Genetics of Renal Disease in African Americans

非裔美国人肾病遗传学

• 批准号: 8552639
• 负责人: Cheryl Winkler
• 金额: $ 51.13万
• 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/8552639
• 关键词: AIDS-Associated Nephropathy; Admixture; Adult; Affect; Africa South of the Sahara; African; African American; African Trypanosomiasis; Age of Onset; Alleles; American; Angiotensin-Converting Enzyme Inhibitors; Apolipoproteins; Biopsy; Bowman' s space; Candidate Disease Gene; Child; Childhood; Chromosomes, Human, Pair 22; Chronic; Chronic Kidney Failure; Cicatrix; Clinical; Code; Computer software; Creatinine; Data; Development; Dialysis procedure; Disease; Disease Attributes; Disease Progression; Drug Delivery Systems; Early Diagnosis; End stage renal failure; Enrollment; Essential Hypertension; European; Family; Family member; Focal Segmental Glomerulosclerosis; Foreign Bodies; Frequencies; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Screening; Genetic screening method; Genome; Genotype; HIV; HIV-1; Haplotypes; Heterozygote; Hypertension; Hypertrophic Cicatrix; Impairment; Individual; Infection; Journals; Keloid; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knowledge; Life; Link; Linkage Disequilibrium Mapping; Maps; Medicine; Microsatellite Repeats; Modeling; Nephrons; Nephrosclerosis; Nigeria; Non-Insulin-Dependent Diabetes Mellitus; Nonmuscle Myosin Type IIA; Participant; Patients; Penetrance; Persons; Phenotype; Plasma; Play; Population; Prevalence; Proteins; Proteinuria; Publishing; Quality Control; Relative (related person); Rest; Risk; Risk Factors; Role; Serum; Signal Transduction; Smoking; Societies; Staging; Structural Protein; Syndrome; Time; Trauma; Trypanosoma brucei brucei; Urine; Variant; Wound Healing; base; blood pressure regulation; clinical phenotype; cohort; cost; design; emerging adult; evidence base; exome; follow-up; functional decline; gene environment interaction; genetic association; genetic linkage analysis; genetic variant; global health; glomerulosclerosis; health disparity; interest; interstitial; lifetime risk; lung small cell carcinoma; modifiable risk; non-diabetic; podocyte; programs; trait; wound; wound cleaning

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. Structural proteins expressed in podocytes are postulated to play a critical role in influencing hydraulic flow and protein exit from the plasma space into the urinary space in the kidney. 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. We subsequently fine-mapped MYH9, but no obvious functional variants were identified. These intronic variants were common in African Americans and nearly absent from Europeans; they are strongly associated with FSGS, HIVAN, and ESKD attributable to hypertension, explaining nearly all the 4-fold excess risk for CKD and ESKD observed in African Americans. 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.Accomplishments1. We studied patients with biopsy proven idiopathic focal segmental glomerulosclerosis (FSGS) and HIVAN to define more precisely the genetic risk and to determine whether APOL1-associated FSGS has a distinct clinical phenotype. We determined APOL1 genotypes for 271 African American FSGS and HIVAN cases, 168 European American FSGS cases and 939 control subjects. In the recessive model, APOL1 variants were associated with OR 17 for FSGS and 29 for HIVAN compared to subjects with no or one APOL1 risk allele. The association with HIV is a robust example of a gene-environment interaction. For FSGS associated with two APOL1 risk alleles, compared to other FSGS patients, onset age was approximately a decade earlier and progression to ESKD was significantly faster. Two APOL1 risk alleles confer an attributable risk of 67% for FSGS and HIVAN and an explained fraction of 18% for FSGS and 35% for HIVAN; this is similar to the risk conferred by smoking for small-lung-cell carcinoma. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for FSGS and those with untreated HIV disease have a 50% lefetime risk for HIVAN. These data add to the evidence base required to define the role for APOL1 genetic testing in personalized medicine. These results were published in Journal of American Society of Nephrology.2. In spite of intensive blood pressure control with angiotensin converting enzyme inhibitors in subjects enrolled in the African American Study of Kidney Disease and Hypertension (AASK) trial, there was no significant effect on renal progression endpoints (creatinine doubling or ESKD). We evaluated the role of APOL1 G1 and G2 variants for association with hypertension-attributed nephropathy in 675 AASK participants with CKD and 618 African American non-nephrology controls. In a recessive model, APOL1 risk variants were significantly associated with clinical endpoints in AASK cases versus controls. (OR 2.57; p=1.4x10-8); the effects were slightly higher in participants with baseline proteinuria. We also found that APOL1 variants were associated with higher baseline urine protein/creatinine ratios (OR 6.29; p=2.6x10-14) and higher serum creatinine during follow-up (OR 4.61; p=5.6x10-15). In summary, nephropathy risk variants in the APOL1 gene are significantly associated with CKD attributed to essential hypertension in non-diabetic AASK participants. The results were most robust in individuals with progressive renal functional decline and higher baseline levels of proteinuria. It is unlikely that these variants are associated with essential hypertension per se, as results were consistent when comparing hypertensive AASK cases to controls with and without high blood pressure. These results strongly suggest that progressive kidney disease attributed to hypertensive nephrosclerosis and characterized by focal global glomerulosclerosis, arteriolar nephrosclerosis and interstitial scarring, commonly present in the renal biopsies of AASK participants, belongs to the same disease spectrum as idiopathic FSGS and HIVAN. These results were published in Kidney International.3. APOL1 variants do not explain all of the risk for kidney disease in persons with hypertension nor do they associate with hypertension. Using a case only design, we have genotyped the AASK cohort for 1750 ancestry informative markers to detect association using an admixture mapping by linkage disequilibrium strategy. In brief, we compare each marker for ancestry using a hidden Markoff chain analysis. Regions-of-interest harboring the causal variation associated with kidney disease or hypertension, both more prevalent in African Americans, should show an increase in African ancestry relative to the rest of the genome. The genotyping and quality control steps have been completed and the software programs adapted for quantitative traits. 4. Our interest in common diseases with strong racial disparities prompted a study of keloid development in African Americans. Keloids, unlike hypertrophic scarring, overgrow the wound border and have a strong racial propensity; estimates for prevalence in the African American population range from 3-15%. With the exception of trauma, precise etiologic factors responsible for keloid formation have not been fully elucidated. Keloids are frequently associated with negative wound healing factors, such as infection, excessive tension, foreign bodies, and repetitive trauma; however, keloids may form in simple clean wounds. They generally first manifest in childhood and early adulthood; it is rare to see keloids develop after the third decade of life. We have collected multiple three-generation families segregating for keloids, where the mode of inheritance is autosomal dominant with incomplete penetrance. To date we have performed a linkage analysis using 800 microsatellite markers for 60 family members to localize the region linked to the keloid phenotype. We have obtained exome sequences for 12 affected and unaffected family members for identity by descent analysis. We have identified three regions showing LOD scores >2, but results to date suggest that the propensity to develop keloids is polygenic.

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100,000多名患者患末期肾脏疾病（ESKD），近500,000人接受透析或肾脏移植，年费用为300亿美元。 ESKD的三个主要原因是2型糖尿病，高血压和肾小球硬化。 与白人同行相比，非洲裔美国人的终结ESKD的可能性高3-4倍。 局灶性节段性肾小球硬化（FSGS）是成年人原发性肾脏综合征的主要原因，也是儿童ESKD的主要原因。假定在足细胞中表达的结构蛋白在影响肾脏空间中的液压流和蛋白质出口中起关键作用。 FSG代表一种综合征，其中包括特发性形式和与肾脏数量减少，高血压和HIV-1感染相关的形式。以前，我们使用混合图映射将与FSG和HIV相关肾病（Hivan）相关的22号染色体上的区域定位。最强的信号以MYH9为中心，编码了合理的候选基因肌球蛋白IIA。 随后，我们对映射的myh9进行了细映射，但是没有确定明显的功能变体。 这些内含子的变体在非裔美国人中很常见，欧洲人几乎没有。它们与归因于高血压的FSG，Hivan和ESKD密切相关，这解释了在非洲裔美国人中观察到的几乎所有4倍CKD和ESKD的过量风险。 随后，在编码载脂蛋白1（apol1）的Apol1基因中鉴定出了绝对连锁疾病中的2个错义变体（G1等位基因）的编码变体（G1等位基因）。与MYH9变体相比，APOL1编码变体与FSG更加密切相关。 apol1提供了锥虫布鲁氏锥虫的保护，可防止感染； APOL1 G1和G2风险等位基因恢复对T. b的保护。 Rhodesiense，这是杂合子中睡眠疾病的原因。 APOL1 G1和G2等位基因已在最近的阳性选择下，导致整个包含MYH9/APOL1的区域的单倍型纯合性。 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。 非裔美国人的G1和G2等位基因的频率约为35％，尼日利亚的约鲁巴人的频率约为60％。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，从而为全球主要的健康差异提供了遗传基础。我们研究了活检证明的特发性局灶性节段性肾小球硬化症（FSGS）和Hivan患者，以更准确地定义遗传风险，并确定与APOL1相关的FSG是否具有独特的临床表型。我们确定了271例非裔美国人FSG和Hivan病例，168例欧美FSG案例和939例对照受试者的APOL1基因型。在隐性模型中，与没有或一个APOL1风险等位基因的受试者相比，apol1变体与FSG相关的APOL1变体与HIVG的17相关。 与HIV的关联是基因环境相互作用的强大例子。 对于与其他FSGS患者相比，与两个APOL1风险等位基因相关的FSG，发病年龄大约早于十年，而发展到ESKD的速度明显更快。两个APOL1风险等位基因赋予FSG和Hivan的67％的可归因风险，而FSG的分数为18％，Hivan的分数为35％；这类似于小肺癌吸烟带来的风险。患有两个APOL1风险等位基因的个体对FSG估计有4％的寿命风险，而患有未经治疗的HIV疾病的人患Hivan的左旋时期风险为50％。这些数据增加了定义个性化医学中APOL1基因检测作用所需的证据基础。 这些结果发表在美国肾脏学杂志上。2。尽管具有血管紧张素的强烈血压控制，但在参加非裔美国人的肾脏疾病和高血压研究（AASK）试验的受试者中转化酶抑制剂（AASK）试验，对肾脏进展端点没有显着影响（肌酐倍增或ESKD）。 我们评估了675 AASK参与者和618名非裔美国人非副学控制者中APOL1 G1和G2变体在675 AASK参与者中的作用。在隐性模型中，APOL1风险变异与AASK病例与对照组中的临床终点显着相关。 （OR 2.57; P = 1.4x10-8）;基线蛋白尿的参与者的影响略高。 我们还发现，在随访期间（OR 4.61; P = 5.6x10-15），APOL1变体与较高的基线尿液蛋白/肌酐比（OR 6.29; P = 2.6x10-14）和较高的血清肌酐有关（P = 5.6x10-15）。总之，Apol1基因中的肾病风险变异与归因于非糖尿病AASK参与者的基本高血压的CKD显着相关。 在具有肾脏肾功能下降和较高基线蛋白尿水平的个体中，结果最强大。 这些变体本身不可能与必需的高血压本身有关，因为在将高血压AASK病例与有或没有高血压的对照进行比较时，结果是一致的。 这些结果强烈表明，归因于高血压性肾硬化的进行性肾脏疾病，其特征是全球全球肾小球硬化，小动脉肾脏骨硬化和间质性疤痕，通常存在于AASK参与者的肾脏活检中，是与个性疾病谱相同的疾病谱系，是原发性疾病谱。这些结果发表在肾脏国际。3。 APOL1变体不能解释患有高血压患者的肾脏疾病的所有风险，也不能与高血压相关。 使用只有案例设计，我们使用了通过链接不平衡策略进行混合映射的1750个祖先信息标记的AASK队列来检测关联。 简而言之，我们使用隐藏的Markoff链分析比较了每个标记的祖先。 具有与肾脏疾病或高血压相关的因果变异的利益区域，在非洲裔美国人中更为普遍，应该显示出相对于基因组的其余部分而增加的非洲血统。基因分型和质量控制步骤已经完成，软件程序适用于定量性状。 4。我们对种族差异的常见疾病的兴趣促使对非洲裔美国人的乳子虫的发展进行了研究。 与肥厚的疤痕不同，乳子状体过多地生长了伤口边界，并具有强烈​​的种族倾向。非裔美国人人口患病率的估计范围为3-15％。除了创伤外，尚未完全阐明导致乳杆菌形成的精确病因。 Keloids经常与伤口愈合因子（例如感染，过度张力，异物和重复创伤）有关。但是，酮可以在简单的清洁伤口中形成。他们通常在童年和成年初期表现出来。在生命的第三个十年之后，很少见到乳突发展。 我们已经收集了多个三代家族，这些家族分离了乳子状，其中遗传模式是常染色体主导的，并且渗透不完全。 迄今为止，我们已经使用800个微卫星标记对60个家庭成员进行了链接分析，以定位与Keloid表型相关的区域。 我们已经获得了通过下降分析的12个受影响和未受影响的家庭成员的外显子组序列。 我们已经确定了三个显示LOD得分> 2的区域，但迄今为止的结果表明，开发乳球的倾向是多基因的。