Cytokine gene polymorphisms in hemodialysis patients: Association with comorbidity, functionality, and serum albumin
Cytokine gene polymorphisms in hemodialysis patients: Association with comorbidity, functionality, and serum albumin
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DOI：
10.1111/j.1523-1755.2004.00531.x
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发表时间：
2004-04-01
影响因子：
19.6
通讯作者：
Pereira, BJG
中科院分区：
文献类型：
--
作者：
Balakrishnan, VS;Guo, DQ;Pereira, BJG
背景。细胞因子协调的慢性炎症在接受血液透析（HD）的终末期肾病（ESRD）患者的长期发病率和死亡率中起着重要作用。在这项横断面研究中，我们评估了来自两个波士顿中心招募参加血液透析 (HEMO) 研究的 183 名 ESRD 患者的队列中特定等位基因/基因型以及白细胞介素 (IL)-6、肿瘤坏死因子-α (TNF-α) 和 IL-10 基因型组合与合并症指数、功能状态和其他生物标志物之间的关联。对 IL-6 (- 174 G --> C)、TNF-α (- 308 G --> A) 和 IL-10 (-1082 G --> A) 启动子区域的单核苷酸多态性进行基因分型。研究了特定基因型与共存疾病指数 (ICED) 评分（共病指数）、卡诺夫斯基指数（功能状态的衡量标准）、血清白蛋白和营养指数（人体测量值、体重指数、标准化蛋白质分解代谢比）的关系。还通过酶联免疫吸附测定 (ELISA) 测量血浆 IL-6 水平以及内毒素刺激的外周血单核细胞 (PBMC) 产生的 TNF-α 和 IL-10。结果。与这些细胞因子低产生基因型（分别为 C/C 和 G/G）的患者相比，促炎细胞因子 IL-6（G/G 和 G/C）和 TNF-α（G/A 和 A/A）高产生基因型的患者具有显着较高的合并症（ICED 评分为 2）和较低的功能评分（卡诺夫斯基指数）。相比之下，抗炎细胞因子IL-10的高和中生产基因型（G/G和G/A）的患者与低生产基因型（A/A）的患者相比，具有更高的卡诺夫斯基指数。与低生产基因型（G/A 和 A/A）患者相比，TNF-α 高生产基因型（G/A 和 A/A）患者的血清白蛋白水平较低。在多变量分析中，与低 IL-6 产生基因型患者相比，IL-6 高产生基因型与较高合并症（ICED 评分大于或等于 2）的比值比 (OR) 为 4.87（P = 0.02），与较低卡诺夫斯基指数（较低功能状态）（P = 0.04）相关，比值比 (OR) 为 4.9。同样，与具有该细胞因子低生产基因型的患者相比，TNF-α 高生产基因型与较高 ICED 评分、较低卡诺夫斯基指数和较低血清白蛋白的几率增加相关。相比之下，IL-10 高/中生产者基因型与卡诺夫斯基指数较高的几率增加相关（P = 0.05）。细胞因子基因型组合——TNF-α高生产者和IL-6高生产者基因型组合，以及IL-6高生产者和IL-10低生产者基因型组合与较高的ICED评分独立相关。这些基因型组合以及 TNF-α 高生产者和 IL-10 低生产者基因型组合也与较低的卡诺夫斯基指数相关。结论。在长期 HD 的 ESRD 患者中，促炎细胞因子 IL-6 和 TNF-α 以及调节单核因子 IL-10 启动子区域的单核苷酸多态性显示出与合并症和功能指数以及生物和营养标志物密切相关。
Background. Cytokine-orchestrated chronic inflammation plays a major role in long-term morbidity and mortality in patients with end-stage renal disease (ESRD) on hemodialysis (HD). In this cross-sectional study, we evaluated the association between specific alleles/genotypes and combinations of genotypes of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), and IL-10 with indices of comorbidity, functional status, and other biological markers in a cohort of 183 ESRD patients recruited to the Hemodialysis (HEMO) Study from two Boston centers.Methods. Genotyping was performed for single nucleotide polymorphisms in the promoter region of IL-6 (- 174 G --> C), TNF-alpha (- 308 G --> A), and IL-10 (-1082 G -->A). The relationship of specific genotypes to the index of coexistent disease (ICED) score (an index of comorbidity), Karnofsky Index (a measure of functional status), serum albumin, and nutritional indices (anthropometric measurements, body mass index, normalized protein catabolic ratio) were studied. Plasma IL-6 levels, as well as TNF-alpha and IL-10 production by endotoxin- stimulated peripheral blood mononuclear cells (PBMC), were also measured by enzyme-linked immunosorbent assay (ELISA).Results. Patients with the high producer genotypes for the proinflammatory cytokines IL-6 (G/G and G/C) and TNF-alpha (G/A and A/A) had significantly higher comorbidity (ICED scores of 2) and lower functional scores (Karnofsky Index) compared with patients with the low producer genotypes for these cytokines (C/C and G/G, respectively). In contrast, patients with the high and intermediate producer genotypes (G/G and G/A) for the anti-inflammatory cytokine IL-10 had a higher Karnofsky Index compared with those with the low producer genotype (A/A). Serum albumin levels were lower in patients with the TNF-alpha high producer genotype (G/A and A/A) compared with those with the low producer genotype (G/A and A/A). On multivariate analysis, the IL-6 high producer genotypes were associated with an odds ratio (OR) of 4.87 for higher comorbidity (ICED scores greater than or equal to2) (P = 0.02), and 4.9 for lower Karnofsky Index (lower functional status) (P = 0.04) compared with patients with the low IL-6 producer genotypes. Similarly, the TNF-alpha high producer genotype was associated with increased odds for a higher ICED score, lower Karnofsky Index, and lower serum albumin compared with patients with the low producer genotype for this cytokine. In contrast, the IL-10 high/intermediate producer genotype was associated with increased odds for a higher Karnofsky Index (P = 0.05). Cytokine genotype combinations-the TNF-alpha high producer and IL-6 high producer genotype combination, and the IL-6 high producer and IL-10 low producer genotype combination were independently associated with a higher ICED score. These genotype combinations, as well as the TNF-alpha high producer and IL-10 low producer genotype combination, were also associated with a lower Karnofsky Index.Conclusion. In ESRD patients on long-term HD, single nucleotide polymorphisms in the promoter region of the proinflammatory cytokines IL-6 and TNF-alpha, and the regulatory monokine IL-10, show a strong association with indices of comorbidity and function, and biological and nutritional markers.