Genetics of Renal Disease in African Americans

非裔美国人肾病遗传学

• 批准号: 8348948
• 负责人: Cheryl Winkler
• 金额: $ 44.59万
• 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/8348948
• 关键词: AIDS-Associated Nephropathy; Accounting; Adult; Affect; African; African American; Age of Onset; Alleles; American; Angiotensin-Converting Enzyme Inhibitors; Biopsy; Bowman' s space; Child; Chromosomes; Chromosomes, Human, Pair 22; Chronic; Chronic Kidney Failure; Clinical; Code; Collaborations; Creatinine; Data; Detection; Diabetes Mellitus; Diabetic Nephropathy; Dialysis procedure; Disease; Disease Progression; Drug Delivery Systems; Early Diagnosis; End stage renal failure; Enrollment; Etiology; European; Extramural Activities; Focal Segmental Glomerulosclerosis; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Screening; Genetic screening method; Genotype; HIV; HIV-1; Haplotypes; Homozygote; Hypertension; Impairment; Individual; Infection; Investigation; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knowledge; Logistic Regressions; Lupus; Masks; Medicine; Modeling; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Nephritis; Nephrons; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Participant; Patients; Phenotype; Plasma; Play; Population; Predisposition; Proteins; Proteinuria; Regression Analysis; Renal function; Reporting; Risk; Risk Factors; Role; Series; Serum; Sickle Cell Anemia; Site; Smoking; Staging; Structural Genes; Structural Protein; Surveys; Susceptibility Gene; Syndrome; Time; Translational Research; Universities; Urine; Variant; base; blood pressure regulation; clinical phenotype; cost; diabetic; early onset; evidence base; follow-up; forest; genetic association; genetic variant; genome wide association study; glomerulosclerosis; health disparity; lifetime risk; lung small cell carcinoma; men; modifiable risk; non-diabetic; podocyte

Chronic kidney disease, affecting over 26 million Americans, frequently leads to kidney failure requiring either dialysis or kidney transplant. Each year more than 100,000 individuals develop kidney failure and nearly 500,000 receive dialysis or kidney transplants at an annual cost of $30 billion dollars. The three leading causes of kidney failure requiring dialysis or kidney replacement for survival are type 2 diabetes, hypertension, and glomerulosclerosis. African Americans are 3-4 times more likely to develop end stage renal disease (ESRD) compared to their white counterparts. FSGS is the leading cause of primary nephritic syndrome in adults and the leading cause of end-stage renal disease (ESRD) in children. FSGS represents a syndrome that includes idiopathic variants and variants associated with reduced nephron numbers, hypertension, and HIV-1 infection. African-Americans are at a four-fold risk of developing idiopathic FSGS, and at a 50 to 70-fold increased risk for HIV-associated FSGS, also known as HIV-associated nephropathy (HIVAN). HIVAN is the third leading cause of kidney failure in African American adult men. In collaboration with the Kidney Disease Section, NIDDK, patients have been enrolled from 13 extramural sites. The study comprises biopsy-proven sporadic FSGS or HIV-1-associated nephropathy (HIVAN) cases with biopsy-proven collapsing glomerulosclerosis and 919 donor controls. More than 60% of end stage kidney disease is associated with diabetes and hypertension, and approximately 30% with glomerulopathies, mainly due to FSGS. We have have also entered into collaborations to investigate the role of host genetic factors in other etiologies of kidney disease (e.g., sickle cell anemia nephritis, pre-elampsia, lupus, diabetes, and hypertension). A major on-going investigation is to determine genetic predictors of proteinuria and endstage renal disease (ESRD) in African Americans with hypertension enrolled in the African American Kidney Disease and Hypertension (AASK) Trial. 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. Mutations in podocyte-expressed structural genes have been associated with both autosomal recessive and dominant Mendelian focal segmental glomerulosclerosis, generally with early onset, but variants in the same genes have not been associated with idiopathic FSGS with generally later age of onset. We recently reported that risk alleles in the Chr 22 region harboring MYH9 and APOL1 were strongly associated with FSGS, HIVAN, and non-diabetic end stage renal disease. In highly collaborative studies we have refined the association of APOL1 structural variants with FSGS phenotypes and extended the association for the first time to HIVAN. The APOL1 associations with CKD and ESRD are among the strongest and most frequent observed for a common disease. These series of studies have important implications for translational research and for personalized medicine. Accomplishments In a collaborative study we recently reported that trypanolytic mutations in APOL1, encoding apolipoproteinL1, were associated with FSGS and ESKD in African Americans; their role in HIV-associated nephropathy (HIVAN) was not investigated. 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 a recessive model, APOL1 variants were associated with 20-fold increased risk for FSGS and 40-fold increased risk for HIVAN compared to subjects without the risk alleles. 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 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 developing FSGS and those with untreated HIV disease have a 50% risk for developing HIVAN. A survey of world populations indicates that the APOL1 kidney risk alleles are present only on African chromosomes. These data add to the evidence base required to define the role for APOL1 genetic testing in personalized medicine. We have also investigated the role of APOL1 and MYH9 variation in diabetic and non-diabetic kidney disease. In spite of intensive blood pressure control with angiotensin converting enzyme inhibitors in subjects enrolled in the AASK trial, there was no significant effect on renal progression endpoints. Coding variants in APOL1 gene that are strongly associated with non-diabetic nephropathy in African Americans were evaluated for association with hypertension-attributed nephropathy in 675 AASK participants and with clinical outcomes and 618 African American controls, including progressive renal function loss. To determine AASK participants (675) and 618 AA non-nephropathy controls were genotyped for the APOL1 G1 and G2 coding variants. In a recessive model, APOL1 risk variants were significantly associated with kidney disease in all AASK cases vs. controls. (OR 2.57; p=1.4E-8). We also found that APOL1 variants were associated with higher baseline urine protein/creatinine ratios (OR 6.29; p=2.6E-14) and higher serum creatinine during follow-up (OR 4.61; p=5.6E-15). Kidney disease in AASK participants was associated with APOL1 risk variants, particularly for those with baseline proteinuria. This study suggests that APOL1 variants may initiate chronic kidney disease previously attributed to hypertension. We also showed that chromosome 22 variants may interact with other genes. Many African Americans with type 2 diabetes (T2D), the leading cause of CKD and ESKD, have non-diabetic kidney disease, potentially masking detection of diabetic nephropathy genes. In a collaborative study with NIDDK and Wake Forest University, genome-wide association analyses were performed in 966 African Americans with T2D nephropathy (T2DN) and 1,032 non-diabetic, non-nephropathy (NDNN) controls, with and without adjustment for chromosome (c) 22 MYH9 and APOL1 nephropathy risk variants. No associations were seen between FRMD3 SNPs and T2DN before adjusting for c22 variants. However, logistic regression analysis revealed seven FRMD3 SNPs significantly interacting with MYH9. This finding was replicated in 1323 African American T2DN cases and NDNN controls. FRMD3 SNPs appeared to interact with the MYH9 E1 haplotype (interaction p-value = 9.3E-7). FRMD3 alleles were associated with increased risk of T2DN only in subjects lacking two MYH9 E1 risk haplotypes, but not in homozygotes for MYH9 E1 risk haplotype. FRMD3 SNPS were associated with T2DN, and not type 2 diabetes, comparing AAs with T2DN to those with diabetes lacking nephropathy. T2DN-associated FRMD3 SNPs were detectable in AAs only after accounting for MYH9, with differential effects for APOL1. These analyses reveal a role for FRMD3 in AA T2DN susceptibility and accounting for c22 nephropathy risk variants can assist in detecting DN susceptibility genes.

慢性肾病影响着超过 2600 万美国人，经常导致肾衰竭，需要透析或肾移植。每年有超过 100,000 人出现肾衰竭，近 500,000 人接受透析或肾移植，每年费用达 300 亿美元。 需要透析或肾脏替代才能生存的肾衰竭的三个主要原因是 2 型糖尿病、高血压和肾小球硬化症。与白人相比，非裔美国人患终末期肾病 (ESRD) 的可能性高出 3-4 倍。 FSGS 是成人原发性肾病综合征的主要原因，也是儿童终末期肾病 (ESRD) 的主要原因。 FSGS 代表一种综合征，包括特发性变异和与肾单位数量减少、高血压和 HIV-1 感染相关的变异。非裔美国人患特发性 FSGS 的风险是其四倍，而患 HIV 相关 FSGS（也称为 HIV 相关肾病 (HIVAN)）的风险增加 50 至 70 倍。 HIVAN 是非裔美国成年男性肾衰竭的第三大原因。 与 NIDDK 肾脏病科合作，已从 13 个校外地点招募了患者。该研究包括经活检证实的散发性 FSGS 或 HIV-1 相关肾病 (HIVAN) 病例以及经活检证实患有塌陷性肾小球硬化症的病例以及 919 名供体对照。超过 60% 的终末期肾病与糖尿病和高血压有关，约 30% 与肾小球病有关，主要由 FSGS 引起。我们还开展合作，研究宿主遗传因素在其他肾脏疾病病因（例如镰状细胞性贫血肾炎、子痫前期、狼疮、糖尿病和高血压）中的作用。正在进行的一项主要研究是确定参加非裔美国人肾脏病和高血压 (AASK) 试验的非裔美国人患有高血压的蛋白尿和终末期肾病 (ESRD) 的遗传预测因素。 足细胞中表达的结构蛋白被认为在影响肾脏的水流和蛋白质从血浆空间进入泌尿空间方面发挥着关键作用。足细胞表达的结构基因突变与常染色体隐性和显性孟德尔局灶节段性肾小球硬化症相关，通常发病较早，但相同基因的变异与通常发病年龄较晚的特发性 FSGS 无关。我们最近报道，含有 MYH9 和 APOL1 的 Chr 22 区域的风险等位基因与 FSGS、HIVAN 和非糖尿病终末期肾病密切相关。在高度合作的研究中，我们完善了 APOL1 结构变异与 FSGS 表型的关联，并首次将这种关联扩展到 HIVAN。 APOL1 与 CKD 和 ESRD 的关联是常见疾病中观察到的最强且最常见的关联之一。这一系列研究对转化研究和个性化医疗具有重要意义。成就 在一项合作研究中，我们最近报道了编码载脂蛋白 L1 的 APOL1 的锥虫分解突变与非裔美国人的 FSGS 和 ESKD 相关。尚未研究它们在 HIV 相关肾病 (HIVAN) 中的作用。我们研究了活检证实为特发性局灶节段性肾小球硬化症 (FSGS) 和 HIVAN 的患者，以更准确地定义遗传风险并确定 APOL1 相关 FSGS 是否具有独特的临床表型。我们确定了 271 名非裔美国人 FSGS 和 HIVAN 病例、168 名欧洲裔美国人 FSGS 病例和 939 名对照受试者的 APOL1 基因型。在隐性模型中，与没有风险等位基因的受试者相比，APOL1 变异与 FSGS 风险增加 20 倍相关，与 HIVAN 风险增加 40 倍相关。对于与两个 APOL1 风险等位基因相关的 FSGS，与其他 FSGS 患者相比，发病年龄大约早十年，并且进展为 ESKD 的速度更快。两个 APOL1 风险等位基因赋予 FSGS 和 HIVAN 67% 的归因风险，以及 FSGS 18% 和 HIVAN 35% 的解释分数；这与吸烟导致小肺细胞癌的风险相似。具有两个 APOL1 风险等位基因的个体一生中患 FSGS 的风险估计为 4%，而患有未经治疗的 HIV 疾病的个体患 HIVAN 的风险为 50%。对世界人口的调查表明，APOL1 肾脏风险等位基因仅存在于非洲染色体上。这些数据增加了定义 APOL1 基因检测在个性化医疗中的作用所需的证据基础。我们还研究了 APOL1 和 MYH9 变异在糖尿病和非糖尿病肾病中的作用。尽管参加 AASK 试验的受试者使用血管紧张素转换酶抑制剂强化血压控制，但对肾脏进展终点没有显着影响。在 675 名 AASK 参与者中评估了与非裔美国人非糖尿病肾病密切相关的 APOL1 基因编码变异与高血压肾病的关系，以及与临床结果和 618 名非裔美国人对照者（包括进行性肾功能丧失）的关系。为了确定 AASK 参与者 (675) 和 618 名 AA 非肾病对照者，我们对 APOL1 G1 和 G2 编码变体进行了基因分型。在隐性模型中，与对照组相比，所有 AASK 病例中 APOL1 风险变异与肾脏疾病显着相关。 （或 2.57；p=1.4E-8）。我们还发现，APOL1 变异与较高的基线尿蛋白/肌酐比值（OR 6.29；p=2.6E-14）和随访期间较高的血清肌酐（OR 4.61；p=5.6E-15）相关。 AASK 参与者的肾脏疾病与 APOL1 风险变异相关，特别是对于基线有蛋白尿的参与者。这项研究表明，APOL1 变异可能引发先前归因于高血压的慢性肾脏疾病。 我们还表明 22 号染色体变异可能与其他基因相互作用。许多患有 2 型糖尿病 (T2D)（CKD 和 ESKD 的主要原因）的非裔美国人患有非糖尿病肾病，可能掩盖了糖尿病肾病基因的检测。在 NIDDK 和维克森林大学的一项合作研究中，对 966 名患有 T2D 肾病 (T2DN) 的非裔美国人和 1,032 名非糖尿病、非肾病 (NDNN) 对照进行了全基因组关联分析，并进行或不进行染色体调整 (c) ) 22 MYH9 和 APOL1 肾病风险变异。在针对 c22 变体进行调整之前，未发现 FRMD3 SNP 与 T2DN 之间存在关联。然而，逻辑回归分析显示七个 FRMD3 SNP 与 MYH9 显着相互作用。这一发现在 1323 例非裔美国人 T2DN 病例和 NDNN 对照中得到了重复。 FRMD3 SNP 似乎与 MYH9 E1 单倍型相互作用（相互作用 p 值 = 9.3E-7）。 FRMD3 等位基因仅在缺乏两种 MYH9 E1 风险单倍型的受试者中与 T2DN 风险增加相关，但在 MYH9 E1 风险单倍型的纯合子中则不然。将含有 T2DN 的 AA 与无肾病的糖尿病患者进行比较，FRMD3 SNPS 与 T2DN 相关，但与 2 型糖尿病无关。仅在考虑了 MYH9 后，才能在 AA 中检测到 T2DN 相关的 FRMD3 SNP，对 APOL1 具有不同的影响。这些分析揭示了 FRMD3 在 AA T2DN 易感性​​中的作用，并且解释 c22 肾病风险变异可以帮助检测 DN 易感性​​基因。