Association of microRNA gene polymorphisms with Type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic disorder with growing prevalence and increasing economic burden. Based on the role of genetics and epigenetic factors on T2DM, we aimed to carry a systematic review and meta-analysis for all miRNA gene polymorphisms and risk of T2DM. MATERIALS AND METHODS: A computerized literature search was carried out on PubMed, Web of Science, Scopus, Embase, as well as references of relevant review/meta-analysis. Key search terms were "Diabetes Mellitus, Type 2," "MicroRNAs," and "Polymorphism, Single Nucleotide." All types of observational studies from January 1, 1992, to November 30, 2019, were included, without language restriction. Data analysis was performed using R programming language (3.5.2). Level of heterogeneity was obtained by Cochran's Q test (P < 0.05), and subgroup analysis was performed based on ethnicity. RESULTS: Thirty-two polymorphisms from fifteen articles were included. Meta-analysis was carried out based on minor allele frequencies. Seven studies with 2193 cases and 3963 controls were included for rs2910164 polymorphism. In subgroup analysis, there were significant results in Caucasian population in dominant model (odds ratio [OR] =1.12; 95% confidence interval [CI]: 0.83-1.51), homozygote model (OR = 1.78; 95% CI: 1.06-3.00), heterozygote model (OR = 1.77; 95% CI: 1.03-3.05), and recessive model (OR = 1.78; 95% CI: 1.07-2.96). Four studies with 2085 cases and 1933 controls were included for rs895819 polymorphism. Overall, there was no significant result for association with rs895819, but subgroup analysis revealed that minor allele significantly decreased the risk of T2DM in Caucasians by recessive model (OR = 0.34; 95% CI: 0.18-0.66), dominant model (OR = 0.70; 95% CI: 0.52-0.94), homozygote model (OR = 0.32; 95% CI: 0.16-0.62), heterozygote model (OR = 0.37; 95% CI: 0.19-0.74), allelic model (OR = 0.67; 95% CI: 0.52-0.85). CONCLUSION: The minor allele of rs2910164 may increase the risk of T2DM by leading to lower level of miR-146a. In contrast, minor allele of rs895819 may decrease the risk of T2DM by leading to higher level of miR-27a.

Immune response mechanisms in acute and chronic pancreatitis: strategies for therapeutic intervention.

Acute pancreatitis (AP) is one of the most common inflammatory diseases of the gastrointestinal tract and a steady rising diagnosis for inpatient hospitalization. About one in four patients, who experience an episode of AP, will develop chronic pancreatitis (CP) over time. While the initiating causes of pancreatitis can be complex, they consistently elicit an immune response that significantly determines the severity and course of the disease. Overall, AP is associated with a significant mortality rate of 1-5%, which is caused by either an excessive pro-inflammation, or a strong compensatory inhibition of bacterial defense mechanisms which lead to a severe necrotizing form of pancreatitis. At the time-point of hospitalization the already initiated immune response is the only promising common therapeutic target to treat or prevent a severe disease course. However, the complexity of the immune response requires fine-balanced therapeutic intervention which in addition is limited by the fact that a significant proportion of patients is in danger of development or progress to recurrent and chronic disease. Based on the recent literature we survey the disease-relevant immune mechanisms and evaluate appropriate and promising therapeutic targets for the treatment of acute and chronic pancreatitis.

IRAK3-mediated suppression of pro-inflammatory MyD88/IRAK signaling affects disease severity in acute pancreatitis.

Acute pancreatitis (AP), which is characterized by self-digestion of the pancreas by its own prematurely activated digestive proteases, is a major reason for hospitalization. The autodigestive process causes necrotic cell death of pancreatic acinar cells and the release of damage associated molecular pattern which activate macrophages and drive the secretion of pro-inflammatory cytokines. The MYD88/IRAK signaling pathway plays an important role for the induction of inflammatory responses. Interleukin-1 receptor associated kinase-3 (IRAK3) is a counter-regulator of this pathway. In this study, we investigated the role of MYD88/IRAK using Irak3-/- mice in two experimental animal models of mild and severe AP. IRAK3 is expressed in macrophages as well as pancreatic acinar cells where it restrains NFκB activation. Deletion of IRAK3 enhanced the migration of CCR2+ monocytes into the pancreas and triggered a pro-inflammatory type 1 immune response characterized by significantly increased serum levels of TNFα, IL-6, and IL-12p70. Unexpectedly, in a mild AP model this enhanced pro-inflammatory response resulted in decreased pancreatic damage, whereas in a severe AP model, induced by partial pancreatic duct ligation, the increased pro-inflammatory response drives a severe systemic inflammatory response syndrome (SIRS) and is associated with an increased local and systemic damage. Our results indicate that complex immune regulation mechanism control the course of AP, where moderate pro-inflammation not necessarily associates with increased disease severity but also drives tissue regenerative processes through a more effective clearance of necrotic acinar cells. Only when the pro-inflammation exceeds a certain systemic level, it fuels SIRS and increases disease severity.

Vascular Endothelial Growth Factor Genetic Variant Is Associated with in-Stent Restenosis after Percutaneous Coronary Intervention.

Background: In-stent restenosis (ISR) is an inevitable complication of percutaneous coronary intervention, with genetic factors thought to play a role in its pathogenesis. The vascular endothelial growth factor (VEGF) gene can have an inhibitory effect on ISR development. Accordingly, in the present study, we investigated the role of -2549 VEGF (insertion/deletion [I/D]) variants in ISR formation. Methods: Patients with ISR (ISR+) (n=53) and patients without ISR (ISR-) (n=67) were enrolled in this case-control study based on follow-up angiography 1 year after percutaneous coronary intervention between 2019 and 2020. The clinical characteristics of the patients were evaluated, and the frequencies of the alleles and genotypes of -2549 VEGF (I/D) variants were determined using polymerase chain reaction. The χ2 test was performed for the calculation of genotypes and alleles. A P value of less than 0.05 was considered the level of significance. Results: This study recruited 120 individuals at a mean age of 61.43±8.91 years in the ISR+ group and 62.09±7.94 years in the ISR- group. Women and men, respectively, comprised 26.4% and 73.6% of the ISR+ group and 43.3% and 56.7% of the ISR- group. A significant association was observed between the VEGF -2549 genotype frequency and ISR. The frequency of the insertion/insertion (I/I) allele was significantly higher in the ISR+ group than in the ISR- group, while the frequency of the D/D allele was higher in the latter group. Conclusion: Regarding ISR development, the I/I allele may be a risk allele and the D/D allele a protective allele.

Adenosine deaminase gene variant in diabetes and obesity.

Purpose: Personal medicine is a new notion for individualizing treatment in the future. Studying pathogenic markers including genetic variants would be beneficial in better diagnosis and management of complex diseases such as diabetes and obesity. Adenosine deaminase (ADA) is a purine metabolic enzyme and modulates insulin activity in various tissues through several different mechanisms. Increased ADA activity is associated with decreased glucose uptake. A significant increase in serum deaminase activity has been reported in patients with T2DM and obesity. ADA gene polymorphisms seem to affect ADA enzymatic activity and a polymorphism at the position 4223 in the first intron of ADA gene (ADA 4223 A/C) has been previously associated with obesity. The aim of this study was to explore ADA gene 4223 A/C polymorphism and its association with obesity in patients with Type 2 diabetes. Methods: Obese patients (N = 133: 64 diabetic +69 non-diabetic) with BMI ≥ 30 and subjects with BMI < 30 (N = 152: 83 diabetics +69 non-diabetic) were recruited into a case-control association study. Blood samples were collected and after DNA extraction, the allele and genotype frequency for ADA gene polymorphism was determined using PCR-RFLP technique. Results: We observed a significant increase for the frequency of AA+CA genotype in non-obese patients with diabetes compared to obese patients with diabetes (P = 0.04, OR = 2.1, 95%CI; 0.93-4.9). Conclusion: The higher frequency of AA+CA genotype in none obese diabetes individuals and lower frequency of this genotype in obese diabetes subjects indicates an important role for ADA gene polymorphism in diabetes subjects without obesity.

Short term effects of coffee components consumption on gut microbiota in patients with non-alcoholic fatty liver and diabetes: A pilot randomized placebo-controlled, clinical trial.

The aim of this study was to determine the effects of caffeine and chlorogenic acid supplementation on gut microbiota, and metabolic disturbances in patients with NAFLD and diabetes. In this randomized, placebo-controlled, clinical trial, 26 patients with diabetes and NAFLD were randomly assigned to four groups to receive either 200 mg caffeine plus 200 mg chlorogenic acid (CFCA), or 200 mg caffeine plus 200 mg placebo (starch) (CFPL), or 200 mg chlorogenic acid plus 200 mg placebo (CAPL), or 200 mg placebo plus 200 mg placebo (PLPL) for 12 weeks. After 3 months of supplementation, patients in the intervention groups showed a significant decrease in body weight (CFCA group =-3.69 kg; CFPL group=-0.7kg; CAPL group=-0.43kg; PLPL group=0.26 kg) (p=0.004). Weight reduced significantly more in CFCA group compared to all other three groups (p=0.005 for PLPL; p=0.023 for CAPL; and p=0.031 for CFPL). Although the number of gut Bifidobacteria increased in CFCA group, there were no statistically significant differences within and between the groups in any of bacteria numbers. In conclusion, our study showed that 12 weeks consumption of 200 mg/day caffeine plus 200 mg/day chlorogenic acid is effective in reduction of weight in patients with NAFLD and diabetes which might be at least partially through the rise in gut Bifidobacteria. This pilot study shed a light on the pathway of future clinical trials assessing the effects of coffee consumption in these patients. This trial has been registered at clinicaltrial.gov with registration number of NCT02929901.

The Role of ERRFI1+808T/G Polymorphism in Diabetic Nephropathy.

Nephropathy is a common diabetes complication. ERRFI1 gene which participates in various cellular pathways has been proposed as a candidate gene in diabetic nephropathy. This study aimed to investigate the role of +808T/G polymorphism (rs377349) in ERRFI1 gene in diabetic nephropathy. In this case-control study, patients including diabetes with nephropathy (DN=104), type 2 diabetes without nephropathy (DM=100), and healthy controls (HC=106) were included. DNA was extracted from blood, and genotyping of the +808T/G polymorphism was carried out using PCR-RFLP technique. The differences for genotype and allele frequencies for +808T/G polymorphism in ERRFI1 gene between DN vs. HC and DN+DM vs. HC were significant (P<0.05) while no significant difference between DN and DM was observed. The allele frequencies were significantly different in DN vs. HC and DN+DM vs. HC in males but not in females. G allele of +808T/G polymorphism in ERRFI1 gene has no significant role in development and progression of diabetic nephropathy in diabetes patients while it is a risk allele for developing diabetes in Iranian population.

Haplotypes in vitamin D receptor gene encode risk in diabetic nephropathy.

BACKGROUND: Diabetic Nephropathy (DN) is one of the microvascular complications of diabetes and its early diagnosis can improve patient's quality of life. Genetic factors may increase the risk of DN development. This study aimed to evaluate the association of vitamin D receptor (VDR) gene polymorphisms and DN. METHOD: A total of 313 Iranian participants including 104 diabetic patients with nephropathy (DN), 100 diabetic patients without nephropathy (D) and 109 healthy people (HC) were studied. The frequencies of rs7975232, rs731236 and rs4516035 variants of VDR gene were determined and compared between three groups. Estimated haplotype frequencies between polymorphisms in the cases and controls were also calculated. RESULTS: No significant differences were identified for allele /genotype frequencies in HC, D and DN groups. However haplotype analysis showed that haplotype encompassing CCC alleles for rs7975232, rs731236 and rs4516035 variants, respectively was more frequent in DN subjects compared to HC (p-value = 0.01) and also, haplotype comprising TCC alleles was more frequent in DN group compared to both HC and D groups (p-value = 0.004 and 0.007, respectively). CONCLUSION: Our study identified that CCC and TCC VDR haplotypes are risk factors for DN in patients with diabetes type 2.