，塌陷性肾小球病是人类 HIV 相关肾病的一种组织学表现。我们在一项病例对照研究中，通过对 377 例原发性 FSGS 或塌陷性肾小球病患者和 900 名对照者的 PDSS2 基因中的 9 个单核苷酸多态性 (SNP) 进行基因分型，检验了人类 PDSS2 多态性与 FSGS 或塌陷性肾小球病相关的假设。在欧洲美国人 (EA) 中，一对代理 SNP 与足细胞疾病显着相关，并且一个 PDSS2 单倍型纯合的患者患足细胞疾病的风险显着增加。相比之下，PDSS2 基因型和单倍型的分布在 AA 病例和对照中相似。因此，PDSS2 单倍型在 EA 对照群体中的频率为 13%，纯合子频率为 1.2%，与 EA 中 FSGS 和塌陷性肾小球病的风险显着增加相关。 FSGS 患者的类淋巴母细胞系 (LCL) 的辅酶 Q10 含量明显低于对照细胞系；出乎意料的是，这一发现与 PDSS2 单倍型无关。这些结果表明 FSGS 患者存在辅酶 Q10 缺乏症，并且这种缺乏症表现在患者来源的 LCL 中。这项研究发表在《美国肾脏生理学杂志》上。 2. 一系列研究表明，非洲血统人群慢性肾病最常见原因的较高发生率是由于非洲人锥虫病 (HAT) 正选择下的 APOL1 变异所致。这些变体存在于 APOL1 的血清抗性相关 (SRA) 相互作用域编码区中或附近。为了探索 APOL1 潜在功能变异的分布，我们研究了 187 名个体的核苷酸变异，这些个体来自 10 个地理和遗传上不同的非洲种族，这些个体接触了两种导致 HAT 的布氏锥虫亚种。我们在编码裂解寄生虫所需功能域的区域观察到异常高水平的非同义多态性。正如我们之前在人类基因组多样性项目的非洲样本中显示的那样，G2 等位基因频率在所有人群中相似 (3%-8%)，而 G1 等位基因仅在约鲁巴人中常见 (39%)。我们假设，显示最近选择信号的两个新变体可能与 HAT 抗性相关，因为它们发生在锥虫裂解所需的域内。我们现在正在探索这些新变异与 HAT 抵抗和 CKD 的关联。这项研究发表在《美国人类遗传学杂志》上。 3) 为了检查 APOL1 风险变异在患有高血压肾病的非裔美国人中的作用，我们研究了 APOL1 等位基因与非裔美国人肾病和高血压研究 (AASK) 队列参与者肾脏终点的关联。在该队列中，随机分配到两个治疗组和两个血压目标，无论治疗组如何，肾病都会持续进展至终末期肾病。为了更好地理解这一点，在一项包含 675 名 AASK 参与者病例和 618 名非肾病对照个体的研究中，评估了载脂蛋白 L1 (APOL1) 的编码变异与高血压肾病和临床结果的关联。通过逻辑回归多变量模型对 APOL1 G1 和 G2 以及 44 个祖先信息标记进行基因分型和分析。在隐性模型中，与对照组相比，APOL1 风险变异在所有病例中均与肾脏疾病显着相关，优势比为 2.57。在患有更晚期疾病的 AASK 病例中，这种关联得到加强，比值比为 4.61-6.29。 APOL1 风险变异与不同药物类别和血压目标的肾脏疾病进展始终相关。这项研究发表在《国际肾脏病杂志》上。 4) A 型血友病患者体内 VIII 因子抑制性抗体的形成是一个复杂的过程，涉及多种遗传和环境因素，包括导致缺陷的 F8 突变类型。为了研究抑制剂发展的遗传基础，我们开发了血友病抑制剂遗传学研究 (HIGS) 联合队列，由来自 3 个独立队列的 833 名受试者组成：有或没有抑制剂病史的兄弟对和单身，以及 104 对抑制剂不一致的兄弟对地位。使用 Illumina iSelect 平台，我们从 1081 个免疫反应和免疫调节基因中设计了一组 13 331 个单核苷酸多态性。在调整潜在的混杂因素后，发现 53 个单核苷酸多态性是抑制剂状态的重要预测因子。在 53 个标记中，13 个具有元 P .001。 53 个中的 8 个是不一致对中的显着预测因子。这些结果表明，遗传对抑制剂发展的贡献是复杂的，并且可能涉及许多基因或途径。这项研究发表在《血液》杂志上。