Genetics of Renal Disease in African Americans

慢性肾脏疾病影响着2600多万美国人，经常导致肾衰竭，需要透析或肾移植。每年有超过10万人患上肾衰竭，近50万人接受透析或肾脏移植，每年花费300亿美元。肾衰竭的三个主要原因需要透析或肾脏替代生存是2型糖尿病，高血压和肾小球硬化。非裔美国人患终末期肾病（ESRD）的可能性是白人的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是一种综合征，包括特发性变异和与肾细胞数量减少、高血压和HIV-1感染相关的变异。非洲裔美国人发生特发性FSGS的风险为4倍，发生hiv相关FSGS的风险为50 - 70倍，也称为hiv相关肾病（HIVAN）。hiv是非裔美国成年男性肾衰竭的第三大原因。在与NIDDK肾脏疾病科的合作下，从13个校外地点招募了患者。该研究包括活检证实的散发性FSGS或hiv -1相关肾病（HIV-1-associated nephropathy， HIVAN）伴塌陷性肾小球硬化病例和919例供体对照。超过60%的终末期肾病与糖尿病和高血压有关，约30%与肾小球病变有关，主要是由FSGS引起的。我们还开展了合作，研究宿主遗传因素在其他肾病病因中的作用（如镰状细胞性贫血肾炎、痫前期、狼疮、糖尿病和高血压）。一项正在进行的主要调查是确定非裔美国人肾病和高血压（AASK）试验中患有高血压的非裔美国人蛋白尿和终末期肾病（ESRD）的遗传预测因子。足细胞中表达的结构蛋白被认为在影响水力流动和蛋白质从血浆空间进入肾脏尿空间的过程中起关键作用。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相关，通常发病早，但相同基因的变异与特发性FSGS无关，通常发病年龄较晚。我们最近报道了Chr 22区携带MYH9和APOL1的风险等位基因与FSGS、HIVAN和非糖尿病终末期肾脏疾病密切相关。在高度合作的研究中，我们已经完善了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的关联是一种常见疾病中最强烈和最常见的。这一系列研究对转译研究和个体化医疗具有重要意义。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有关；它们在hiv相关肾病（HIVAN）中的作用尚未被研究。我们研究了活检证实为特发性局灶节段性肾小球硬化（FSGS）和HIVAN的患者，以更精确地定义遗传风险，并确定apol1相关的FSGS是否具有独特的临床表型。我们检测了271例非洲裔美国人FSGS和hiv病例、168例欧美人FSGS病例和939例对照者的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倍和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患者，与其他FSGS患者相比，发病年龄大约早十年，进展到ESKD的速度更快。两个APOL1风险等位基因导致FSGS和HIVAN的归因风险为67%，FSGS和HIVAN的解释比例分别为18%和35%；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患FSGS的终生风险估计为4%，而未经治疗的HIV疾病患者患HIV的风险为50%。一项世界人口调查表明，APOL1肾脏风险等位基因只存在于非洲染色体上。这些数据增加了确定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。尽管在参加AASK试验的受试者中，血管紧张素转换酶抑制剂对血压进行了强化控制，但对肾脏进展终点没有显著影响。在675名AASK参与者和618名非裔美国人对照（包括进行性肾功能丧失）中，对APOL1基因编码变异与非裔美国人非糖尿病肾病密切相关的高血压肾病的相关性进行了评估。为了确定AASK参与者（675名）和618名AA非肾病对照，对APOL1 G1和G2编码变体进行基因分型。在隐性模型中，与对照组相比，APOL1风险变异在所有asask病例中与肾脏疾病显著相关。（OR 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，特别是基线蛋白尿患者。这项研究表明，APOL1变异可能引发以前归因于高血压的慢性肾脏疾病。我们还发现22号染色体变异可能与其他基因相互作用。2型糖尿病（T2D）是CKD和ESKD的主要病因，许多非裔美国人患有非糖尿病肾病，这可能掩盖了糖尿病肾病基因的检测。在一项与NIDDK和维克森林大学的合作研究中，研究人员对966名患有T2DN的非洲裔美国人和1032名非糖尿病、非肾病（NDNN）对照进行了全基因组关联分析，并对染色体(c) 22 MYH9和APOL1肾病风险变异进行了调整。在调整c22变异之前，没有发现FRMD3 snp和T2DN之间的关联。然而，逻辑回归分析显示，7个FRMD3 snp与MYH9显著相互作用。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&#8202；= 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，而在MYH9 E1风险单倍型的纯合子中则无相关。FRMD3 snp与T2DN相关，而与2型糖尿病无关，将T2DN的AAs与糖尿病缺乏肾病的患者进行比较。t2dn相关的FRMD3 snp只有在考虑MYH9后才能在AAs中检测到，对APOL1有不同的影响。这些分析揭示了FRMD3在AA - T2DN易感性中的作用，并且计算c22肾病风险变异可以帮助检测DN易感性基因。

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.