Finnish Institute of Occupational Health, Topeliuksenkatu 41 a A, FI-00250, Helsinki, Finland.
BMC Pulm Med. 2013 Jun 4;13:36. doi: 10.1186/1471-2466-13-36.
The imbalance between proteases and antiproteases has been proposed to participate to the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. Gene level variation in different metalloproteinases, metalloproteinase inhibitors, and cytokines affecting them may contribute to this imbalance and destruction of the lung parenchyma. We investigated whether polymorphisms in selected protease-antiprotease balance pathway genes predispose to different emphysema subtypes (centrilobular, paraseptal, panlobular, and bullae) and airflow limitation among Finnish construction workers.
Eleven single nucleotide polymorphisms (SNPs) from seven genes (GC: rs7041 and rs4588; MMP1: rs1799750; MMP9: rs3918242; MMP12: rs652438; TIMP2: rs2277698; TNF: rs1799724 and rs1800629; TGFB1: rs1800469, rs1800470, and rs2241718) were analyzed from 951 clinically and radiologically characterized construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV₁), and maximal expiratory flow at 50% of FVC (MEF50) by using linear and logistic regression analyses, adjusted for potential confounders.
The TIMP2 rs2277698 SNP was associated with overall (p = 0.022) and paraseptal (p = 0.010) emphysema, as well as with FEV₁/FVC ratio (p = 0.035) and MEF50 (p = 0.008). The TGFB1 rs2241718 and MMP9 rs3918242 SNPs were associated with centrilobular emphysema (p = 0.022 and p = 0.008), and the TNF rs1800629 SNP with paraseptal emphysema (p = 0.017). In stratified analysis, individuals with at least one TIMP2 rs2277698 or TNF rs1800629 variant allele were found to be at around two-fold risk for pathological paraseptal changes (OR 1.94, 95% CI 1.14-3.30; OR 2.10, 95% CI 1.24-3.56). On the contrary, the risk for pathological centrilobular changes was halved for individuals with at least one MMP9 rs3918242 (OR 0.51, 95% CI 0.30-0.86) or TGFB1 rs2241718 (OR 0.53, 95% CI 0.30-0.90) variant allele, or TGFB1 rs1800469-rs1800470 AT-haplotype (OR 0.55, 95% CI 0.33-0.93). MEF50, in turn, was significantly reduced among individuals with at least one TIMP2 rs2277698 variant allele (p = 0.011).
Our findings strengthen the hypothesis of the importance of protease-antiprotease balance in pathogenesis of emphysema and shed light on the aetiology of different emphysema subtypes by associating MMP9 and TGFB1 to centrilobular emphysema, and TIMP2 and TNF to paraseptal emphysema and/or airflow obstruction.
蛋白酶与抗蛋白酶之间的失衡被认为参与了慢性阻塞性肺疾病（COPD）和肺气肿的发病机制。不同金属蛋白酶、金属蛋白酶抑制剂和影响它们的细胞因子的基因水平变化可能导致这种失衡和肺实质的破坏。我们研究了选择的蛋白酶-抗蛋白酶平衡途径基因中的多态性是否易患不同的肺气肿亚型（小叶中心型、小叶间隔型、全小叶型和大疱型）以及芬兰建筑工人的气流受限。
从七个基因（GC：rs7041 和 rs4588；MMP1：rs1799750；MMP9：rs3918242；MMP12：rs652438；TIMP2：rs2277698；TNF：rs1799724 和 rs1800629；TGFB1：rs1800469、rs1800470 和 rs2241718）中分析了 11 个单核苷酸多态性（SNP），这些 SNP 来自 951 名临床和放射学特征明确的建筑工人。使用线性和逻辑回归分析比较基因型和单倍型数据与高分辨率计算机断层扫描（HRCT）、用力肺活量（FVC）、一秒用力呼气量（FEV₁）和最大呼气流量的不同肺气肿迹象，调整潜在的混杂因素在 50%FVC（MEF50）处。
TIMP2 rs2277698 SNP 与总肺气肿（p=0.022）和小叶间隔型肺气肿（p=0.010），以及 FEV₁/FVC 比值（p=0.035）和 MEF50（p=0.008）相关。TGFB1 rs2241718 和 MMP9 rs3918242 SNP 与小叶中心型肺气肿相关（p=0.022 和 p=0.008），TNF rs1800629 SNP 与小叶间隔型肺气肿相关（p=0.017）。在分层分析中，发现至少有一种 TIMP2 rs2277698 或 TNF rs1800629 变异等位基因的个体发生病理性小叶间隔改变的风险约为两倍（OR 1.94，95%CI 1.14-3.30；OR 2.10，95%CI 1.24-3.56）。相反，对于至少有一种 MMP9 rs3918242 或 TGFB1 rs2241718 变异等位基因的个体，发生病理性小叶中心型改变的风险减半（OR 0.51，95%CI 0.30-0.86；OR 0.53，95%CI 0.30-0.90），或 TGFB1 rs1800469-rs1800470 AT 单倍型（OR 0.55，95%CI 0.33-0.93）。MEF50 也显著降低，在至少有一种 TIMP2 rs2277698 变异等位基因的个体中（p=0.011）。
我们的研究结果加强了蛋白酶-抗蛋白酶平衡在肺气肿发病机制中的重要性的假设，并通过将 MMP9 和 TGFB1 与小叶中心型肺气肿相关联，将 TIMP2 和 TNF 与小叶间隔型肺气肿和/或气流受限相关联，为不同肺气肿亚型的病因学提供了新的见解。
