Rasa Liutkeviciene

The Role of Matrix Metalloproteinases Polymorphisms in Age-Related Macular Degeneration

Abstract Background: Matrix metalloproteinases (MMP) are responsible for the degradation of extracellular matrix components and play an important role in the physiological and pathological remodeling of tissues. Purpose: To assess the impact of MMP-2 Rs2285053 (C –> T), MMP-3 Rs3025039 (5A –> 6A), and MMP-9 Rs3918242 (C –> T) single nucleotide polymorphism on the development of early age-related macular degeneration (AMD). Methods: The study group comprised 148 patients with AMD, and the control group enrolled 526 randomly selected persons. The genotyping of MMP-3 Rs3025039, MMP-2 Rs2285053, and MMP-9 Rs3918242 was performed by using the real-time PCR method. Results: The frequency of the MMP-2 (−735) C/T and MMP-3 (−1171) 5A/6A genotypes did not differ significantly between the patients with AMD and the control group, while the MMP-9 (−1562) C/C genotype was more frequently detected in patients with AMD than the control group (73.7% vs. 64.6%, p = 0.048). Logistic regression analysis showed that the MMP-9 (−1562) C/C genotype increased the likelihood of developing early AMD (OR = 1.51, 95% CI: 1.01–2.21; p = 0.046). After the subdivision into the groups by age, a significant difference only in the frequency of the MMP-9 (−1562) C/C genotype was found comparing the AMD patients and the control group younger than 65 years (79.7% vs. 66.4%, p = 0.039). Conclusions: Only MMP-9 Rs3918242 (C –> T) single nucleotide polymorphism was found to play a significant role in the development of AMD, and the effect was more pronounced at the age of less than 65 years.

Early Age-Related Macular Degeneration in Patients with Myocardial Infarction

Purpose: To investigate the prevalence of early age-related macular degeneration (AMD) in patients with acute myocardial infarction (MI). Methods: Enrolled in the study were 262 acute MI patients (MI group), aged 40–64 years, as well as 1,155 non-MI persons, aged 40–64 years, from a random sample (reference group) of the Kaunas population. Results: The prevalence of early AMD in the random sample was 7.3%, while in MI patients, the prevalence was 54.5% (P < 0.001). For all age groups, the prevalence of early AMD was significantly (P < 0.005) higher in MI patients than in reference-group persons. In the reference group, the prevalence of early AMD increased significantly with age, whereas no such trend was observed in the MI group. At the 45- to 54-year-olds, the prevalence was significantly higher in males than in females (9.9% vs. 3.7%; P < 0.05) in the reference group, while overall, the prevalence of early AMD in the males and females of the much larger reference group was 8.6% versus 6.2%, respectively (P > 0.05). It increased more with age for females (3.7% and 10.8% at the age 45–54 and 55–64 years, P < 0.05, respectively) while in males, frequency of AMD did not differ significantly between latter age groups (9.9% vs. 11.6%; P > 0.05). Conclusions: We conclude that the prevalence of early AMD is significantly higher in patients with MI than in a random sample of the population.

Associations of cholesteryl ester transfer protein (CETP) gene variants with predisposition to age-related macular degeneration

PURPOSE To determine the frequency of the genotypes of single nucleotide polymorphisms (SNPs) in the gene encoding cholesteryl ester transfer protein (CETP) and their associations with age-related macular degeneration (AMD) in the Lithuanian population. STUDY DESIGN A total of 1264 subjects were examined: 251 patients with early AMD, 206 patients with exudative AMD, and 807 healthy controls. METHODS The genotyping of CETP (rs5882, rs708272, rs3764261, rs1800775, rs2303790) was carried out using the RT-PCR. RESULTS Binomial logistic regression analysis revealed that each copy of rs5882 allele A was associated with a 1.3-fold increased risk of exudative AMD (p=0.046). The G/A and A/A genotypes of the rs708272 polymorphism were associated with 1.5-fold and 1.7-fold increased risks of exudative AMD (p=0.049 and p=0.021, respectively). Combination of two genotypes (G/A+A/A) under the dominant model were associated with a 1.5-fold increased risk of exudative AMD (p=0.021). Analysis of rs708272 revealed that the G/A and A/A genotypes under the co-dominant model were associated with 1.5-fold and 1.7-fold increased risks of exudative AMD, respectively (OR=1.450, 95% CI=1.002-2.098; p=0.049 and OR=1.710, 95% CI=1.064-2.156; p=0.021, respectively). Both genotypes (G/A+A/A) under the dominant model were associated with the 1.5-fold increased risk of exudative AMD, as well (OR=1.514, 95% CI=1.064-2.156; p=0.021) and each additional copy A allele was associated with a 1.3-fold increased risk of exudative AMD (OR=1.316, 95% CI=1.051-1.646; p=0.016). The rs3764261 polymorphism was identified to be protective: the C/A genotype and the combination of two genotypes (C/A+A/A) were associated with 1.8-fold and 1.5-fold decreased risks of exudative AMD (p=0.001 and p=0.015, respectively). CONCLUSION Our study identified two polymorphisms with a higher risk of AMD development (rs5882 and rs708272) and a protective polymorphism for AMD (rs3764261).

Role of MMP-2 (-1306 C/T) Polymorphism in Pituitary Adenoma

Purpose. To determine if the frequency of the genotype of MMP-2 (-1306 C/T) Rs243865 has an influence on the development of pituitary adenoma (PA). Methods. The study enrolled n = 84 patients with PA and a random sample of the population n = 318 (reference group). The genotyping test of MMP-2 (-1306 C/T) was carried out using the real-time polymerase chain reaction method. Results. Analysis of MMP-2 (-1306 C/T) gene polymorphism has not revealed any differences in the genotype (C/C, C/T, and T/T) distribution between the PA patients and the reference group (as follows: 50%, 44%, and 6% versus 59.75%, 33.96%, and 6.29%). MMP-2 (-1306) C/C genotype was rarely observed in noninvasive PA compared to healthy controls: 35.1% versus 59.75%; p = 0.0049, as well C/C genotype being more frequently detected in nonrecurrence PA compared to healthy controls: 46.5% versus 59.75%; p = 0.0468. MMP-2 (-1306) C/T genotype was more frequently present in PA females compared to healthy controls females: 49.1% versus 33.66%; p = 0.041. Conclusion. Patients with noninvasive and nonrecurrence pituitary adenoma were the carriers of the C/C genotype significantly more frequently than their control counterparts and the C/T genotype in females was more frequent.

Associations between Rs4244285 and Rs762551 gene polymorphisms and age-related macular degeneration.

ABSTRACT Background: Age-related macular degeneration is the leading cause of blindness in elderly individuals in developed countries. The etiology and pathophysiology of age-related macular degeneration have not been elucidated yet. Knowing that the main pathological change of age-related macular degeneration is formation of drusen containing about 40% of lipids, there have been attempts to find associations between age-related macular degeneration and genes controlling lipid metabolism. Purpose: To determine the frequency of CYP2C19 (G681A) Rs4244285 and CYP1A2 (-163C>A) Rs762551 genotypes in patients with age-related macular degeneration. Methods: The study enrolled 150 patients with early age-related macular degeneration and 296 age- and gender-matched healthy controls. The genotyping of Rs4244285 and Rs762551 was carried out by using the real-time polymerase chain reaction method. Results: The CYP1A2 (-163C>A) Rs762551 C/C genotype was more frequently detected in patients with age-related macular degeneration than in the control group (32.7% vs. 21.6%, p = 0.011) and was associated with an increased risk of developing early age-related macular degeneration (OR = 1.759, 95% CI: 1.133–2.729; p = 0.012). The CYP1A2 (-163C>A) Rs762551 C/A genotype was more frequently documented in the control group compared with patients with age-related macular degeneration (46.3% vs. 30.7%, p = 0.002) and was associated with a decreased risk of having age-related macular degeneration (OR = 0.580. 95% CI: 0.362–0.929, p = 0.023) in the co-dominant model. Conclusion: The study showed that the CYP1A2 (-163C>A) Rs762551 C/C genotype was associated with an increased risk of age-related macular degeneration.

N-myc downstream-regulated gene 2 ( NDRG2 ) promoter methylation and expression in pituitary adenoma

BackgroundPituitary adenoma (PA) is a benign primary tumor that arises from the pituitary gland and is associated with ophthalmological, neurological and endocrinological abnormalities. However, causes that increase tumor progressing recurrence and invasiveness are still undetermined. Several studies have shown N-myc downstream regulated gene 2 (NDRG2) as a tumor suppressor gene, but the role of NDRG2 gene in pituitary adenoma pathogenesis has not been elucidated. The aim of our research has been to examine NDRG2 mRNA expression in PA and to determine the associations between the NDRG2 gene epigenetic changes and the development of recurrence or invasiveness of PA and patient clinical data.MethodsThe MS-PCR was used for NDRG2 promoter methylation analysis and gene mRNA expression levels were evaluated by qRT-PCR in 68 non-functioning and 73 functioning adenomas. Invasiveness was evaluated using magnetic resonance imaging with Hardy’s modified criteria. Statistical analysis was performed to find correlations between NDRG2 gene mRNA expression, promoter methylation and patient clinical characteristics and PA activity.ResultsThe NDRG2 mRNA expression was significantly lower in the case of acromegaly (GH and IGF-1 hypersecretion) than in other diagnoses of PAs (p < 0.05). Also, the NDRG2 expression was significantly higher in prolactinoma (PRL hypersecretion) than in in other diagnoses of PAs (p < 0.05). The promoter of NDRG2 was methylated in 22.69% (12/58 functioning and 15/61 non-functioning) of patients with PA. However, the NDRG2 gene mRNA expression was not significantly related to its methylation status. Clinical factors, such as: age, gender, relapse and diagnoses of Cushing syndrome were of no significance for NDRG2 promoter methylation and mRNA expression levels, as well as secreting or non-secreting PAs and the invasiveness of PAs.ConclusionThe different NDRG2 promoter methylation and expression levels in PA samples showed tumor heterogeneity and indicates a potential role of this gene in pituitary adenoma pathogenesis, but the corresponding details require intensive research.

Role of MMP-2 (-1306 C/T) Polymorphism in Age-Related Macular Degeneration.

Abstract Purpose: To determine if the frequency of the MMP-2 (-1306 C/T) genotype has an influence on the development of early age-related macular degeneration (AMD). Methodology: The study enrolled 387 patients with early AMD and a random sample of 682 healthy persons (control group). The genotyping of MMP-2 (-1306 C/T) was carried out using the real-time polymerase chain reaction method. Results: The analysis of the MMP-2 (-1306 C/T) gene polymorphism did not reveal any differences in the genotype distribution between the patients with AMD and the control subjects. When the study population was divided into age groups, the C/C genotype was more prevalent in the AMD patients aged <65 years than those aged ≥65 years (65.19% versus 53.88%, p = 0.0294), and the C/T genotype was more frequent in the AMD patients aged ≥65 years when compared with the AMD patients aged <65 years (40.78% versus 26.52%, p = 0.0037). Moreover, in the female group younger than 65 years, the frequency of the C/C genotype was greater in the AMD group than the control group (75% versus 58.91%, p = 0.0232). Conclusions: This study showed a significantly greater prevalence of the C/C and C/T genotypes in the patients with AMD younger than 65 years and those aged ≥65 years, respectively. Moreover, the AMD women aged <65 years were the carriers of the C/C genotype significantly more frequently than their control counterparts.

Best vitelliform macular dystrophy: literature review

Best vitelliform macular dystrophy (BVD) is a slowly progressive form of macular dystrophy. In most cases this disease begins in childhood although sometimes it can develop in later age. The diagnosis of BVD is based on family history, clinical and electrophysiological findings. Clinical signs are variable, yet the majority of patients have a typical yellow yolk-like macular lesion in the eye fundus. Lesions are usually bilateral, but in rare cases can be unilateral. Atrophy of the macula may develop after many years. The mutations responsible for Best vitelliform macular dystrophy are found in a gene called VMD2, which encodes a transmembrane protein named bestrophin-1 (hBest1) that is a Ca2+-sensitive chloride channel. Most reported cases causing the disease are in exons 2, 4, 6 and 8 in patients with BVD. In this article we discuss the etiology of Best’s vitelliform macular dystrophy, clinical presentation, diagnostics, genetic and current treatment possibilities.

The association of matrix metalloproteinases polymorphisms and interleukins in advanced age-related macular degeneration

ABSTRACT Purpose: To assess the impact of matrix metalloproteinase (MMP)1-1607 1G/2G (rs1799750), MMP7-181 A/G (rs11568818) single-nucleotide polymorphism and systemic cytokins interleukin-1 beta (IL-1β), IL-6 levels on the development of exudative age-related macular degeneration (eAMD) Methodology: The study group comprised 282 patients with eAMD, and the control group enrolled 379 randomly selected persons. The genotyping of MMP1-1607 (rs1799750) and MMP7-181 (rs11568818) was performed by using the polymerase chain reaction-based restriction fragment length polymorphism method. To determine IL-1β and IL-6 serum levels, the immunoenzymatic method with monoclonal antibodies coated plates was performed. Results: MMP1 rs1799750 1G/2G genotype was more frequently found in the development of eAMD. It was associated with a 4.3-fold increased risk for eAMD under the codominant model and a 4.9-fold increased risk for eAMD under the overdominant model. The effect was more pronounced at the age of less than 65 years. IL-1β concentration was significantly higher for MMP1 rs1799750 1G/1G genotype and MMP7 rs11568818 A/G genotype in eAMD patients compared with control group subjects. Conclusions: MMP1 rs1799750 1G/2G genotype was found to play a significant role in the development of eAMD at the age of less than 65 years. IL-1β concentration was significantly higher in eAMD patients for MMP1 rs1799750 1G/1G genotype and MMP7 rs11568818 A/G genotype compared with control group subjects.

The role of apolipoprotein E (rs7412 and rs429358) in age-related macular degeneration

ABSTRACT Background: Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in the developed countries. The main pathological change in AMD is the formation of drusen containing 40% of lipids, dominated by esterified cholesterol (EC) and phosphatidylcholine (PC), and protein. Haplotype ε4 of apolipoprotein E (ApoE) acts as a ligand for the low-density lipoprotein receptor and is involved in the maintenance and repair of neuronal cell membranes. Purpose: This study aimed to evaluate the association of AMD with ApoE gene polymorphism variants (rs7412 and rs429358). Methodology: A total of 2133 subjects were enrolled in our research. The study group comprised patients with early AMD (n = 413) and exudative AMD (n = 307), and the control group enrolled randomly selected persons (n = 1413). The genotyping of ApoE (rs7412 and rs429358) was performed using the real-time polymerase chain reaction (PCR) method. Results: Statistical analysis revealed that ApoE 4/2 genotype was less frequently observed in in older patients with exudative AMD compared to older healthy controls (0.4% vs. 4.0%, p = 0.003). Conclusion: Our data demonstrated that ApoE 4/2 genotype was less frequently observed in old patients (65 years and more) with exudative AMD compared to old healthy controls. It leads to hypothesis on the protective effect of ApoE 4/2 to develop AMD in the elderly.