Mossense Polymorphims in Matrix Metalloproteinase Genes and Skin Cancer Risk
Matrix metalloproteinases (MMP) degrade various components of the extracellular matrix, and their overexpression has been implicated in tumor progression. Nonsynonymous single nucleotide polymorphisms (SNPs) lead to amino acid substitutions that can alter the function of the encoded protein. We evaluated the associations of six nonsynonymous SNPs in the MMP3, MMP8, and MMP9 genes with skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 normal controls. We observed that the MMP9 Arg668Gln polymorphism was significantly associated with a decreased risk of SCC. Compared with the Arg/Arg group, the multivariate odds ratio was 0.67 (95% confidence interval, 0.47-0.97) for the Arg/Gln group and 0.21 (95% confidence interval, 0.05-0.97) for the Gln/Gln group (P(trend) = 0.004). We did not observe any association of this SNP with the risks of melanoma and basal cell carcinoma. No associations were found for other SNPs with skin cancer risk. This study provides evidence for the contribution of the MMP9 Arg668Gln to SCC development.
- [Show abstract] [Hide abstract] ABSTRACT: Extracellular matrix (ECM) abnormality is implicated in the pathogenesis of schizophrenia. Matrix metalloproteinases (MMPs) mediate the proteolysis of ECM and may play a crucial role in neuronal plasticity. We investigated whether single nucleotide polymorphisms (SNPs) of MMP1 and MMP8 are associated with the development of schizophrenia. We also assessed the relationships between MMP1, MMP8 SNPs and the core symptoms of schizophrenia such as persecutory delusion, auditory hallucinations, affective disturbances, and poor concentration according to the Operation Criteria Checklist for Psychotic Illness (OPCRIT). Three coding SNPs (rs470558, Ala216Ala in MMP1; rs3740938, Leu291Leu and rs1940475, Lys87Glu in MMP8) were selected, and 263 patients and 283 controls were evaluated. SNPStats was used to obtain the odds ratio (OR), 95% confidence intervals (CI), and P value adjusted for age and gender as covariables. Multiple logistic regression models (codominant1, codominant2, dominant, recessive, and log-additive) were employed to analyze genetic data. As a result, the three examined SNPs were not associated with the development of schizophrenia. In the analysis of clinical symptoms, the genotype frequency of rs470558 in MMP1 was associated with auditory hallucinations (P=0.04 in the codominant1 model, P=0.014 in the dominant1 model, and P=0.0066 in the log-additive model). The allele frequency of rs470558 also showed a significant difference between schizophrenia without auditory hallucinations [the auditory hallucination (−) group] and schizophrenia with auditory hallucinations [the auditory hallucination (+) group] (P=0.009, OR= 1.94, 95% CI=1.19-3.28). The A allele frequency of rs470558 was higher in the auditory hallucination (+) group (19.2%) than that in the auditory hallucination (−) group (10.8%). Two MMP8 SNPs (rs3740938 and rs1940475) were not associated with the development and core symptoms of schizophrenia, respectively. These results suggest that the A allele of rs470558 (Ala216Ala) in MMP1 may contribute to the susceptibility to auditory hallucinations of schizophrenia.
- [Show abstract] [Hide abstract] ABSTRACT: Matrix metalloproteinase 9 (MMP9) is func-tionally implicated in the process of infarct healing. Several genetic variation of the MMP9 gene have been described, among which the MMP9 Arg668Gln polymorphism. In the pres-ent study, we assessed whether this polymor-phism influences outcome after acute myocar-dial infarction (MI). One thousand forty-nine patients undergoing coronary angiography were genotyped for the MMP9 Arg668Gln poly-morphism by TaqMan allelic discrimination assay. This population included 154 controls, 161 patients with non ST-elevation MI (NSTE-MI), 504 patients with ST-elevation MI (STEMI), and 230 patients with angina. Frequency of the MMP9 Arg668Gln polymor-phism in the global population was 25.1%, and was comparable between all groups. STEMI patients had higher creatine phosphokinase (CPK), troponin T (TnT) and MMP9 plasma levels and had lower ejection fraction (EF) than NSTEMI patients. However, the polymor-phism was not associated with infarct severity as determined by peak CPK and TnT levels, nor with LV remodeling and outcome as assessed by 1-month EF and NYHA class, as well as 2-year mortality. In silico molecular modeling simulations predicted that the MMP9 polymor-phism may decrease MMP9 activity, but this could not be verified by plasma determina-tions. This study investigated for the first time the association between the MMP9 Arg668Gln polymorphism and clinical outcome after acute MI. Our results indicate that the polymorphism does not seem to be associated with clinical outcome and in particular with the develop-ment of left ventricular dysfunction and heart failure.
- [Show abstract] [Hide abstract] ABSTRACT: Matrix metalloproteinases (MMPs) are implicated in the development of cancers including malignant melanoma (MM) and breast cancer. We tested the possible association of MMP1 and MMP8 gene variation with these two types of cancer. We genotyped 300 unselected patients with MM, 300 consecutive breast cancer cases, 300 controls for melanoma, and 300 controls for breast cancer (age-matched and sex-matched healthy adults with negative cancer family histories). Our study showed that the MMP8 gene rs11225395 polymorphism was associated with the risk of developing MM (odds ratio: 1.69; 95% confidence interval: 1.02-2.80; P=0.040) for the A/A genotype and 1.49 (95% confidence interval: 1.03-2.17; P=0.035) for the A/G genotype compared with the G/G genotype. The A allele was over-represented among MM cases compared with controls (odds ratio=1.54; P=0.017). In-vitro assays showed that the A allele had a higher promoter activity than the G allele in melanoma cells. No association was detected between this variant and breast cancer susceptibility. We found no strong association between MMP1 variation and the risk of MM or breast cancer. The finding of this study indicates an influence of MMP8 gene variation on melanoma susceptibility.