Association Of Single Nucleotide Polymorphisms In The MMP-12 And MMP-13 Genes With Lung Cancer

Objective: Matrix metalloproteinases (MMPs) are a family of highly conserved zinc-dependent proteolytic enzymescould, which play important roles in tumor development, invasion and metastasis by degradating the extracellular matrix (ECM) and basement membrane (BM), and facilitating angiogenesis. MMP-12 and MMP-13 as two of the MMPs family, Growing evidences indicate that single nucleotide polymorphisms (SNPs) of MMP-12 and MMP-13 genes may alter protein expression levels by regulating transcription activity to influence malignant tumors development and progression. The aim of our study was to investigate the association of MMP-12 -82A/G and MMP-13 -77A/G SNPs with the susceptibility and lymphatic metastasis of Lung Cancer of Han nationality in Northern, China.Methods: This case-control study included 420 Lung cancer patients and 419 healthy controls. Patients with histologically confirmed lung cancer were recruited between September 2005 and September 2009, at the Department of Respiratory, Fourth Hospital, Hebei Medical University. All Patients had never undergone radiotherapy or chemotherapy before venous blood of empty stomath was drawn. The controls were selected from cancer-free individuals who conducted medical check-up in Fourth Hospital, Hebei Medical University in the same period. Genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. MMP-12 -82A/G and MMP-13 -77A/G SNPs were genotyped by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis.Statistical analysis was performed using SPSS13.0 software package (SPSS Company, Chicago, Illinois, USA). Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in study groups using Chi-square test. The t test was used to examine the difference of ages between cases and controls. Comparison of the genotype and allelotype distributions in the two groups was performed by means of two-sided contingency tables using Chi-square test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model. The MMP-12 -82A/G, MMP-13 -77A/G haplotype frequencies and linkage disequilibrium coefficient were estimated by using EH linkage software and 2LD software. P<0.05 was considered significant for all statistical analyses.Results:1 The frequency of the three genotypes (A/A, A/G, and G/G) of MMP-12 -82 A/G in patients and controls were 96.2%, 3.8%, 0 and 95.2%, 4.8%, 0, respectively. There was no significant difference between the two groups (P=0.491); the frequency of A, G alleles of the MMP-12 -82A/G SNP in cases was not different from that in healthy controls(P=0.496). Compared to the A/A genotype, A/G genotype did not significantly modify the risk of lung cancer(OR=0.760, 95%CI=0.385~1.501). The MMP-12 -82A/G was not associated with the risk of lung cancer when stratified by histological subtypes.2 The frequency of the three genotypes (G/G, A/G, and A/A) of MMP-13 -77A/G in patients and controls were 25.7%, 49.3%, 25% and 24.1%, 54.2%, 21.7% , respectively. There was no significant difference between the two groups (P=0.340); the frequency of A, G alleles of the MMP-13 -77A/G SNP in cases was not different from that in healthy controls (P=0.732). Compared to the G/G genotype, A/G and A/A genotypes did not significantly modify the risk of lung cancer(OR=0.890, 95%CI=0.637~1.244 and OR=1.100, 95%CI=0.741~1.632 ). The MMP-13 -77A/G was not associated with the risk of lung cancer when stratified by histological subtypes.3 The proportion of smokers in lung cancer patients (47.6%) was significantly different from that in healthy controls (35.3%)(P =0.000).4 No significant difference was observed between MMP-12 -82A/G and MMP-13 -77A/G polymorphisms and the risk of lung cancer when stratified by smoking status.5 No significant difference was observed in the frequencies of the MMP-12 -82A/G and MMP-13 -77A/G genotypes between lymphatic metastasis and non-lymphatic metastasis(P=0.586 and P=0.362). There might be no association between MMP-12 -82A/G and MMP-13 -77A/G polymorphisms and lymphatic metastasis in lung cancer patients(OR=0.702, 95%CI=0.196~2.512 and OR=0.794, 95%CI=0.484~1.304).6 The results of the 2LD program analysis showed that the MMP-12 -82A/G and MMP-13 -77A/G polymorphisms displayed linkage disequilibrium(D′=0.049).Conclusions:1 The MMP-12 -82A/G and MMP-13 -77A/G SNPs may have no susceptibility to the lung cancer of Han nationality in Northern, China.2 The MMP-12 -82A/G and MMP-13 -77A/G were not associated with the risk of lung cancer when stratified by histological subtypes.3 Neither MMP-12 -82A/G nor MMP-13 -77A/G were associated with the risk of lung cancer when stratified by smoking status.4 Neither MMP-12 -82A/G nor MMP-13 -77A/G were associated with lymphatic metastasis of lung cancer.5 The MMP-12 -82A/G and MMP-13 -77A/G polymorphisms displayed linkage disequilibrium.