Tanya Tacheva

Investigation of the role of MMP3 -1171insA polymorphism in cutaneous malignant melanoma – a preliminary study

Coetaneous malignant melanoma is the most aggressive cancer of the skin with a high rate of mortality worldwide. Degradation of basement membranes and extracellular matrix is an essential step in cancer invasion and metastasis. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play key roles in this step. MMP-3 also called stromelysin-1 was one of the first proteinases found to be associated with cancer. In the gene of MMP-3 (MMP3), an insertion/deletion of an A nucleotide at position -1171 in promoter region has been identified and shown to effect the expression activity of the gene. The present study was conducted to investigate the relation of MMP3 -1171insA polymorphism with skin malignant melanoma risk in a pilot case-control study of Bulgarian patients (n = 26) and unaffected controls (n = 172). The genotypes of controls and melanoma patients were in Hardy-Weinberg equilibrium. The results showed no statistically significant difference both in genotype and allele frequencies of MMP3 -1171insA polymorphism between melanoma patients and healthy controls either in crude analyses (p = 0.360 and 0.790, c2-test) or after adjustment for age and sex. The comparison of some clinical characteristics between the patients with different genotypes showed a trend for longer survival of patients with 6A/6A genotype compared to the carriers of 5A allele (5A/5A+5A/6A genotypes, p = 0.118, Log rank test). The results of our current preliminary study do not provide evidence for the role of the promoter polymorphism -1171insA in MMP3 as a risk factor for development of coetaneous melanoma, but suggest its implication in progression of the diseases.

Obesity in Bulgarian patients with chronic obstructive pulmonary disease

It has been well defined that obesity is strongly linked with several respiratory symptoms and diseases, but no convincing evidence has been provided for chronic obstructive pulmonary disease (COPD). In the current study, we aim to assess the possible prevalence of obesity in patients with COPD in a cross-sectional case–control study of individuals from the region of Stara Zagora, Bulgaria, and to explore whether the body mass has some effect on the lung function of COPD patients. The study included 158 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) II, III, and IV stages) and 123 individuals unaffected by the disease (control). A higher frequency of obesity compared to the controls (20.3%) was observed in patients with COPD (29.1%, p = 0.093), especially in those with GOLD II stage (37.7%, p = 0.009). Prevalence of obesity was highest in COPD GOLD II, followed by GOLD III and IV stages (p = 0.068). When diabetes was considered as confounding factor, we found a significant prevalence of obesity in COPD patients than the controls with diabetes (p = 0.031). Interestingly, there was a statistically significant moderate positive correlation between the body mass index and forced expiratory volume in one second as a percentage of predicted value in the whole patients’ group (R = 0.295, p = 0.0002) as well as in the subgroups of GOLD II (R = 0.257, p = 0.024) and GOLD III COPD (R = 0.259, p = 0.031).The results of our study propose that the increased body mass, particularly obesity is frequent comorbidity to COPD, especially to less severe diseases. Moreover, the results suggest that the higher body weight may provide some protection against the impairment of lung functions in patients with stable COPD.

MMP12 -82 A>G Promoter Polymorphism in Bronchial Asthma in a Population of Central Bulgaria

A characteristic feature of inflamed lungs in bronchial asthma (BA) is airway remodeling. Due to limited information on this topic in the literature, we aimed to explore the possible role of polymorphisms in the promoter region of the macrophage elastase gene MMP12 82A>G (rs2276109) as a predisposing factor for BA in an ethnic Bulgarian population. Using restriction fragment length polymorphism analysis of polymerase chain reaction-amplified fragments (PCR-RFLP), we performed genotype analysis of 58 patients and 119 control individuals. We found statistically significant differences in the distribution of genotypes (P = .008) and alleles (P = .004) between patients and nonaffected controls. In the dominant model, carriers of the G allele genotypes had 3.6-fold lower risk for BA, compared with those with the AA genotype, after adjustment for age and sex (odds ratio [OR], -0.277; 95% confidence interval [CI], .12-.65; P = .003). The results of our study suggest that the variant G allele of the MMP12 -82 A>G promoter polymorphism might be considered protective for development of BA in ethnic Bulgarian adults residing in central Bulgaria.

Effects of common functional MMP12 gene polymorphisms on PD in a Polish population

The present study investigated associations of two functional MMP12 polymorphisms with PD risk and cognitive impairment in PD. A total of 478 study subjects (241 PD and 237 age and sex matched controls) were included in the study. UPDRS score, Hoehn-Yahr staging and Schwab-England scale were used to assess motor abilities and activity during daily life. All patients were classified into groups with dementia (PDD, n=72) and without dementia (nPDD, n=159) based on the neuropsychological assessment. The two most common functional single nucleotide polymorphisms (SNPs) in MMP12 gene were determined using TaqMan real-time PCR assays. Frequencies of evaluated MMP12 rs2276109 alleles and genotypes were similar in PD and the controls, whereas rs652438G allele genotypes were significantly more frequent among healthy individuals (p=0.013, OR 0.47 (0.26-0.85). The rs2276109 and rs652438 allele and genotype frequencies were not associated with dementia in PD patients. The current results suggest that MMP12 rs652438 but not MMP12 rs2276109 may affect the risk for PD, as the minor G allele genotypes might be a protective factor.

The G allele of MMP12 -82 A > G promoter polymorphism as a protective factor for COPD in Bulgarian population

Abstract Chronic inflammation and remodelling of the small airways are features related to chronic obstructive pulmonary disease (COPD). In the current study, we aimed to explore the possible role of MMP12 -82 A > G (rs2276109) promoter polymorphism in the development of COPD in a population from Bulgaria (167 patients with COPD and 119 control individuals). The genotype and allele distributions differed significantly between COPD patients and controls (p = .010 and p = .043, respectively, χ2 test). The genotypes containing at least one variant G allele (AA + GG) were more frequent in the control group than in patients (36.1% vs. 22.2%) determining 2.96-fold lower risk for COPD after adjustment for age, sex and smoking habits (OR = 0.338, 95%CI: 0.168–0.682, p = .002). Our results suggest that carriers of genotypes with at least one copy of minor G allele of rs2276109 might have lower risk for COPD development, with no marked effect on the lung function and severity of the disease.

Frequency of the common promoter polymorphism MMP2 -1306 C>T in a population from central Bulgaria.

Matrix metalloproteinases (MMPs) are a family of highly homologous extracellular Zn2+-dependent endopeptidases, also known as matrixins. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are considered to play a key role in a variety of physiological processes as well as in the development and progression of a vast majority of pathological conditions. Most of the genes encoding MMPs, including MMP-2, are highly polymorphic. One of the single nucleotide polymorphisms with functional activity in the promoter region of MMP2 is the transition MMP2 −1306C>T (rs243865). The aim of the present study was to evaluate the genotype and allele frequencies of the common promoter polymorphism −1306C>T in MMP2 in 75 individuals from central Bulgaria and to compare our results with those of other population studies. We found that 76.0% of the randomly enrolled individuals are carriers of the CC genotype, 17.3% of CT, and 6.7% of the TT genotype. The minor allele frequency (MAF) was 15.3%. Interestingly, the obtained genotype frequencies appeared to differ from those of some other Caucasian populations (USA – 55/38/7, MAF 26%; The Netherlands – 52.8/40.5/6.7, MAF 26.9%; Austria – 55.6/35.5/8.9, MAF 27.2%), but were closer to the values of the reported global genotype distribution (75.3/21.3/3.4, MAF 14%).