Li Ping, Sanders Jules, Hawe Emma, Brull David, Montgomery Hugh, Humphries Steve
Cardiovascular Department, Second Affiliated Hospital of Jiangxi Medical College, Nanchang 330006, China.
Chin Med J (Engl). 2005 Aug 5;118(15):1285-90.
Heme-oxygenase 1 (HO-1) is a rate-limiting enzyme in the degradation of heme to bilirubin, ferritin and carbon monoxide (CO) and may have significant anti-inflammatory function. The HO-1 gene promoter region shows microsatellite polymorphism with different (GT)n repeats, reported to differently induce gene expression, with the short allele associated with higher gene expression. We measured the acute inflammatory response using coronary artery bypass surgery (CABG) as a well-characterized and uniform stimulus and examined the correlation between levels of IL-6, C-reactive protein (CRP) and fibrinogen and their relationship to HO-1 genotype.
Two hundred and seventy-five consecutive patients undergoing CABG were genotyped for the HO-1 promoter polymorphism using PCR and automated DNA capillary sequencer. IL-6, CRP and fibrinogen were measured at baseline and 6, 24, 48, 72, 96 and 120 hours after CABG.
Complete IL-6, CRP and fibrinogen measures were available in 220 patients. Before surgery IL-6 levels showed a strong correlation with CRP and fibrinogen (r = 0.48, P < 0.0001; r = 0.41, P < 0.0001 respectively), with a significant correlation between CRP and fibrinogen (r = 0.61, P < 0.0001). All three acute phase reactants showed a significant increase after CABG. After surgery, peak IL-6 was strongly correlated with peak CRP (r = 0.34, P = 0.0009) but not with peak fibrinogen (r = 0.15, P = 0.13), while peak CRP and peak fibrinogen were significantly correlated (r = 0.415, P < 0.0001). HO-1 allelic repeats ranged from 22-42, with (GT)25 and (GT)32 being the two most common alleles, and subsequently divided into three groups according to previous published work: <30 (GT)n were designated as S (short), 30-37 (GT)n as M (middle) and long repeats with >37 (GT)n as L (long); allele frequency 0.35, 0.58 and 0.07 respectively. Baseline CRP differed by genotype: those carrying at least one long allele having higher CRP than those with no long allele (3.76 +/- 0.79 vs. 2.07 +/- 0.17, P = 0.013). Conversely, those carrying at least one short allele had higher fibrinogen levels than those with no short allele (3.83 +/- 0.79 vs. 3.51 +/- 0.88, P = 0.006).
There is a strong correlation between the measured acute phase reactants both at baseline and after the inflammatory response to CABG in patients with coronary disease. There was an association between the HO-1 microsatellite polymorphism and CRP and fibrinogen levels at baseline but there was no similar association following CABG. This may indicate that HO-1 is associated with chronic atherosclerotic inflammatory processes rather than acute.
血红素加氧酶1（HO-1）是血红素降解为胆红素、铁蛋白和一氧化碳（CO）过程中的限速酶，可能具有显著的抗炎功能。HO-1基因启动子区域存在微卫星多态性，具有不同的（GT）n重复序列，据报道其可不同程度地诱导基因表达，短等位基因与较高的基因表达相关。我们以冠状动脉旁路移植术（CABG）作为一种特征明确且统一的刺激因素来测量急性炎症反应，并研究白细胞介素-6（IL-6）、C反应蛋白（CRP）和纤维蛋白原水平之间的相关性及其与HO-1基因型的关系。
对275例连续接受CABG的患者，使用聚合酶链反应（PCR）和自动DNA毛细管测序仪对HO-1启动子多态性进行基因分型。在基线以及CABG术后6、24、48、72、96和120小时测量IL-6、CRP和纤维蛋白原水平。
220例患者获得了完整的IL-6、CRP和纤维蛋白原测量数据。术前IL-6水平与CRP和纤维蛋白原呈强相关（分别为r = 0.48，P < 0.0001；r = 0.41，P < 0.0001），CRP与纤维蛋白原之间也存在显著相关性（r = 0.61，P < 0.0001）。所有三种急性期反应物在CABG术后均显著升高。术后，IL-6峰值与CRP峰值呈强相关（r = 0.34，P = 0.0009），但与纤维蛋白原峰值无相关性（r = 0.15，P = 0.13），而CRP峰值与纤维蛋白原峰值显著相关（r = 0.415，P < 0.0001）。HO-1等位基因重复序列范围为22 - 42，（GT）25和（GT）32是两个最常见的等位基因，随后根据先前发表的研究分为三组：<30（GT）n被指定为S（短），30 - 37（GT）n为M（中），>37（GT）n的长重复序列为L（长）；等位基因频率分别为0.35、0.58和0.07。基线CRP因基因型而异：携带至少一个长等位基因的患者CRP高于无长等位基因的患者（3.76±0.79 vs. 2.07±0.17，P = 0.013）。相反，携带至少一个短等位基因的患者纤维蛋白原水平高于无短等位基因的患者（3.83±0.79 vs. 3.51±0.88，P = 0.006）。
在冠心病患者中，基线时以及对CABG炎症反应后所测量的急性期反应物之间存在强相关性。HO-1微卫星多态性与基线时的CRP和纤维蛋白原水平相关，但CABG术后不存在类似关联。这可能表明HO-1与慢性动脉粥样硬化炎症过程而非急性炎症过程相关。
