Solute Carrier Transporters in Synovial Membrane and Hoffa's Pad of Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a complex autoimmune disease that leads to joint destruction. A number of immune cells that affect joint tissues are involved in the pathogenesis of this disease. This leads to the synthesis of many pro-inflammatory mediators. The transport of drugs, as well as many cytokines involved in the development of inflammation in RA patients, is mediated by membrane transporters. Membrane transporters are proteins that mediate the transfer of substrates across biological membranes. But to date there are no studies examining the expression of solute carrier (SLC) transporters in joint tissues. The aim of the study was to evaluate the expression of individual SLC family transporters in the synovial membranes (SMs) and infrapatellar fat pad (Hoffa's pad) of RA patients. The study included 20 patients with rheumatoid arthritis and 20 with osteoarthritis as the control group who were undergoing joint replacement surgery as a normal part of clinical care. In the SM and Hoffa's pad of RA patients the following 17 membrane transporters were defined at relevant expression levels for SLC transporter superfamily: SLC15A2, SLC16A3, SLC19A1, SLC2A9, SLC22A1, SLC22A3, SLC22A4, SLC22A5, SLC22A18, SLC33A1, SLC47A1, SLC51A, SLC7A5, SLC7A6, SLC01C1, SLC02B1, SLC04A1. The confirmed expression of these transporters in the SMs as well as Hoffa's pad of patients with RA and OA, and the differences in their expression between these groups, suggests the involvement of SLC transporters in both the maintenance of homeostasis under physiological conditions in the tissues of the joints, as well as in the inflammatory process in RA.

LPL rs264, PROCR rs867186 and PDGF rs974819 Gene Polymorphisms in Patients with Unstable Angina.

BACKGROUND: Coronary artery disease is caused by changes in the coronary arteries due to the atherosclerotic process and thrombotic changes. A very important role in the development of the atherosclerotic process in the coronary vessels is played by the inflammatory process and the immune response. Due to the important role of lipids and the coagulation process in the atherosclerotic process, research has also focused on genes affecting lipid metabolism and the coagulation system. Lipoprotein lipase (LPL) is an enzyme that metabolises lipids, hydrolysing triglycerides to produce free fatty acids and glycerol. Protein C (PC) is an essential component of coagulation and fibrinolysis. It is activated on the endothelial surface by the membrane-bound thrombin-thrombomodulin complex. Platelet-derived growth factor (PDGF) has a number of important functions in processes related to fibroblast and smooth muscle cell function. Due to their influence on lipid metabolism and coagulation processes, LPL, PROCR (endothelial cell protein C receptor) and PDGF may affect the atherosclerotic process and, thus, the risk of coronary heart disease. The aim of the study was to examine the associations between the LPL rs264, PROCR rs867186 and PDGF rs974819 gene polymorphisms and the risk of unstable angina and selected clinical parameters. METHODS: The study included 232 patients with unstable angina and 144 healthy subjects as the control group. Genotyping was performed using real-time PCR. RESULTS: There were no statistically significant differences in the distribution of the polymorphisms tested between the patients with unstable angina and the control subjects. The results showed associations between the PROCR rs867186 and PDGF rs974819 polymorphisms and some clinical parameters in patients with unstable angina. In patients with the PDGF rs974819 CC genotype, there were increased values for cholesterol and LDL serum levels in comparison with patients with the PDGF rs974819 CT and TT genotypes. In patients with the PROCR rs867186 AA genotype, HDL serum levels were lower than in patients with the GA genotype. CONCLUSIONS: The results of our study did not show that the LPL rs264, PROCR rs867186 and PDGF rs974819 gene polymorphisms were significant risk factors for unstable angina in our population. The results of the study suggest that PDGF rs974819 and PROCR rs867186 may be associated with some parameters of lipid metabolism.

Comparative Intra-Subject Analysis of Gene Expression and Protein Abundance of Major and Minor Drug Metabolizing Enzymes in Healthy Human Jejunum and Liver.

First pass metabolism by phase I and phase II enzymes in the intestines and liver is a major determinant of the oral bioavailability of many drugs. Several studies analyzed expressions of major drug-metabolizing enzymes (DMEs), such as CYP3A4 and UGT1A1 in the human gut and liver. However, there is still a lack of knowledge regarding other DMEs (i.e., "minor" DMEs), although several clinically relevant drugs are affected by those enzymes. Moreover, there is very limited intra-subject data on hepatic and intestinal expression levels of minor DMEs. To fill this gap of knowledge, we analyzed gene expression (quantitative real-time polymerase chain reaction) and protein abundance (targeted proteomics) of 24 clinically relevant DMEs, that is, carboxylesterases (CES), UDP-glucuronosyltransferases (UGT), and cytochrome P450 (CYP)-enzymes. We performed our analysis using jejunum and liver tissue specimens from the same 11 healthy organ donors (8 men and 3 women, aged 19-60 years). Protein amounts of all investigated DMEs, with the exception of CYP4A11, were detected in human liver samples. CES2, CYP2C18, CYP3A4, and UGT2B17 protein abundance was similar or even higher in the jejunum, and all other DMEs were found in higher amounts in the liver. Significant correlations between gene expression and protein levels were observed only for 2 of 15 jejunal, but 13 of 23 hepatic DMEs. Intestinal and hepatic protein amounts only significantly correlated for CYP3A4 and UGT1A3. Our results demonstrated a notable variability between the individuals, which was even higher in the intestines than in the liver. Our intrasubject analysis of DMEs in the jejunum and liver from healthy donors, may be useful for physiologically-based pharmacokinetic-based modeling and prediction in order to improve efficacy and safety of oral drug therapy.

Level of Disability after Total Hip Replacement in Patients with Some COMT Gene Polymorphism.

BACKGROUND: The COMT gene encodes the enzyme catechol-O-methyltransferase, which is a key modulator of dopaminergic and adrenergic neurotransmission. Hip osteoarthritis is accompanied by reduced mobility and some level of disability. In our study, we analyzed the association between some COMT gene polymorphisms and reduced mobility in patients after total hip replacement (THR). METHODS: The operative procedures were performed on 195 patients with symptomatic and radiologically advanced hip osteoarthritis. In the postoperative follow-up, we assessed hip function with the Harris Hip Score (HHS) and the degree of disability with the Oswestry Disability Index (ODI). These procedures were repeated three times at defined intervals (one week, six weeks, and six months) after the total hip replacement. Genomic DNA was extracted from peripheral blood. SNPs in the COMT genes rs4680:A>G, rs6269:A>G, rs4633:C>T, and rs4818:C>G were genotyped. RESULTS: Our findings suggest an association between COMT gene variability and the level of disability measured by the Oswestry Disability Index (ODI) in patients after total hip replacement (THR). CONCLUSIONS: A higher number of COMT G alleles (rs4818) is an independent factor in a significant reduction in disability degree at both one week and six months after total hip replacement (THR), regardless of age or gender.

Significance of Selected Environmental and Biological Factors on the Risk of FASD in Women Who Drink Alcohol during Pregnancy.

Prenatal alcohol exposure (PAE), which refers to alcohol consumption by pregnant women, is associated with the risk of numerous severe complications during fetal development. The State Agency for Alcohol Problem Solving reports that the incidence of fetal alcohol spectrum disorder (FASD) in Poland's general population is over 1.7%, and the incidence of fetal alcohol syndrome (FAS) is estimated at more than 0.5%. This study aimed to evaluate the significance of alcohol exposure and focused on the pattern of alcohol intoxication exhibited by the mother during pregnancy and other environmental factors of the maternal environment contributing to the development of FASD. The study covered 554 subjects, including 251 mothers and 303 children (213 girls and 90 boys). The mother's drinking problem was determined based on the information obtained from the case history. All children qualified for the study fulfilled the h-PAE (high alcohol exposure) criteria during their fetal life. The clinical diagnosis of FAS and pFAS (occurrence of morphological symptoms of fetal alcohol syndrome) was made using a four-digit diagnostic questionnaire validated in the Polish version of the Washington Questionnaire for the assessment of the spectrum of alcohol-related neurodevelopmental disorders or alcohol-related cognitive impairment (ARND/C). Statistical analysis of the obtained research results was developed using statistical software-STATISTICA PL, version 13.1 (StatSoft, Inc., Szczecin, Poland 2016, STATISTICA-data analysis software system, version 13.1). The most destructive drinking behaviors are compulsive intoxication (BD, binge drinking) during the first 6 weeks of pregnancy and chronic addiction throughout its duration (CHD, chronic drinking). Chronic alcohol intoxication (CHD) leads to a poorer nutritional status in mothers, which is reflected in a lower body mass index (BMI) (<18 kg/m2).

Leptin receptor gene polymorphisms in kidney transplant patients with post-transplant diabetes mellitus treated with tacrolimus.

Post-transplant diabetes mellitus (PTDM) is a metabolic complication that often occurs after kidney transplantation. Factors that increase the risk of this complication are currently being researched, including polymorphisms in genes affecting carbohydrate-lipid metabolism. Leptin is a hormone that affects appetite and adipose tissue and plays an important role in regulating insulin secretion as well as glucose and lipid metabolism. The aim of this study was to examine the association between leptin receptor gene polymorphisms and the development of post-transplant diabetes mellitus in patients treated with tacrolimus. The study was carried out in a group of 201 patients who underwent kidney transplantation. The follow-up period was 12 months. PTDM was diagnosed in 35 patients. Analysing the LEPR gene rs1137101 polymorphism, we observed in patients with PTDM an increased frequency of GG genotype carriers (GG vs AA, OR 3.36; 95 % CI 0.99-11.46; p = 0.04). There were no statistically significant differences in the distribution of the LEPR rs1137100 and LEPR rs1805094 polymorphisms between patients with and without PTDM. Multivariate regression analysis confirmed that female sex, advanced age, increased BMI and a higher number of LEPR rs1137101 G alleles were independent risk factors for PTDM development. The risk of PTDM development was almost 3.5 times greater in LEPR rs1137101 G allele carriers than in AA homozygotes (GG + AG vs AA; OR 3.48; 95 %CI (1.09-11.18), p = 0.035). The results suggest that patients after kidney transplantation with the LEPR gene rs1137101 G allele may have an increased risk of post-transplant diabetes development.

The Association between CDKAL1 Gene rs10946398 Polymorphism and Post-Transplant Diabetes in Kidney Allograft Recipients Treated with Tacrolimus.

Post-transplant diabetes mellitus (PTDM) is a common complication that occurs in kidney transplant patients, increasing the risk of infection, cardiovascular disease and loss of graft function. Currently, factors that increase the risk of this complication are being sought, among them polymorphisms in genes that regulate carbohydrate metabolism and influence pancreatic ß-cell function. The aim of this study was to evaluate the association of selected polymorphisms of genes affecting carbohydrate metabolism, such as CDKAL1 rs10946398, GCK rs1799884, GCKR rs780094 and DGKB/TMEM195 rs2191349, with the development of post-transplant diabetes in kidney transplant patients. This study included 201 Caucasian patients after kidney transplantation treated with tacrolimus. An association was observed between the CDKAL1 rs10946398 gene polymorphism and PTDM. Among patients with PTDM, there was an increased prevalence of the CC genotype in the PTDM group compared to the group without PTDM. The chance of PTDM in those with the CC genotype was 2.60 times higher compared to those with the AC + AA genotypes (CC vs. AC + AA OR (95% CI): 2.60 (1.02-6.61), p = 0.040). Multivariate logistic regression analysis showed that advanced age and the CC genotype (rare homozygote) of CDKAL1 rs10946398 were risk factors for the development of PTDM at 1 year after transplantation. There was no statistically significant association between GCK rs1799884, GCKR rs780094 or DGKB/TMEM195 rs2191349 polymorphisms and the development of post-transplant diabetes mellitus in kidney transplant patients. The results of this study suggest that the CDKAL1 rs10946398 CC genotype is associated with the increased risk of PTDM development in patients after kidney graft transplantation treated with tacrolimus.

ADH1B, ADH1B/C and CYP2E1 Gene Polymorphism and the Risk of Fetal Alcohol Spectrum Disorder.

Increasing alcohol consumption by women of childbearing age contributes to more frequent cases of fetal alcohol spectrum disorder. The cause of the syndrome is fetal alcohol exposure, particularly what is referred to as high prenatal alcohol exposure. Low metabolic activity of fetal enzymes shifts the burden of ethanol removal to maternal metabolism. One of the factors influencing the pathogenesis of FASD is the genetic background. It can determine the rate of elimination of ethanol, thus increasing or decreasing the time of fetal exposure to ethanol and also decreasing its concentration. Genetic polymorphisms could potentially play a significant role in these processes. In the present study, we considered three polymorphisms of genes implicated in the synthesis of enzymes involved in ethanol metabolism, i.e., ADH1b (rs1229984), ADH1b/c (rs1789891), and CYP2E1 (rs3813867). The studied group consisted of 303 children and 251 mothers. Both mothers' and children's genotypes were considered in our analysis. There were no statistically significant differences between the respective groups of genotypes of the studied polymorphisms. However, the genetic background of FASD is still elusive.

Genetic Risk Factors Related to Coronary Artery Disease and Role of Transforming Growth Factor Beta 1 Polymorphisms.

Coronary artery disease (CAD) is one of the leading causes of mortality globally and has long been known to be heritable; however, the specific genetic factors involved have yet to be identified. Recent advances have started to unravel the genetic architecture of this disease and set high expectations about the future use of novel susceptibility variants for its prevention, diagnosis, and treatment. In the past decade, there has been major progress in this area. New tools, like common variant association studies, genome-wide association studies, meta-analyses, and genetic risk scores, allow a better understanding of the genetic risk factors driving CAD. In recent years, researchers have conducted further studies that confirmed the role of numerous genetic factors in the development of CAD. These include genes that affect lipid and carbohydrate metabolism, regulate the function of the endothelium and vascular smooth muscles, influence the coagulation system, or affect the immune system. Many CAD-associated single-nucleotide polymorphisms have been identified, although many of their functions are largely unknown. The inflammatory process that occurs in the coronary vessels is very important in the development of CAD. One important mediator of inflammation is TGFß1. TGFß1 plays an important role in the processes leading to CAD, such as by stimulating macrophage and fibroblast chemotaxis, as well as increasing extracellular matrix synthesis. This review discusses the genetic risk factors related to the development of CAD, with a particular focus on polymorphisms of the transforming growth factor ß (TGFß) gene and its receptor.

The association between CYB5A gene rs1790834 polymorphism and clinical improvement after 6 months of leflunomide treatment in women with rheumatoid arthritis.

INTRODUCTION/OBJECTIVES: Rheumatoid arthritis (RA) is a disease affecting around 1% of the population in developed countries and can be treated with leflunomide. The higher prevalence of RA among women and numerous previous studies suggested the crucial role of sex hormones. Cytochrome CYB5A regulates the synthesis of androgens. Therefore, the aim of this study was to determine the association between common CYB5A gene polymorphism and the response to leflunomide in women with RA. METHODS: This study included 111 patients. All of them received oral leflunomide monotherapy at a dose of 20 mg daily. Women were genotyped for the presence of CYB5A rs1790834 polymorphism and evaluated monthly for 6 months following the initiation of treatment. RESULTS: After 6 months of therapy, patients with the GG genotype had higher DAS28 values and less improvement in DAS28 compared to patients with the GA and AA genotypes (p = 0.04). No statistically significant differences were found in relation to other disease activity parameters. CONCLUSIONS: The results of the current study suggest a possible association of the CYB5A rs1790834 polymorphism with some disease activity parameters in RA patients treated with leflunomide during the initial therapy period. However, confirmation of the effect of this polymorphism on the efficacy of leflunomide treatment requires further studies. Key Points • Leflunomide is the synthetic disease-modifying anti-rheumatic drug used in the therapy of rheumatoid arthritis. • CYB5A rs1790834 gene polymorphism may influence the clinical improvement after 6 months of leflunomide treatment in women with rheumatoid arthritis.

TGF-ß1 and TGFßR2 Gene Polymorphisms in Patients with Unstable Angina.

Acute coronary syndromes result from a sudden reduction in the lumen of a coronary artery as a result of atherosclerotic plaque rupture, its swelling or the formation of thrombotic lesions. Many mediators with inflammatory, prothrombotic and proatherogenic effects have been shown to be involved, including numerous cytokines, chemokines, adhesion molecules and growth factors. TGF-ß1 is a pleiotropic cytokine found in various cells that regulates cell growth, differentiation and matrix production. The aim of our study was to assess the association between polymorphisms in the TGF-ß1 gene (rs1800469, rs1800470) and polymorphisms in the TGFBR2 receptor gene (rs6785358, rs9838682) and the risk of unstable angina, as well as selected clinical parameters affecting the risk of ischemic heart disease. The study included 232 patients with unstable angina. The diagnosis of unstable angina was made by typical clinical presentation and confirmation of significant coronary artery lumen stenosis (>70%) during coronary angiography. There were no statistically significant differences in the distribution of TGFBR2 rs6785358 and rs9838682 genotypes and haplotypes between patients with unstable angina and control subjects. We observed increased values of plasma total and LDL cholesterol levels, as well as triglycerides, in patients with the TGFBR2 rs9838682 AA genotype. In patients with the TGFBR2 rs6785358 AA genotype, we noted increased BMI values. There were no statistically significant associations between other studied polymorphisms and clinical parameters. Polymorphisms in the TGF-ß1 gene (rs1800469, rs1800470) and polymorphisms in the TGFBR2 receptor gene (rs6785358, rs9838682) are not significant risk factors for unstable angina in our population. The TGFBR2 gene rs9838682 polymorphism may influence the lipid parameters in patients with coronary artery disease.

Analysis of selected genetic variants in psoriasis susceptibility and response to treatment.

Introduction: Aetiology of psoriasis is complex with risk factors involving both environmental triggers and genetic background. Although the best characterized genetic risk factor for psoriasis is HLA-C*06 allele, a number of other variants were associated with the disease. Aim: In the current paper we have conducted a confirmation study for SNPs located in 9 gene regions in a case-control analysis of 507 psoriatic patients and 396 controls from the Polish population. Material and methods: Subsequently the impact of genetic variants on response to topical and NB-UVB therapy (reduction in the Psoriasis Area and Severity Index) was analysed. Results: Significant differences in genotype and/or allelic frequency were observed for the following SNPs: rs33980500 (TRAF3IP2), rs582757 (TNFAIP3I), rs12188300 (IL12B), rs28998802 (NOS2), and rs2233278 (TNIP1). None of the genetic factors was associated with treatment outcome. Conclusions: Although the genetic variants have an impact on the disease risk, they are unlikely to be useful in personalization of topical therapy.

IL-18 Gene rs187238 and rs1946518 Polymorphisms and Expression in Gingival Tissue in Patients with Periodontitis.

Periodontitis is a chronic disease with disturbed balance between the immune and inflammatory response of the host to bacteria. Many studies have shown that proinflammatory cytokines play a significant role in the pathogenesis of periodontal disease. In this study, we examined the association between the IL-18 gene rs187238 and rs1946518 polymorphisms and periodontitis in non-smoking and smoking patients. This study enrolled 200 patients with periodontitis (130 non-smokers and 70 smokers) and 156 control subjects (124 non-smokers and 32 smokers). There were no statistically significant differences in the distribution of the rs187238 and rs1946518 IL-18 genotypes and alleles between patients with periodontitis and control subjects, between smoking patients with periodontitis and smoking control subjects, and between non-smoking patients with periodontitis and non-smoking control subjects. There were no statistically significant differences in clinical parameters in relation to the IL18 rs187238 genotypes. In patients with the IL18 rs1946518 GG genotype, we observed increased values of bleeding on probing (BoP) and periodontal probing depth (PPD), compared to subjects with the TT genotype. In patients with periodontitis, we observed statistically significant decreased expression of the IL-18 gene in comparison with healthy subjects (0.231 ± 0.163 vs. 0.663 ± 0.197, p = 0.0008). In addition, the IL-18 gene expression in gingival tissue in patients with periodontitis correlated positively with the number of remaining teeth. The results of our study suggest that the IL-18 rs187238 and rs1946518 polymorphisms are not significant risk indicators of periodontitis in our population. However, in patients with the IL18 rs1946518 GG genotype, we observed increased values of BoP and PPD, compared to subjects with the TT genotype. In addition, in gingival tissue of patients with periodontitis, we have detected decreased expression of IL-18. The gingival expression of IL-18 in patients with periodontitis correlated positively with number of remaining teeth. The above results suggest that IL-18, in addition to its pro-inflammatory effects in periodontal disease, may also exhibit protective properties.

SELL and GUCY1A1 Gene Polymorphisms in Patients with Unstable Angina.

Acute ischaemia is mostly caused by the rupture of an unstable atherosclerotic plaque in a coronary artery, resulting in platelet accumulation and thrombus formation, which closes the lumen of the coronary vessel. Many different factors can cause atherosclerotic plaques to occlude the lumen of a coronary artery, including factors that increase vascular inflammation and blood platelet aggregation, as well as genetic factors. L-selectin is an adhesion molecule encoded by the human SELL gene, playing an important role in leukocyte adhesion to the endothelium and the development of inflammation. Guanylate cyclase 1 soluble subunit alpha 1 (GUCY1A1) is a gene that affects vasoreactivity and platelet function, thereby influencing thrombotic processes and the risk of developing thrombotic lesions in the coronary vessels. In SELL and GUCY1A1 genes, several polymorphisms have been detected, which may affect gene expression. The aim of our study was to assess the association between the SELL rs2205849 and rs2229569 and GUCY1A1 rs7692387 polymorphisms with the risk of acute coronary syndromes in the form of unstable angina pectoris, and the association between these polymorphisms and selected clinical parameters affecting the risk of developing ischemic heart disease. The study included 232 patients with unstable angina. The diagnosis of unstable angina was achieved by a typical clinical presentation and confirmation of significant coronary artery lumen stenosis (>70%) during coronary angiography. There were no statistically significant differences in GUCY1A1 rs7692387 and SELL rs2205849 and rs2229569 polymorphism distribution between the total study and the control groups. However, when only analysing patients over 55 years of age, we found a decreased frequency of the GUCY1A1 rs7692387AA genotype (AA vs. GA + GG, OR: 0.07; 95% CI: 0.01−0.78) and an increased frequency of the SELL rs2205849 CC genotype (CC vs. TC + TT p = 0.022) and SELL rs2229569 AA genotype (AA vs. GA + GG p = 0.022) in patients with unstable angina. Our results suggest that the SELL rs2205849 and rs2229569 and GUCY1A1 rs7692387 polymorphisms are not risk factors for unstable angina in the Polish population. The GUCY1A1 rs7692387 polymorphism may increase the risk of unstable angina in patients younger than 55 years, while the SELL polymorphisms rs2205849 and rs2229569 may increase the risk of unstable angina in patients older than 55 years in the Polish population.

COBLL1 and IRS1 Gene Polymorphisms and Placental Expression in Women with Gestational Diabetes.

Gestational diabetes mellitus (GDM) is carbohydrate intolerance in pregnant women leading to various complications. Currently, there is a search for factors predisposing to GDM. Among them are genetic polymorphisms of genes involved in insulin secretion as well as carbohydrate metabolism. Due to the similar pathogenesis of GDM to type 2 diabetes (T2DM), genetic polymorphisms associated with T2DM are considered. The aim of this study was to examine the associations between the COBLL1 rs7607980 T > C and IRS1 rs2943641 T > C gene polymorphisms and the risk of GDM as well as selected clinical parameters in women with GDM. Additionally, we examined the expression of these genes in the placenta of women with and without GDM in correlation with selected clinical parameters. This study included 328 pregnant women with normal glucose tolerance (NGT) and 251 pregnant women with GDM diagnosed on the basis of a 75 g oral glucose tolerance test (OGTT) at 24−28 weeks gestation. There were no statistically significant differences in the distribution of IRS1 rs2943641 gene polymorphisms between women with GDM and pregnant women with NGT. In the GDM group, we observed a decreased frequency of COBLL1 rs7607980 CC homozygous women (CC vs. TC+TT, p = 0.048); however, there was no statistically significant difference in the frequency of alleles between women with GDM and the control group. There were no statistically significant associations between COBLL1 rs7607980 gene polymorphism and clinical parameters in women with GDM. In GDM women with the IRS1 rs2943641 TT genotype, fasting glucose levels were significantly higher than in women with CC and TC genotypes. There was no statistically significant difference in the expression of COBLL1 and IRS1 genes in the placenta between women with GDM and healthy women. There were no statistically significant correlations between COBLL1 gene expression in the placenta and clinical parameters. The expression of IRS1 correlated significantly with an increase in BMI during pregnancy. The results of this study suggest that COBLL1 rs7607980 and IRS1 rs2943641 gene polymorphisms are not significant risk factors for GDM in our population. The IRS1 TT genotype may be associated with higher fasting glucose levels in women with GDM. Expression of the IRS1 gene in the placenta positively correlates with an increase in BMI during pregnancy in women with GDM.

KCNJ11 and KCNQ1 Gene Polymorphisms and Placental Expression in Women with Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) represents carbohydrate intolerance in pregnant women. The pathogenesis of GDM is very complex, but abnormalities in insulin production and secretion underlie the disease. Potassium channels play an important role in insulin production and secretion. The family of potassium channels includes (among others) the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) and voltage-gated K+ channel (KCNQ1). The aim of the study was to examine the distribution of the KCNJ11 rs5219 and KCNQ1 rs151290 and rs2237892 gene polymorphisms in women with GDM and pregnant women with normal carbohydrate tolerance, to verify whether these polymorphisms are risk factors for GDM. This study included 204 Caucasian pregnant women with GDM and 207 pregnant women with normal glucose tolerance (NGT) from the West Pomeranian region of Poland. The diagnosis of GDM was based on a 75 g oral glucose tolerance test (OGTT) at 24-28 weeks gestation. There were no statistically significant differences in distribution of the KCNJ11 rs5219 and KCNQ1 rs151290 and rs2237892 gene polymorphisms between women with GDM and pregnant women with normal carbohydrate tolerance. Moreover, there were no statistically significant associations between the studied genotypes and the selected clinical parameters in women with GDM. The results of our study suggest that the KCNJ11 rs5219 and KCNQ1 rs2237892 and rs151290 gene polymorphisms are not significant risk factors associated with the development of GDM in our population. There were also no differences in the expression of KCNJ11 and KCNQ1 genes in the placenta of women with GDM and normal carbohydrate tolerance. However, an association between KCNJ11 gene expression in placenta and APGAR score in newborns was found.

Membrane Transporters and Carriers in Human Seminal Vesicles.

Seminal vesicles play an important role in the male reproductive system, producing seminal fluid and thus adequate environment for sperm. However, mechanisms underlying secretory functions of the seminal vesicles' epithelium have not been defined yet. The aim of the present study was to characterize expression and immunolocalization of selected membrane transporters and carriers in the seminal vesicles. The study included biopsy specimens collected from non-affected parts of seminal vesicles from 53 patients of Caucasian origin subjected for prostatectomy. RT-PCR was used to define expression of 15 genes coding for ABC-family and 37 genes encoding 37 SLC-family transporters/carriers. Immunohistochemistry was used to define localization of 6 transporters. In the seminal vesicles, the following membrane transporters and carriers were defined: ABCA1, ABCB1, ABCB5, ABCB6, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCG2, SLC01C1, SLC02B1, SLC04A1, SLC04C1, SLC10A1, SLC15A1, SLC15A2, SLC16A1, SLC16A3, SLC19A1, SLC22A1, SLC22A3, SLC22A11, SLC22A18, SLC22A4, SLC22A5, SLC28A1, SLC2A9, SLC33A1, SLC47A1, SLC47A2, SLC51A, SLC51B, SLC7A5, SLC7A6. Age-dependent expression was evidenced for ABCB1, ABCG2, SLC04C1, SLC15A1, SLC16A1, SLC22A11, SLC22A18, SLC47A1 and SLC47A2. ABCG2, P-gp, MRP1, MRP3, MCT1 and LAT1 were localized in the apical membrane and P-gp in the basolateral membrane of the seminal vesicle epithelium. The expression of the membrane transporters and carriers in the seminal vesicle epithelium confirms its secretory and barrier functions.

Influence of COMT (rs4680) and DRD2 (rs1076560, rs1800497) Gene Polymorphisms on Safety and Efficacy of Methylphenidate Treatment in Children with Fetal Alcohol Spectrum Disorders.

Fetal alcohol spectrum disorders (FASD) in a course of high prenatal alcohol exposure (hPAE) are among the most common causes of developmental disorders. The main reason for pharmacological treatment of FASD children is attention deficit hyperactivity disorder (ADHD), and methylphenidate (MPH) is the drug of choice. The aim of the study was to assess whether children born of hPAE with ADHD, with or without morphological FASD, differ in terms of catechol-O-methyltransferase (COMT) and dopamine receptor D2 (DRD2) gene polymorphisms, and if genetic predisposition affects response and safety of MPH treatment. The polymorphisms of COMT (rs4680) and DRD2 (rs1076560, rs1800497) were analyzed in DNA samples. A borderline significance was found for the correlation between MPH side effects and the G allele of COMT (rs4680) (p = 0.04994) in all ADHD children. No effect of COMT (rs4680) and DRD2 (rs1076560, rs1800497) polymorphisms and the treatment efficacy was observed. The analyzed DRD2 and COMT gene polymorphisms seem to play no role in MPH efficacy in ADHD children with hPAE, while low-activity COMT (Met158) variant carriers may be more intolerant to MPH. The MPH treatment is effective in ADHD independent of FASD, although the ADHD-FASD variant requires higher doses to be successful. These results may help in optimization and individualization in child psychiatry.

PPARG, TMEM163, UBE2E2, and WFS1 Gene Polymorphisms Are Not Significant Risk Factors for Gestational Diabetes in the Polish Population.

Gestational diabetes mellitus (GDM) is a common disorder that occurs in pregnant women, leading to many maternal and neonatal complications. The pathogenesis of GDM is complex and includes risk factors, such as: age, obesity, and family history of diabetes. Studies have shown that genetic factors also play a role in the pathogenesis of GDM. The present study investigated whether polymorphisms in the PPARG (rs1801282), TMEM163 (rs6723108 and rs998451), UBE2E2 (rs6780569), and WFS1 (rs4689388) genes are risk factors for the development of GDM and whether they affect selected clinical parameters in women with GDM. This study included 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance (NGT). The diagnosis of GDM was based on a 75 g oral glucose tolerance test (OGTT) at 24-28 weeks gestation, according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. There were no statistically significant differences in the distribution of polymorphisms studied between women with GDM and pregnant women with normal carbohydrate tolerance, which suggests that these polymorphisms are not risk factors for GDM. We also examined the associations between studied gene polymorphisms and clinical parameters: fasting glucose, daily insulin requirement, body mass before pregnancy, body mass at birth, body mass increase during pregnancy, BMI before pregnancy, BMI at birth, BMI increase during pregnancy, new-born body mass, and APGAR score in women with GDM. We observed lower BMI values before pregnancy and at birth in women with PPARG rs17036160 TT genotype. The results of this study suggest that the PPARG (rs1801282), TMEM163 (rs6723108 and rs998451), UBE2E2 (rs6780569), and WFS1 (rs4689388) gene polymorphisms are not significant risk factors for GDM development in the Polish population and do not affect the clinical parameters in women with GDM; only rs1801282 of the PPARG gene may influence BMI values in women with GDM.

PECAM1, COL4A2, PHACTR1, and LMOD1 Gene Polymorphisms in Patients with Unstable Angina.

Coronary artery disease (CAD) is a syndrome resulting from myocardial ischaemia of heterogeneous pathomechanism. Environmental and genetic factors contribute to its development. Atherosclerotic plaques that significantly narrow the lumen of coronary arteries cause symptoms of myocardial ischaemia. Acute coronary incidents are most often associated with plaque rupture or erosion accompanied by local activation of the coagulation system with thrombus formation. Plaque formation and stability are influenced by endothelial function and vascular smooth muscle cell function. In this study, we investigated the association between polymorphisms in genes affecting endothelial and vascular smooth muscle cell (VSMC) function and the occurrence of unstable angina pectoris. The aim of this study was to evaluate the association between the PECAM1 (rs1867624), COL4A2 (rs4773144), PHACTR1 (rs9349379) and LMOD1 (rs2820315) gene polymorphisms and the risk of unstable angina. The study included 232 patients with unstable angina diagnosed on the basis of clinical symptoms and coronary angiography and 144 healthy subjects with no significant coronary lumen stenosis at coronary angiography. There were no statistically significant differences in the distribution of COL4A2 rs4773144 and PECAM1 rs1867624 gene polymorphisms between patients with unstable angina and control subjects. In patients with unstable angina, there was an increased frequency of PHACTR1 rs9349379 G allele carriers (GG and AG genotypes) (GG+AG vs. AA, OR 1.71; 95% CI 1.10-2.66, p = 0.017) and carriers of the LMOD1 rs2820315 T allele (TT and CT genotypes) (TT+CT vs. CC, OR 1.65; 95% CI 1.09-2.51, p = 0.019) compared to the control group. The association between these alleles and unstable angina was confirmed by multivariate logistic regression analysis, in which the number of G (PHACTR1 rs9349379) and T (LMOD1 rs2820315) alleles was an independent risk factor for unstable angina. The results suggest an association between PHACTR1 rs9349379 and LMOD1 rs2820315 polymorphisms and the risk of unstable angina.