Effect of heme oxygenase-1 polymorphisms on lung function and gene expression.
Effect of heme oxygenase-1 polymorphisms on lung function and gene expression.
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DOI：
10.1186/1471-2350-12-117
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发表时间：
2011-09-08
影响因子：
--
通讯作者：
Sandford AJ
中科院分区：
文献类型：
--
作者：
Tanaka G;Aminuddin F;Akhabir L;He JQ;Shumansky K;Connett JE;Anthonisen NR;Abboud RT;Paré PD;Sandford AJ
吸烟引起的氧化应激被认为在慢性阻塞性肺疾病(COPD)的发病机制中起重要作用。血红素加氧酶-1(Hmox1)是氧化应激诱导的血红素分解代谢过程中的一种重要酶，在肺内可能起到抗氧化剂的保护作用。我们确定Hmox1基因多态是否与COPD患者的肺功能相关，以及这些变异是否具有功能效应。我们在NHLBI肺健康研究中从吸烟者中挑选出FEV1%下降最快(n=278)和最慢(n=304)的高加索人中，对Hmox1基因中的5个单核苷酸多态(SNPs)进行了基因分型。这些SNPs也在基线肺功能最低(n=)或最高(n=533)的高加索人中进行了研究。构建了含有3个Hmox1启动子多态性的报告基因，并检测了这些多态性对过氧化氢和氯化高铁血红素刺激基因表达的影响。研究Hmox1rs2071749单核苷酸对肺泡巨噬细胞基因表达的影响。我们发现在一个内含子Hmox1SNP(Rs2071749)和肺功能下降之间存在名义上的关联(p=0.015)，但这种关联在多次比较中没有得到纠正。该SNP与Hmox1启动子上的rs3761439处于完全连锁不平衡状态。我们在报告基因分析中检测了rs3761439和另外两个假定的功能多态(rs2071746和(GT)n多态)，但没有发现对基因表达有显著影响。Rs2071749对肺泡巨噬细胞Hmox1基因表达也无影响。我们没有发现五个Hmox1标签SNP与肺功能下降相关，也没有证据表明这三个启动子多态影响Hmox1基因的调节。
Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects. We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1 % predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2 and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated. We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)n polymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages. We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.
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影响因子：
4
作者：
Guenegou, A.;Leynaert, B.;Aubier, M.
通讯作者：
Aubier, M.
影响因子：
5.8
作者：
Cartharius, K;Frech, K;Werner, T
通讯作者：
Werner, T
影响因子：
1.8
作者：
Burkett, K;McNeney, B;Graham, J
通讯作者：
Graham, J
DOI：
10.1073/pnas.94.20.10925
发表时间：
1997-09-30
影响因子：
11.1
作者：
Poss, KD;Tonegawa, S
通讯作者：
Tonegawa, S
影响因子：
5.3
作者：
Ono, K;Goto, Y;Iwai, N
通讯作者：
Iwai, N