Variations in TM6SF2, PCSK9 and PCSK7 genes and risk of hepatic steatosis after liver transplantation: a cross-sectional study.

BACKGROUND: Genetic abnormalities might have important role in pathogenesis of hepatic steatosis after liver transplantation. We aimed to investigate association between genetic variations in transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, proprotein convertase subtilisin/kexin type 9 (PCSK9) rs505151 and proprotein convertase subtilisin/kexin type 7 (PCSK7) rs2277287 with hepatic steatosis in liver transplant recipients. METHODS: In a cross-sectional study, adult (> 18 years) liver transplant recipients who were referred for their routine post-transplant follow-up between June 2018 and September 2018 were included in the study. Hepatic steatosis in transplant recipients was assessed by controlled attenuation parameter (CAP). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to study TM6SF2 rs58542926, PCSK7 rs2277287 and PCSK9 rs505151 genotypes. RESULTS: 107 liver transplant recipients were included. There was no association between different genotypes of PCSK9 rs505151 and PCSK7 rs2277287 with hepatic steatosis in liver transplant recipients (P value > 0.05). The presence of TT genotype of TM6SF2 rs58542926 was higher in patients with hepatic steatosis measured by CAP after liver transplantation. In patients with moderate and severe hepatic steatosis (grade 2 and 3 steatosis), AG + GG genotypes of PCSK9 rs505151 were more prevalent than AA genotype (OR 8.667; 95% CI 1.841-40.879; P value = 0.004) compared to patients with mild steatosis (grade 1). In multivariate regression model, AG + GG genotypes of PCSK9 rs505151 were associated with moderate and severe steatosis in liver transplant recipients (OR 5.747; 95% CI 1.086-30.303; P value = 0.040). CONCLUSIONS: Genetic variations in TM6SF2 rs58542926 and PCSK9 rs505151 might be associated with hepatic steatosis in liver transplant recipients.

Genetic and Phylogenetic Characterization of the M Gene of Influenza A Virus Isolated from Iranian Patients.

BACKGROUND: A few studies have been done on the molecular analysis of Iranian influenza A isolates M gene. METHODS: In 2014, nasal swabs collected from outpatients with clinical symptoms in the hospital clinics of Tehran, Iran were subjected for influenza detection and subtyping using Real-Time RT-PCR. Sequence and phylogenetic analysis performed on four randomly selected isolates from each subtype (H1N1 and H3N2) using neighbor-joining method. RESULTS: Phylogenetic dendrograms drawn based on M nucleotide sequence of H1N1 isolates showed close relatedness with Omanian isolates while the most isolates of H3N2 have clustered with Kuwait isolates and isolates from outside of geographical location. Amino acid sequence analysis showed S31N substitution in all isolates rendering the virus resistant to adamantanes. CONCLUSION: This study determined the sequence identity and phylogenetic relatedness of M gene sequence got from Iranian influenza A isolates to elucidate the modality of relationship of this gene in comparison with its counterparts from other regions.

Glutathione S-Transferase Gene Polymorphisms and the Development of New-Onset Diabetes After Liver Transplant.

OBJECTIVES: The association between the glutathione S-transferase polymorphisms and the development of new-onset diabetes mellitus after liver transplant was studied. MATERIALS AND METHODS: Peripheral blood samples were collected from 106 liver transplant patients divided into 2 groups: 52 with new-onset diabetes mellitus and 54 without new-onset diabetes mellitus; 169 healthy individuals with no clinical evidence of diabetes mellitus were selected as a control group. The multiplex polymerase chain reaction technique was used for genotyping GSTM1 and GSTT1 genes, using the cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) gene as an internal control. The genotype of GSTP1 was determined using the restriction fragment length polymorphism-polymerase chain reaction technique. RESULTS: The frequency of both GSTM1 null and GSTT1 null genotypes was not significantly different in liver transplant patients with new-onset diabetes mellitus compared with the control group (P = .11 for GSTM1; P = .71 for GSTT1). Also, there was no statistically significant association between the frequency of the GSTP1 genotypes in the liver transplant patients with new-onset diabetes mellitus compared with controls. Neither GSTM1 nor GSTT1 null genotypes were associated with the risk of developing new-onset diabetes mellitus (P = .22 for GSTM1; P = .56 for GSTT1). However, the frequency of the heterozygous mutation (AG) in the A313G GSTP1 polymorphism in patients with new-onset diabetes mellitus was significantly higher than in patients without new-onset diabetes mellitus (55.8% vs 7.4%; P = .00). Thus, the risk of developing new-onset diabetes mellitus was significantly higher in patients presenting with heterozygous GSTP1 genotypes (odds ratio = 15.76; 95% confidence interval = 4.53-60.28; P = .00). CONCLUSIONS: The GSTP1 AG genotype was associated with an increased susceptibility to the development of new-onset diabetes mellitus after liver transplant.

Incidence of antiviral drug resistance markers among human influenza A viruses in the Eastern Mediterranean Region, 2005-2016.

BACKGROUND: Two classes of antiviral drugs are available for influenza antiviral therapy: the adamantanes and the neuraminidase inhibitors (NAIs). Due to the emergence of adamantane-resistant variants, the use of these drugs has been largely limited in the world. The NAIs became the drugs of choice for treatment of influenza A infections. However, amino acid substitutions in the NA protein might lead to reduced sensitivity to NAIs. METHODS: The frequency and distribution of matrix protein 2 (M2) and neuraminidase (NA) variants which confer resistance to antiviral drugs was investigated in the Eastern Mediterranean Region (EMR) between 2005 and 2016. A total of 314 M2 and 1209 NA protein sequences from influenza A/H1N1, A/H1N1pdm09, A/H3N2, and A/H5N1 available in the public database were analyzed. RESULTS: Eighty-six percent of the influenza A viruses detected in the EMR were resistant to adamantanes, among which, H3 strains exhibited the highest (95.32%) level of adamantane resistance. Approximately 98.51% (265/269) of influenza A/H1N1 and H3N2 resistant viruses had the S31N substitution in their M2 sequences. The V27A mutation was the only resistance marker found in A/H5N1 viruses and was detected at a frequency of 7.40% among the investigated viruses. Other resistant mutations L26F, A30T, G34E, and L38F were not detected in any of the variants. We found that 2.81% (n = 34) of the detected NA sequences from influenza A viruses possessed at least one NAI-resistant mutation and the vast majority of resistant viruses 79.41% (27/34) bear the H274Y mutation. The frequency of NAI-resistant viruses was 3.29% (24/729) for the H1N1pdm09, 10.64% (5/47) for the seasonal H1N1, and 4.06% (5/123) for H5N1 viruses. None of the H3N2 viruses analyzed during the study period were resistant to NAIs. CONCLUSION: Our study reveals the emergence and spread of antiviral drug resistant influenza A viruses in the EMR and emphasizes the importance of continuous surveillance to maintain the effective use of the current antivirals.

Characterization of the neuraminidase genes from human influenza A viruses circulating in Iran from 2010 to 2015.

BACKGROUND: Characterization of influenza viruses is critical for detection of new emerging variants. Herein, we analyzed the genetic diversity and drug susceptibility of the neuraminidase gene (NAs) expressed by influenza A/H1N1pdm09 and A/H3N2 viruses circulating in Iran from 2010 to 2015. METHODS: We genetically analyzed the NAs of 38 influenza A/H1N1pdm09 and 35 A/H3N2 isolates. RESULTS: The Iranian A/H1N1pdm09 viruses belonged to seven genogroups/subgenogroups, with the dominant groups being genogroups 6B and 6C. The A/H3N2 isolates fell into six gneogroups/subgenogroups, with the dominant genogroups being 3C and 3C.2a. The most common mutations detected among the A/H1N1pdm09 viruses included N44S, V106I, N200S, and N248D. All H1N1pdm09 viruses were genetically susceptible to the NAIs. However, one A/H1N1pdm09 virus from the 2013-2014 season possessed an NA-S247N mutation, which reduces the susceptibility to oseltamivir. In case of H3N2, none of the analyzed Iranian strains carried a substitution that might affect its susceptibility to NAIs. CONCLUSION: The ongoing evolution of influenza viruses and the detect of influenza viruses with reduced susceptibility to NAIs warrants continuous monitoring of the circulating strains.

Molecular characterization and phylogenetic analysis of human influenza A viruses isolated in Iran during the 2014-2015 season.

Influenza A viruses are an important cause of severe infectious diseases in humans and are characterized by their fast evolution rate. Global monitoring of these viruses is critical to detect newly emerging variants during annual epidemics. Here, we sought to genetically characterize influenza A/H1N1pdm09 and A/H3N2 viruses collected in Iran during the 2014-2015 influenza season. A total of 200 nasopharyngeal swabs were collected from patients with influenza-like illnesses. Swabs were screened for influenza A and B using real-time PCR. Furthermore, positive specimens with high virus load underwent virus isolation and genetic characterization of their hemagglutinin (HA) and M genes. Of the 200 specimens, 80 were influenza A-positive, including 44 A/H1N1pdm09 and 36 A/H3N2, while 18 were influenza B-positive. Phylogenetic analysis of the HA genes of the A/H1N1pdm09 viruses revealed the circulation of clade 6C, characterized by amino acid substitutions D97N, V234I and K283E. Analysis of the A/H3N2 viruses showed a genetic drift from the vaccine strain A/Texas/50/2012 with 5 mutations (T128A, R142G, N145S, P198S and S219F) belonging to the antigenic sites A, B, and D of the HA protein. The A/H3N2 viruses belonged to phylogenetic clades 3C.2 and 3C.3. The M gene trees of the Iranian A/H1N1pdm09 and A/H3N2 mirrored the clustering patterns of their corresponding HA trees. Our results reveal co-circulation of several influenza A virus strains in Iran during the 2014-2015 influenza season.

Genetic polymorphisms of glutathione-s-transferase M1 and T1 genes with risk of diabetic retinopathy in Iranian population.

OBJECTIVES: To the best of our knowledge, this is the first report on the contributions of GST genetic variants to the risk of diabetic retinopathy in an Iranian population. Therefore, the objective of this study was to determine whether sequence variation in glutathione S-transferase gene (GSTM1 and GSTT1) is associated with development of diabetic retinopathy in type 2 diabetes mellitus (T2DM) Iranian patients. MATERIALS AND METHODS: A total of 605 subjects were investigated in this case-control study; Study groups consisted of 201 patients with diabetic retinopathy (DR), 203 subjects with no clinically significant signs of DR and a group of 201 cases of healthy volunteers with no clinical evidence of diabetes mellitus or any other diseases. The GSTM1 and GSTT1 were genotyped by multiplex-polymerase chain reaction (multiplex-PCR) analysis in all 404 T2DM patients and 201 healthy individuals served as control. RESULTS: Increased odds ratio showed that GSTM1-null genotype had a moderately higher occurrence in T2DM patients (OR=1.43, 95% CI=1.01-2.04; P=0.03) than in healthy individuals. However, the frequency of GSTT1 genotype (OR=1.41; 95% CI=0.92-2.18; P=0.09) was not significantly different comparing both groups. Although, regression analysis in T2DM patients showed that GSTM1 and GSTT1 genotypes are not associated with T2DM retinopathy development. CONCLUSION: Our findings suggest that GSTM1 and GSTT1 genotypes might not be involved in the pathogenesis of type 2 diabetes mellitus retinopathy in the Southern Iranian population. However, further investigations are needed to confirm these results in other larger populations.

Study of the association between glutathione S-transferase (GSTM1, GSTT1, GSTP1) polymorphisms with type II diabetes mellitus in southern of Iran.

Diabetes Mellitus is characterized by chronic hyperglycemia and associated with an increased production of reactive oxygen species (ROS). Oxidative stress is the result of accumulation of free radicals in tissues which specially affects beta cells in pancreas. Glutathione S-transferases (GSTs) are a family of antioxidant enzymes that include several classes of GSTs. These enzymes have important roles in decreasing of ROS species and act as a kind of antioxidant defense. To investigate the association between GSTs polymorphism with type 2 diabetes mellitus (T2DM), we investigated the frequency of GSTM1, T1 and P1 genotypes in patients with T2DM and controls. The genotypes of GSTT1, M1 and P1 were determined in 171 clinically documented T2DM patients and 169 normal cases (as controls) by multiplex polymerase chain reaction and PCR-RFLP. In diabetic patients, the frequency of GSTM1-null genotype was significantly (OR = 1.74; 95 % CI = 1.13-2.69, P = 0.016) higher than that in control. However, the frequency of GSTT1 (OR = 1.29; 95 % CI = 0.07-2.14, P = 0.367) and GSTP1 (OR = 0.83; 95 % CI = 0.53-1.30, P = 0.389) genotypes were not significantly different comparing both groups. Also, the frequency of both GSTT1-null and GSTM1-null genotypes in patients (19.88 %) was significantly higher compared to controls with the same genotypes (11.83 %, P = 0.022). Our results indicated that GSTM1 and GSTT1 genotypes might be involved in the pathogenesis of T2DM in south Iranian population.