The role of genetic risk factors, diet, and gut microbiota in type 1 diabetes mellitus, pancreas and pancreatic islet transplantation.

Despite advances in insulin delivery and glucose monitoring technology, prevention of the progression of secondary complications in patients with type 1 diabetes (T1DM) remains a challenge. Beta cell replacement therapy in the form of islet or pancreas transplantation can restore long-term normoglycaemia with sustained periods of insulin independence among T1DM patients. However, the same genetic, behavioural, or gut microbiota-related factors that promoted autoimmunity and primary islet destruction may also affect the function of transplanted islets and the ultimate results of transplant procedures. In such cases, identifying genetic risk factors and modifying behavioural factors and those related to gut microbiota may be beneficial for the outcomes of transplant procedures. Herein, we review related literature to the identified current gap in knowledge to be addressed in future clinical trials.

Up-regulated mRNA expression of VEGFA receptors (FLT1 and KDR) in placentas after assisted reproductive technology fertilization.

Placental angiogenesis is a pivotal process for feto-maternal circulation and ensures efficient development of the placenta throughout pregnancy. Many factors during in vitro fertilization and embryo transfer procedures may affect placental gene expression and fetus development. The present study aimed to identify differences in angiogenesis-related gene (VEGFA, FGF2, FLT1, and KDR) expression profiles in placentas after assisted reproductive technology fertilization and natural conception in healthy women. In a case-control study, term placentas were collected from Caucasian women after assisted reproductive technology fertilization (N = 20) and after natural conception in women with uncomplicated pregnancy (N = 9). The mRNA expression in placentas was examined for VEGFA, FGF2, FLT1, and KDR genes by real-time quantitative polymerase chain reaction (RT-qPCR). Group stratification was performed for comparison of investigated genes between the type of embryo transferred (fresh/frozen), place of tissue donation (center/margin), and newborns' gender (male/female). In the ART placentas, significant down-regulation of VEGFA gene (p = 0.016) and up-regulation of FLT1 (p = 0.026) and KDR (p < 0.001) gene receptors were observed. Genes encoding VEGFA receptors were up-regulated in both fresh (ET) and frozen (FET) embryo transfer groups compared to controls. For the FLT1 gene, a statistically significant difference was observed between the frozen embryo transfer group and the controls (p = 0.032). Relative expression of KDR was significantly higher for both embryo transfer groups compared to controls (p < 0.001) and between ET and FET (p = 0.002). No statistically significant differences were observed between placental expression in different places of tissue donation and newborns' gender. We observed differences in the placental expression of VEGFA and its receptors FLT1 and KDR in pregnancies after assisted reproductive technology compared to naturally conceived pregnancies. More research is needed to clarify these alterations that may affect placental development and fetal health.

Are variants of the RBP4 gene associated with serum retinol-binding protein 4 concentrations and carotid intima-media thickness values in women with obesity?

INTRODUCTION: Several studies showed the correlation of retinol-binding protein 4 (RBP4) with increased cardiovascular risk - including higher values of carotid intima-media thickness (cIMT) - particularly in individuals with obesity. OBJECTIVES: Our study aimed to investigate the impact of rs10882273; rs3758538; rs3758539, and rs7094671 RBP4 gene variants on RBP4 serum concentrations as well as cIMT values (a marker of subclinical atherosclerosis) among female patients with obesity. PATIENTS AND METHODS: We recruited 74 women with obesity and 24 women without obesity as a study and control group, respectively. The genotypic and allelic frequencies of RBP4 gene variants were evaluated for associations with serum RBP4 and cIMT. RESULTS: The median serum RBP4 concentrations were 20.30 µg/mL and 19.80 µg/mL in the patients and control group, respectively (p = 0.740). No significant differences were seen in cIMT values between the two studied groups (0.60 [0.50-1.00] vs. 0.60 ± 0.10 in the patient and control group, respectively); however, the results were close to reaching significance (p = 0.071), similar as in observed association of the minor haplotype AA for rs7084671 and rs375839 with female obesity (p = 0.0559). The correlation analysis showed no significant differences between RBP4 gene variants with serum RBP4 and cIMT. CONCLUSIONS: According to our knowledge, this is the first study investigating the association between RBP4 gene variants and serum RBP4 and cIMT among Polish female patients with obesity. However, our results show that genetic variants rs10882273, rs3758538, rs3758539, and rs7094671 of the RBP4 gene are not associated with RBP4 serum concentrations or cIMT values among women with obesity.

Variants of the CASP9 gene as candidate markers for primary response to anti-TNF therapy in Crohn's disease patients.

Anti-tumor necrosis factor (TNF) therapy is used to induce and maintain remission in Crohn's disease (CD) patients. However, primary non-responders to initial treatment constitute 20-40% of cases. The causes of this phenomenon are still unknown. We aim to investigate the impact of the caspase 9 (CASP9) gene variants on the variable reactions of CD patients to anti-TNF therapy. The study group included 196 diagnosed and clinically characterized CD Polish patients following anti-TNF therapy. The sequence of the CASP9 gene was analyzed using next-generation and Sanger sequencing and was analyzed with the response to biological treatment. Using the RT-qPCR analysis, we estimated the CASP9 gene mRNA level in colon biopsies material from inflamed and non-inflamed tissue (21 CD patients: 14 responders and seven non-responders to anti-TNF therapy and six controls), as well as in vitro in a peripheral blood mononuclear cells (PBMCs) from CD patients (seven responders and seven non-responders to anti-TNF therapy) and eight controls. Our findings indicated association of variants rs1052571 and rs4645978 with response to anti-TNF monoclonal antibodies (mAbs). Moreover, we observed tendency for reduced expression after incubation with anti-TNF in the group of CD patients, in contrast to the control group. Our results suggest that response to anti-TNF therapy in CD patients may be an effect of variants of the CASP9 gene as a key effector of the internal pathway of apoptosis; however, further population and functional research are necessary.

Apoptosis and inflammatory genes variants in primary non-response to anti-TNF therapy in Crohn's disease patients.

Anti-TNF therapy has indeed revolutionized the treatment of Crohn's disease, leading to higher rates of response and remission in patients. However, a significant proportion of 20-40% of patients do not respond to the initial therapy, others experience a secondary loss of response with ongoing treatment. Adverse drug reactions also occur in some patients. The effectiveness of anti-TNF treatment may be influenced by genetic variability, including FCGR3A, ADAM17, TNFRSF1A, TNFRSF1B, FAS, FASL, IL1B, CASP9 , and MIF genes. In this article, we provide an overview of the current knowledge and findings in the pharmacogenetics of anti-TNF drugs in CD focusing on the aspect of apoptosis and inflammatory genes variants in primary non-response. Pharmacogenetic investigations have been conducted to identify genetic markers that can predict response to anti-TNF therapy. However, large multi-center validation studies and multi-loci algorithms development are required to effectively prognose the treatment effect. The identification of predictive markers of response to anti-TNF therapy can help clinicians make informed decisions about treatment options and minimize adverse drug reactions in patients.

Association of the ILR1 and FAS gene variants with primary nonresponse to anti-tumor necrosis factor therapy in patients with Crohn disease.

INTRODUCTION: Crohn disease (CD) is a chronic inflammatory disease characterized by an uncontrolled immune response of the intestinal mucosal cells to antigens derived from the gut lumen. Specifically, the introduction of anti-tumor necrosis factor (TNF) drugs has changed the approach to the treatment of inflammatory bowel disease, and set new therapeutic goals, such as that of controlling clinical symptoms while simultaneously achieving complete endoscopic and mucosal remission. The mechanisms of action of anti-TNF drugs-and consequently the mechanisms of resistance to anti­TNF therapy-are unknown. OBJECTIVES: Our study was an attempt to discover whether the potential mechanism of nonresponse may be conditioned by polymorphisms in the genes involved in independent inflammatory or apoptotic pathways. PATIENTS AND METHODS: The study included 196 diagnosed and clinically characterized Polish patients with CD treated with anti­TNF therapy. Variants rs7539036, rs2041747, rs5746053, rs5746054, rs1061624, rs1143634, rs7896789, and rs55790676 of the FCGR3A, IL1R, TNFRSF1B, IL1B, FAS, and ADAM17 genes were genotyped using Sanger sequencing, and analyzed in the context of response to biologic treatment. RESULTS: We observed that 33 patients (16.8%) did not respond to the therapy, which was associated with carrying the rs2041747 G allele variant of the ILR1 gene (odds ratio [OR], 3.72; P = 0.009). Moreover, the presence of the FAS rs7896789 homozygous CC genotype correlated with increased susceptibility to the lack of response to the anti­TNF therapy (OR, 15.22; P = 0.003), whereas TT was identified as a potentially protective genotype. CONCLUSIONS: In patients with CD treated with anti­TNF drugs, complex pathways with multigene conditioning participate in the mechanism underlying treatment resistance. The genes involved in apoptosis, FAS and ILR1, seem to play an essential role in the lack of response to the treatment, and would be interesting objects of further population and functional research.

Alterations in Gut Microbiota Composition in Patients with COVID-19: A Pilot Study of Whole Hypervariable 16S rRNA Gene Sequencing.

It is crucial to consider the importance of the microbiome and the gut-lung axis in the context of SARS-CoV-2 infection. This pilot study examined the fecal microbial composition of patients with COVID-19 following a 3-month recovery. Using for the first time metagenomic analysis based on all hypervariable regions (V1-V9) of the 16S rRNA gene, we have identified 561 microbial species; however, 17 were specific only for the COVID-19 group (n = 8). The patients' cohorts revealed significantly greater alpha diversity of the gut microbiota compared to healthy controls (n = 14). This finding has been demonstrated by operational taxonomic units (OTUs) richness (p < 0.001) and Chao1 index (p < 0.01). The abundance of the phylum Verrucomicrobia was 30 times higher in COVID-19 patients compared to healthy subjects. Accordingly, this disproportion was also noted at other taxonomic levels: in the class Verrucomicrobiae, the family Verrucomicrobiaceae, and the genus Akkermansia. Elevated pathobionts such as Escherichia coli, Bilophila wadsworthia, and Parabacteroides distasonis were found in COVID-19 patients. Considering the gut microbiota's ability to disturb the immune response, our findings suggest the importance of the enteric microbiota in the course of SARS-CoV-2 infection. This pilot study shows that the composition of the microbial community may not be fully restored in individuals with SARS-CoV-2 following a 3-month recovery.

Where Do We Stand in the Behavioral Pathogenesis of Inflammatory Bowel Disease? The Western Dietary Pattern and Microbiota-A Narrative Review.

Despite the increasing knowledge with regard to IBD (inflammatory bowel disease), including ulcerative colitis (UC) and Crohn's disease (CD), the etiology of these conditions is still not fully understood. Apart from immunological, environmental and nutritional factors, which have already been well documented, it is worthwhile to look at the possible impact of genetic factors, as well as the composition of the microbiota in patients suffering from IBD. New technologies in biochemistry allow to obtain information that can add to the current state of knowledge in IBD etiology.

Cytotoxicity of Thiopurine Drugs in Patients with Inflammatory Bowel Disease.

The effectiveness of thiopurine drugs in inflammatory bowel disease (IBD) was confirmed more than a half-century ago. It was proven that these can be essential immunomodulatory medications. Since then, they have been used routinely to maintain remission of Crohn's disease (CD) and ulcerative colitis (UC). The cytotoxic properties of thiopurines and the numerous adverse effects of the treatment are controversial. However, the research subject of their pharmacology, therapy monitoring, and the search for predictive markers are still very relevant. In this article, we provide an overview of the current knowledge and findings in the field of thiopurines in IBD, focusing on the aspect of their cytotoxicity. Due to thiopurines' benefits in IBD therapy, it is expected that they will still constitute an essential part of the CD and UC treatment algorithm. More studies are still required on the modulation of the action of thiopurines in combination therapy and their interaction with the gut microbiota.

Does the VDR gene polymorphism influence the efficacy of denosumab therapy in postmenopausal osteoporosis?

Introduction: One of the challenges of personalized medicine is a departure from traditional pharmacology toward individualized, genotype-based therapies. Postmenopausal osteoporosis is a prevalent condition requiring intensive treatment, whose effects are measurable only after a long time, and the goal is bone fracture prevention. This study aimed to determine the influence of VDR gene variation on anti-osteoporotic one-year treatment with denosumab in 63 Polish women with postmenopausal osteoporosis. Materials and methods: The correlation between bone mineral density (BMD) of the lumbar vertebral column (L1-L4) and femoral neck, and genotype distributions for the ApaI, BsmI, FokI, and TaqI variants of the VDR gene was analyzed. Bone fractures during denosumab therapy were also investigated. Results: In the case of the Bsml polymorphism, female patients with BB and Bb genotypes had statistically significantly higher values of BMD and T-score/Z-score indicators, which persisted after a year of denosumab treatment. Our results indicated that the Bsml polymorphism contributes to better bone status, and, consequently, to more efficient biological therapy. The study did not reveal significant differences between changes (delta) in BMD and genotypes for the analyzed VDR gene loci. In the entire study group, one bone fracture was observed in one patient throughout the yearlong period of denosumab therapy. Conclusions: BB and Bb genotypes of the Bsml polymorphism of the VDR gene determine higher DXA parameter values both before and after one-year denosumab therapy in postmenopausal women with osteoporosis.

Myostatin and Follistatin-New Kids on the Block in the Diagnosis of Sarcopenia in IBD and Possible Therapeutic Implications.

Sarcopenia, which is a decrease in muscle strength and quality of muscle tissue, is a common disorder among patients suffering from inflammatory bowel disease. This particular group of patients often presents with malnutrition and shows low physical activity, which increases the risk of sarcopenia. Another important factor in the development of sarcopenia is an imbalanced ratio of myostatin and follistatin, which may stem from inflammation as well as genetic factors. Currently, research in this area continues, and is aimed at identifying an effective medication for the treatment of this condition. Additionally, we still have no sarcopenia markers that can be used for diagnosis. In this paper, we address the role of myostatin and follistatin as potential markers in the diagnosis of sarcopenia in patients with Crohn's disease and ulcerative colitis, particularly in view of the genetic and biological aspects. We also present data on new perspectives in the pharmacotherapy of sarcopenia (i.e., myostatin inhibitors and gene therapy). Nevertheless, knowledge is still scarce about the roles of follistatin and myostatin in sarcopenia development among patients suffering from inflammatory bowel disease, which warrants further study.

Effect of Anti-TNF Therapy on Mucosal Apoptosis Genes Expression in Crohn's Disease.

Crohn's disease (CD) is a chronic immune-mediated disorder for which there is not a fully effective treatment. Moreover, biological therapy with anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies leads to an effective response in only 60-70% of patients. Our previous data suggested that specific loci polymorphism of the TNFRSF1B, FCGR3A, IL1R, IL1B, and FAS genes could be a predictor of the primary non-response to anti-TNF therapy in CD patients. In this work, we propose to explain this hypothesis by functional analysis in colon biopsies and in a cell culture model. Using the RT-qPCR analysis, we estimated the FCGR3A, IL1R, TNFRSF1B, IL1B, FAS, and ADAM17 genes mRNA level in colon biopsies material from inflamed and non-inflamed tissue from 21 CD patients (14 responders and 7 non-responders to anti-TNF therapy) and 6 controls, as well as in vitro in a peripheral blood mononuclear cells (PBMCs) from 14 CD patients (seven responders and seven non-responders to anti-TNF therapy) and eight controls cultured for 72 h with 10 µg/ml of anti-TNF antibody. Our findings demonstrated a significant down-regulation of TNFRSF1B gene expression in non-responders both in inflamed and in non-inflamed colon tissue, while the expression of the FCGR3A and IL1B genes was significantly up-regulated in non-responders in the inflamed colon region. In vitro research results indicate that the anti-TNF drug induced a significant decrease in TNFRSF1B, FCGR3A, and FAS gene expression in non-responders. These results show that altered TNFRSF1B, FCGR3A, and IL1B genes expression can be a predictor of the primary non-response to anti-TNF therapy in CD patients.

NGS study of glucocorticoid response genes in inflammatory bowel disease patients.

INTRODUCTION: Despite intensive research and a long history of glucocorticoids being applied in various clinical areas, they still generate a challenge for personalized medicine by causing resistance or dependence in nearly 50% of patients treated. The objective of the present study was to determine the genetic predictors of variable reactions in inflammatory bowel disease patients to glucocorticoid therapy. Therefore, based on the current knowledge on how glucocorticoids act, we have compiled a panel of 21 genes for variant analysis: NR3C1, NLRP1, IPO13, FKBP5, HSPA4, ABCB1, STIP1, HSP90AA1, IL-1A, IL-1B, IL-2, IL-4, CXCL8, IL-10, NFKBIA, JUN, MIF, TNF, MAPK14, CYP3A4, and CYP3A5. MATERIAL AND METHODS: These genes were analyzed using the amplicon next-generation sequencing method in a group of 139 diagnosed and clinically characterized inflammatory bowel disease patients with a confirmed glucocorticoid response. RESULTS: Analysis of all the targeted DNA sequences for the whole patient group indicated 121 different functional variants. After association analyses of 31 selected variants, the polymorphism c.1088A>G in the NR3C1 gene was linked with glucocorticoid resistance (p = 0.002), variant c.241+6A>G of the FKBP5 gene with glucocorticoid sensitivity (p = 0.040), and deletion c.306-7delT in the MAPK14 gene with an adverse therapeutic effect (dependency and resistance, p = 0.041) in ulcerative colitis patients. In Crohn's disease, the change c.2685+49T>C of the ABCB1 gene related to glucocorticoid resistance (p = 0.034). CONCLUSIONS: Among the 21 analyzed genes, four (NR3C1, FKBP5, MAPK14, and ABCB1) revealed a significant impact on the glucocorticoid treatment response, which could result in valuable pharmacogenetic biomarkers after being confirmed in other populations and in functional studies.

Dysbiosis of gut microbiota in Polish patients with ulcerative colitis: a pilot study.

Ulcerative colitis (UC) is a chronic immune-mediated disorder, whose etiology is not fully understood and for which no effective treatment is available. Recently, research has focused on the dysbiosis of gut microbiome in UC. However, the results so far remain inconsistent and insufficient to understand the microbial component in UC pathogenesis. In this study, we determine specific changes in the gut microbial profile in Polish UC patients compared to healthy subjects for the first time. Using 16S rRNA gene-based analysis we have described the intestinal microbial community in a group of 20 individuals (10 UC patients and 10 controls). Our results after multiple hypothesis testing correction demonstrated substantially lower gut microbiome diversity in UC cases compared to the controls and considerable differences at the phylum level, as well as among 13 bacterial families and 20 bacterial genera (p < 0.05). UC samples were more abundant in Proteobacteria (8.42%), Actinobacteria (6.89%) and Candidate Division TM7 (2.88%) than those of healthy volunteers (2.57%, 2.29% and 0.012%, respectively). On the other hand, Bacteroidetes and Verrucomicrobia were presented at a lower level in UC relative to the controls (14% and 0% vs 27.97% and 4.47%, respectively). In conclusion, our results show a reduced gut microbial diversity in Polish UC patients, a reduction of taxa with an anti-inflammatory impact and an increased abundance of potentially pathogenic bacteria.

Vitamin D, Vitamin D Receptor (VDR) Gene Polymorphisms (ApaI and FokI), and Bone Mineral Density in Patients With Inflammatory Bowel Disease.

In the etiology of inflammatory bowel disease (IBD) and osteoporosis, the connecting element is the involvement of environmental and genetic factors. Vitamin D receptor (VDR) gene polymorphisms may be associated with the pathogenesis of IBD and bone mineral density (BMD). The study aimed to analyze the relationship between ApaI and FokI polymorphisms of the VDR gene, serum vitamin D concentration, and BMD in patients with IBD. The studied group consisted of 172 patients (85 with Crohn's disease [CD], 87 with ulcerative colitis [UC], and 39 healthy subjects - control group [CG]) were examined. Lumbar spine densitometry (L1-L4) and the femoral neck (FN) measurements were performed using dual-energy X-ray absorptiometry (DXA). Serum concentrations of 25-hydroxyvitamin D were determined using electrochemiluminescence binding assay (ECLIA). Polymorphisms were determined with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). . We found no statistically significant differences in vitamin D concentration between the 3 studied groups. CD patients who were FF homozygotes had significantly lower FN BMD than FF homozygous from CG (p-value < 0.05). CD patients who were Aa heterozygotes had significantly lower lumbar spine (L2-L4) BMD than Aa heterozygotes from CG (p-value < 0.05). Among patients with the same polymorphic variants, but belonging to different studied groups, statistically significant differences in bone mineral density in the lumbar spine and the closer end of the femoral neck were observed. We consider that it is the disease entity, not the polymorphism variant, may have a decisive impact on BMD.

Is Polymorphism in the Apoptosis and Inflammatory Pathway Genes Associated With a Primary Response to Anti-TNF Therapy in Crohn's Disease Patients?

Anti-tumor necrosis factor (TNF) therapy is used for the induction and maintenance of remission in Crohn's disease (CD) patients. However, primary nonresponders to initial treatment constitute 20%-40% of cases. The causes of this phenomenon are still unknown. In this study, we aimed to determine the genetic predictors of the variable reactions of CD patients to anti-TNF therapy. Using long-range PCR libraries and the next-generation sequencing (NGS) method, we performed broad pharmacogenetic studies including a panel of 23 genes (TNFRSF1A, TNFRSF1B, CASP9, FCGR3A, LTA, TNF, FAS, ADAM17, IL17A, IL6, MMP1, MMP3, S100A8, S100A9, S100A12, TLR2, TLR4, TLR9, CD14, IL23R, IL23, IL1R, and IL1B) in a group of 107 diagnosed and clinically characterized CD patients following anti-TNF therapy. In the studied group, we indicated, in total, 598 single nucleotide variants for all analyzed genomic targets. Twelve patients (11.2%) did not respond to the induction therapy, which was associated with alleles in 11 loci located in FCGR3A (rs7539036, rs6672453, rs373184583, and rs12128686), IL1R (rs2041747), TNFRSF1B (rs5746053), IL1B (rs1071676, rs1143639, rs1143637, and rs1143634), and FAS (rs7896789) genes. After multiple comparison corrections, the results were not statistically significant, however for nonresponders the alleles distribution for those loci presented large differences and specified scheme compared to responders and populations. These findings require further investigation in an independent larger cohort before introducing them for a clinical setting, however, we identified an interesting direction. Polymorphism of the FCGR3A, IL1R, TNFRSF1B, IL1B, and FAS genes could be a predictor of the primary response to anti-TNF therapy in CD patients.

The Effectiveness of Multi-Session FMT Treatment in Active Ulcerative Colitis Patients: A Pilot Study.

The modification of the microbiome through fecal microbiota transplantation (FMT) is becoming a very promising therapeutic option for inflammatory bowel disease (IBD) patients. Our pilot study aimed to assess the effectiveness of multi-session FMT treatment in active ulcerative colitis (UC) patients. Ten patients with UC were treated with multi-session FMT (200 mL) from healthy donors, via colonoscopy/gastroscopy. Patients were evaluated as follows: at baseline, at week 7, and after 6 months, routine blood tests (including C reactive protein (CRP) and calprotectin) were performed. 16S rRNA gene (V3V4) sequencing was used for metagenomic analysis. The severity of UC was classified based on the Truelove-Witts index. The assessment of microbial diversity showed significant differences between recipients and healthy donors. FMT contributed to long-term, significant clinical and biochemical improvement. Metagenomic analysis revealed an increase in the amount of Lactobacillaceaea, Micrococcaceae, Prevotellaceae, and TM7 phylumsp.oral clone EW055 during FMT, whereas Staphylococcaceae and Bacillaceae declined significantly. A positive increase in the proportion of the genera Bifidobacterium, Lactobacillus, Rothia, Streptococcus, and Veillonella and a decrease in Bacillus, Bacteroides, and Staphylococcus were observed based on the correlation between calprotectin and Bacillus and Staphylococcus; ferritin and Lactobacillus, Veillonella, and Bifidobacterium abundance was indicated. A positive change in the abundance of Firmicutes was observed during FMT and after 6 months. The application of multi-session FMT led to the restoration of recipients' microbiota and resulted in the remission of patients with active UC.

Vitamin C Deficiency and the Risk of Osteoporosis in Patients with an Inflammatory Bowel Disease.

Recent research studies have shown that vitamin C (ascorbic acid) may affect bone mineral density and that a deficiency of ascorbic acid leads to the development of osteoporosis. Patients suffering from an inflammatory bowel disease are at a risk of low bone mineral density. It is vital to notice that patients with Crohn's disease and ulcerative colitis also are at risk of vitamin C deficiency which is due to factors such as reduced consumption of fresh vegetables and fruits, i.e., the main sources of ascorbic acid. Additionally, some patients follow diets which may provide an insufficient amount of vitamin C. Moreover, serum vitamin C level also is dependent on genetic factors, such as SLC23A1 and SLC23A2 genes, encoding sodium-dependent vitamin C transporters and GSTM1, GSTP1 and GSTT1 genes which encode glutathione S-transferases. Furthermore, ascorbic acid may modify the composition of gut microbiota which plays a role in the pathogenesis of an inflammatory bowel disease.

Is the Retinol-Binding Protein 4 a Possible Risk Factor for Cardiovascular Diseases in Obesity?

Although many preventive and treatment approaches have been proposed, cardiovascular disease (CVD) remains one of the leading causes of deaths worldwide. Current epidemiological data require the specification of new causative factors, as well as the development of improved diagnostic tools to provide better cardiovascular management. Excessive accumulation of adipose tissue among patients suffering from obesity not only constitutes one of the main risk factors of CVD development but also alters adipokines. Increased attention is devoted to bioactive adipokines, which are also produced by the adipose tissue. The retinol-binding protein 4 (RBP4) has been associated with numerous CVDs and is presumably associated with an increased cardiovascular risk. With this in mind, exploring the role of RBP4, particularly among patients with obesity, could be a promising direction and could lead to better CVD prevention and management in this patient group. In our review, we summarized the current knowledge about RBP4 and its association with essential aspects of cardiovascular disease-lipid profile, intima-media thickness, atherosclerotic process, and diet. We also discussed the RBP4 gene polymorphisms essential from a cardiovascular perspective.

Analysis of the tumor necrosis factor superfamily member 11 gene polymorphism with bone mineral density and bone fracture frequency in patients with postmenopausal osteoporosis.

PURPOSE: We aimed to examine the polymorphism of the promoter and exon 5 of the TNFSF11 gene and their impact on bone mineral density (BMD) and the frequency of bone fractures. TNFSF11 encodes the receptor activator of the NF-kB ligand (RANKL), a key regulator of bone metabolism and osteoporosis drug targets. BMD is an essential measure in diagnosing osteoporosis and assessing the risk of fractures. In vivo, RANKL expression research suggests that promoter TNFSF11 variants influence BMD. Moreover, exon 5 polymorphism of a linear epitope sequence for a denosumab could be related to the effectiveness of biological therapy. PATIENTS AND METHODS: The study included 114 postmenopausal osteoporosis patients. BMD was measured in the lumbar spine and the femoral neck. Genetic analysis was performed using Sanger sequencing. Genotypes data for 263 female European population group were obtained from the 1000Genomes database. RESULTS: We identified six promoter polymorphisms (rs9525641, rs9533155, rs9533156, rs11839112, rs28926171, rs183599708) and one silent TNFSF11 variant in exon 5 (rs9562415). Three of the sequence variants detected (rs9525641, rs9533155, rs9533156) proved to be polymorphic, whereas the others four occurred at a frequency below 2%. The statistical analysis demonstrated no significant differences between polymorphisms and BMD, and bone fractures. However, variant rs9533156 was relevant with the lumbar spine T-score (p = 0.0273), and no association with BMD was of borderline significance (p = 0.0529). CONCLUSIONS: Variant rs9533156 may contribute to the genetic regulation of BMD in Polish postmenopausal osteoporosis, while the exon 5 sequence of the TNFSF11 gene is very conservative.