Nandakumar Priyanka, Tin Adrienne, Grove Megan L, Ma Jianzhong, Boerwinkle Eric, Coresh Josef, Chakravarti Aravinda
McKusick - Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
Predoctoral Training Program in Human Genetics and Molecular Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2017 Aug 3;12(8):e0176734. doi: 10.1371/journal.pone.0176734. eCollection 2017.
In older adults (aged 70-74 years), African-Americans have 4-fold higher risk of developing hypertension-attributed end-stage renal disease (ESRD) than European-Americans. A hypothesized mechanism linking hypertension and progressive chronic kidney disease (CKD) is the innate immune response and inflammation. Persons with CKD are also more susceptible to infection. Gene expression in peripheral blood can provide a view of the innate immune activation profile. We aimed to identify differentially expressed genes, microRNAs, and pathways in peripheral blood between cases with CKD and high blood pressure under hypertension treatment versus controls without CKD and with controlled blood pressure in African Americans.
Case and control pairs (N = 15x2) were selected from those without diabetes and were matched for age, sex, body mass index, APOL1 risk allele count, and hypertension medication use. High blood pressure under hypertension treatment was defined as hypertension medication use and systolic blood pressure (SBP) ≥ 145 mmHg. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. Cases were selected from those with CKD and high blood pressure under hypertension treatment, and controls were selected from those without CKD (eGFR: 75-120 mL/min/1.73m2 and urine albumin-to-creatinine ratio < 30mg/g) and with blood pressure controlled by hypertension medication use (SBP < 135 mmHg and D(diastolic)BP < 90 mm Hg). We perform RNA sequencing of mRNA and microRNA and conducted differential expression and co-expression network analysis.
Of 347 miRNAs included in the analysis, 14 were significantly associated with case status (Benjamini-Hochberg adjusted p-value [BH p] < 0.05). Of these, ten were downregulated in cases: three of each belong to the miR-17 and miR-15 families. In co-expression network analysis of miRNA, one module, which included 13 of the 14 significant miRNAs, had significant association with case status. Of the 14,488 genes and 41,739 transcripts included in the analysis, none had significant association with case status. Gene co-expression network analyses did not yield any significant associations for mRNA.
We have identified 14 differentially expressed miRNAs in the peripheral blood of CKD cases with high blood pressure under hypertension treatment as compared to appropriate controls. Most of the significant miRNAs were downregulated and have critical roles in immune cell functions. Future studies are needed to replicate our findings and determine whether the downregulation of these miRNAs in immune cells may influence CKD progression or complications.
在70 - 74岁的老年人中，非裔美国人患高血压所致终末期肾病（ESRD）的风险是欧裔美国人的4倍。一种将高血压与进行性慢性肾病（CKD）联系起来的假说机制是先天免疫反应和炎症。CKD患者也更容易感染。外周血中的基因表达可以反映先天免疫激活情况。我们旨在确定非裔美国人中，接受高血压治疗的CKD合并高血压患者与无CKD且血压得到控制的对照者外周血中差异表达的基因、微小RNA（miRNA）和信号通路。
从无糖尿病患者中选取病例和对照对（N = 15×2），并根据年龄、性别、体重指数、载脂蛋白L1（APOL1）风险等位基因数量和高血压药物使用情况进行匹配。接受高血压治疗的高血压定义为使用高血压药物且收缩压（SBP）≥145 mmHg。CKD定义为估算肾小球滤过率（eGFR）< 60 mL/min/1.73m²。病例选自接受高血压治疗的CKD合并高血压患者，对照选自无CKD（eGFR：75 - 120 mL/min/1.73m²且尿白蛋白与肌酐比值< 30mg/g）且血压通过使用高血压药物得到控制（SBP < 135 mmHg且舒张压（DBP）< 90 mmHg）的患者。我们对mRNA和miRNA进行RNA测序，并进行差异表达和共表达网络分析。
在分析的347个miRNA中，14个与病例状态显著相关（Benjamini - Hochberg校正P值[BH p] < 0.05）。其中，10个在病例中下调：各有3个属于miR - 17和miR - 15家族。在miRNA的共表达网络分析中，一个模块（包含14个显著miRNA中的13个）与病例状态显著相关。在分析的14488个基因和41739个转录本中，没有一个与病例状态显著相关。mRNA的基因共表达网络分析未产生任何显著关联。
我们已经确定，与适当对照相比，接受高血压治疗的CKD合并高血压患者外周血中有14个差异表达的miRNA。大多数显著的miRNA下调，且在免疫细胞功能中起关键作用。未来需要进行研究以重复我们的发现，并确定这些miRNA在免疫细胞中的下调是否可能影响CKD的进展或并发症。
