Oxidative stress and neuroinflammation are involved in the pathogenesis of alcohol addiction. However, little is known regarding the effect of genetic, behavioral, psychological, and environmental ...sources of origin on the inflammation and oxidative stress pathways of patients with alcohol addiction. Our study aimed to evaluate the impact of selected common functional single-nucleotide polymorphisms in inflammation and oxidative stress genes on alcohol addiction, and common comorbid psychosymptomatology. Our study included 89 hospitalized alcohol-addicted patients and 93 healthy individuals, all Slovenian males. Their DNA was isolated from peripheral blood and patients were genotyped for
rs705379, rs705381, rs854560, and rs662,
rs4880,
rs1050450,
rs1143623, rs16944, and rs1071676,
rs1800795,
rs2228145, and miR146a rs2910164. Kruskal-Wallis and Mann-Whitney tests were used for the additive and dominant genetic models, respectively. Our findings suggested the involvement of
rs1800795 in alcohol addiction. Moreover, our data indicated that the genetic variability of
and
, as well as
and
may be related to comorbid psychosymptomatology, revealing a potential indirect means of association of both the oxidative stress and inflammation pathways.
Background. It is generally accepted that poor glycemic control, arterial hypertension and/or hyperlipidemia, and the associated oxidative stress may contribute to the development of macro- and ...microvascular complications in type 2 diabetes (T2D). Such metabolic damage signals may activate inflammasome and trigger chronic inflammation. We investigated common polymorphisms in inflammasome coding genes and the risk for macro- and microvascular complications in T2D. Methods. In total 181 clinically well-characterised T2D patients were genotyped for NLRP3 rs35829419 and CARD8 rs2043211. Risk for diabetic complications was assessed using logistic regression. Results. Patients with median duration of T2D 11 (6–17) years had relatively well controlled blood glucose and lipid levels and blood pressure on the prescribed treatment regimen. Duration of T2D and plasma cholesterol levels were the most important clinical risk factors for macrovascular complications ( P = 0.007 and P = 0.031 ). NLRP3 rs35829419 was associated with increased risk for macrovascular complications ( P = 0.004 ), with myocardial infarction in particular ( P = 0.052 ). No association was observed between CARD8 polymorphism and any of T2D complications. Conclusions. Our preliminary data suggest the role of NLRP3 polymorphism in diabetic macrovascular complications, especially in myocardial infarction.
Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but nevertheless 30% of patients experience MTX inefficacy. Our aim was to develop a clinical pharmacogenetic model to ...predict which RA patients will not respond to MTX monotherapy. We also assessed whether this model can be generalized to other populations by validating it on a group of Serbian RA patients.
In 110 RA Slovenian patients, data on clinical factors and 34 polymorphisms in MTX pathway were analyzed by Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression to select variables associated with the disease activity as measured by Disease Activity Score (DAS28) score after 6 months of MTX monotherapy. A clinical pharmacogenetic index was constructed from penalized regression coefficients with absolute value above 0.05. This index was cross-validated and also independently validated on 133 Serbian RA patients.
A clinical pharmacogenetic index for prediction of DAS28 after 6 months of MTX monotherapy in Slovenian RA patients consisted of DAS28 score at diagnosis, presence of erosions, MTX dose, Solute Carrier Family 19 Member 1 (
) rs1051266, Solute Carrier Organic Anion Transporter Family Member 1B1 (
) rs2306283, Thymidylate Synthase (
), and Adenosine Monophosphate Deaminase 1 (
) rs17602729. It correctly classified 69% of Slovenian patients as responders or nonresponders and explained 30% of variability in DAS28 after 6 months of MTX monotherapy. Testing for validity in another population showed that it classified correctly only 22.5% of Serbian RA patients.
We developed a clinical pharmacogenetic model for DAS28 after 6 months of MTX monotherapy in Slovenian RA patients by combining clinical and genetic variables. The clinical pharmacogenetic index developed for Slovenian patients did not perform well on Serbian patients, presumably due to the differences in patients' characteristics and clinical management between the two groups.
We investigated two functional polymorphisms in NLRP3 inflammasome genes (
rs35829419 and
rs2043211) and their association with alcohol dependence and related anxiety, depression, ...obsession-compulsion, or aggression in 88 hospitalised alcohol-dependent patients, 99 abstinent alcohol-dependent participants, and 94 controls, all male Caucasian. Alcohol dependence-related psychiatric disorders were assessed with the Zung Depression and Anxiety scale, Buss-Durkee Hostility Inventory, Alcohol Use Disorders Identification Test, Brief Social Phobia Scale, Obsessive Compulsive Drinking Scale, and Yale-Brown Obsessive-Compulsive Scale. For genotyping we used the allele-specific quantitative polymerase chain reaction-based methods. The three groups differed significantly in
rs2043211 distribution (P=0.049; chi-squared=9.557; df=4). The
rs35829419 polymorphism was not significantly associated with alcohol dependence. In hospitalised alcohol-dependent patients the investigated polymorphisms were not associated with scores indicating alcohol consumption or comorbid symptoms. In abstinent alcohol-dependent subjects homozygotes for the polymorphic
allele presented with the highest scores on the Zung Anxiety Scale (p=0.048; df=2; F=3.140). Among controls,
genotype was associated with high scores on the Obsessive Compulsive Drinking Scale (P=0.027; df=2; F=3.744). In conclusion, our results reveal that
rs2043211 may play some role in susceptibility to alcohol dependence, expression of anxiety symptoms in abstinent alcohol-dependent subjects, and in obsessive compulsive drinking in healthy controls. However, further studies with larger cohorts are required to confirm these preliminary findings.
Metformin plays a consolidated role in the management of polycystic ovary syndrome (PCOS). However, there is no clear answer on how long we should treat and on how long its beneficial impact sustain ...after we stop treatment. We compared the effects of metformin withdrawal after long-term (LT) and short term (ST) treatment in PCOS women that had previously well responded to metformin.
We conducted observational longitudinal study including 44 PCOS women (31 (28-36) years and BMI 32.5 (27.7-34.9) kg/m
) that were followed for 6 months after metformin withdrawal. Prior inclusion, ST group had been treated with metformin on average for 1.03 ± 0.13 year, LT group for 5.07 ± 2.52 years. We followed anthropometric, metabolic, reproductive parameters and eating behavior as assessed by TFEQ-R18.
After metformin withdrawal, ST group gained significant amount of weight (from 92 (75.5-107.3) kg to 96 (76-116) kg; p = 0.019). Weight tended to increase also in LT users (from 87 (75-103) to 87 (73-105) kg; p = 0.058). More women in LT group maintained stable weight (27% in LT group vs 15% in ST group). Eating behavior deteriorated in both groups. Withdrawal of metformin resulted in a decrease of menstrual frequency (6 (6-6) to 6 (4-6) menstrual bleeds per 6 months; p = 0.027) and in borderline increase of androstenedione (6.4 (4.6-7.6) to 7.8 (4.8-9.6) nmol/L; p = 0.053) in LT group. Waist circumference, HOMA and glucose homeostasis remained stable in both groups. There were no differences between groups at 6-month follow up.
Collectively, present study implies some metabolic and endocrine treatment legacy in both groups as well as some group-specific deteriorations in clinical parameters 6 months after metformin withdrawal.
The study is registered at Clinical Trials with reference No. NCT04566718.
The serotonergic system is important in Parkinson's disease (PD) pathogenesis as it can take over dopamine production after a large portion of dopaminergic neurons is lost through neurodegeneration. ...The aim of this study was to evaluate the effect of genetic variability of serotonergic genes on the occurrence of motor complications and psychiatric adverse events (AE) due to dopaminergic treatment. We enrolled 231 patients and their clinical data were collected. Genotyping was performed for eight genetic variants. Logistic regression was used for analysis. Carriers of the
rs6295 GC genotype (OR = 2.58; 95% CI = 1.15-5.78;
= 0.021),
rs4290270 AA genotype (OR = 2.78; 95% CI = 1.08-7.03;
= 0.034), and at least one
rs4570625 T allele (OR = 1.86; 95% CI = 1.00-3.44;
= 0.047) had increased risk for visual hallucinations (VH). Additionally, carriers of at least one
rs25531 S (OR = 0.52; 95% CI = 0.28-0.96;
= 0.037) or at least one L
allele (OR = 0.37; 95% CI = 0.14-0.97;
= 0.044) had a decreased chance for VH. Constructed haplotypes of the
showed increased risk for VH (OR = 1.94; 95% CI = 1.06-3.55;
= 0.032) and impulse control disorders (OR = 5.20; 95% CI = 1.86-14.50;
= 0.002). Finally, individual gene-gene interactions showed decreased odds for the development of motor AE. Our findings suggest that the serotonergic pathway may play an important role in the development of AE resulting from dopaminergic treatment.
This study investigated the association between certain genetic variations and the risk of developing proliferative vitreoretinopathy (PVR) after surgery. The study was conducted on 192 patients with ...primary rhegmatogenous retinal detachment (RRD) who underwent 3-port pars plana vitrectomy (PPV). The distribution of single nucleotide polymorphisms (SNPs) located in genes involved in inflammation and oxidative stress associated with PVR pathways were analyzed among patients with and without postoperative PVR grade C1 or higher. A total of 7 defined SNPs of 5 genes were selected for genotyping: rs4880 (
); rs1001179 (
); rs1050450 (
); rs1143623, rs16944, rs1071676 (
); rs2910164 (
) using competitive allele-specific polymerase chain reaction. The association of SNPs with PVR risk was evaluated using logistic regression. Furthermore, the possible association of SNPs with postoperative clinical parameters was evaluated using non-parametric tests. The difference between two genotype frequencies between patients with or without PVR grade C1 or higher was found to be statistically significant:
rs4880 and
rs1071676. Carriers of at least one polymorphic
rs1071676 GG allele appeared to have better postoperative best-corrected visual acuity only in patients without PVR (
= 0.070). Our study suggests that certain genetic variations may play a role in the development of PVR after surgery. These findings may have important implications for identifying patients at higher risk for PVR and developing new treatments.
Oxidative stress and neuroinflammation are involved in the pathogenesis and progression of glaucoma. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in inflammation and ...oxidative stress genes on the risk of glaucoma, the patients' clinical characteristics and the glaucoma phenotype. In total, 307 patients with primary open-angle glaucoma or ocular hypertension were enrolled. The control group included 339 healthy Slovenian blood donors. DNA was isolated from peripheral blood. Genotyping was performed for
rs4880,
rs1001179,
rs1050450,
rs1695,
gene deletion,
1 gene deletion,
rs1143623,
rs16944,
rs1800795 and
rs1800629. We found a nominally significant association of
gene deletion with decreased risk of ocular hypertension and a protective role of
rs16944 and
rs1800629 in the risk of glaucoma. The CT and TT genotypes of
rs1050450 were significantly associated with advanced disease, lower intraocular pressure and a larger vertical cup-disc ratio. In conclusion, genetic variability in
and
may be associated with glaucoma risk, while
and
may be associated with the glaucoma phenotype. In the future, improved knowledge of these pathways has the potential for new strategies and personalised treatment of glaucoma.
Background. Malignant pleural mesothelioma (MPM) is a rare disease with a relatively short overall survival (OS). Metalloproteinases (MMPs) have a vast biological effect on tumor progression, ...invasion, metastasis formation, and apoptosis. MMP expression was previously associated with survival in MPM. Our aim was to evaluate if genetic variability of MMP genes could also serve as a prognostic biomarker in MPM. Methods. We genotyped 199 MPM patients for ten polymorphisms: rs243865, rs243849 and rs7201, in MMP2; rs17576, rs17577, rs20544, and rs2250889 in MMP9; and rs1042703, rs1042704, and rs743257 in MMP14. We determined the influence on survival using Cox regression. Results. Carriers of polymorphic MMP9 rs2250889 allele had shorter time to progression (TTP) (6.07 versus 10.03 months, HR = 2.45, 95% CI = 1.45–4.14, p=0.001) and OS (9.23 versus 19.2 months, HR = 2.39, 95% CI = 1.37–4.18, p=0.002). In contrast, carriers of at least one polymorphic MMP9 rs20544 allele had longer TTP (10.93 versus 9.40 months, HR = 0.57, 95% CI = 0.38–0.86 p=0.007) and OS (20.67 versus 13.50 months, HR = 0.56, 95% CI = 0.37–0.85, p=0.007). MMP14 rs1042703 was associated with nominally shorter TTP (8.7 versus 9.27 months, HR = 2.09, 95% CI = 1.06–4.12, p=0.032). Conclusions. Selected MMP SNPs were associated with survival and could be used as potential genetic biomarkers in MPM.
Extracellular vesicle‐bound DNA (evDNA) is an understudied extracellular vesicle (EV) cargo, particularly in cancer‐unrelated research. Although evDNA has been detected in urine, little is known ...about its characteristics, localization, and biomarker potential for kidney pathologies. To address this, we enriched EVs from urine of well‐characterized kidney transplant recipients undergoing allograft biopsy, characterized their evDNA and its association to allograft injury. The SEC‐based method enriched pure EVs from urine of kidney transplant recipients, regardless of the allograft injury. Urinary evDNA represented up to 29.2 ± 8% (mean ± SD) of cell‐free DNA (cfDNA) and correlated with cfDNA in several characteristics but was less fragmented (P < 0.001). Importantly, using DNase treatment and immunogold labelling TEM, we demonstrated that evDNA was bound to the surface of urinary EVs. Normalised evDNA yield (P = 0.042) and evDNA copy number (P = 0.027) significantly differed between patients with normal histology, rejection injury and non‐rejection injury, the later groups having significantly larger uEVs (mean diameter, P = 0.045) and more DNA bound per uEV. ddDNA is detectable in uEV samples of kidney allograft recipients, but its quantity is highly variable. In a proof‐of‐principle study, several evDNA characteristics correlated with clinical and histological parameters (P = 0.040), supporting that the potential of evDNA as a biomarker for kidney allograft injury should be further investigated.
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