Mohammad Taheri

HLA genes as modifiers of response to IFN-β-1a therapy in relapsing-remitting multiple sclerosis

AIMS This study investigated the influence of HLA class-I and -II genes in the response to IFN-β in relapsing-remitting multiple sclerosis (MS) patients. PATIENTS & METHODS In this cohort, 231 relapsing-remitting MS patients who are classified into IFN-β responders (n = 146) and nonresponders (n = 85) and 180 ethnic-matched healthy controls were analyzed. Clinical outcome of IFN-β therapy particularly Expanded Disability Status Scale scores were evaluated in relation to HLA-A, -B and -DRB1 alleles and haplotypes. RESULTS Increased frequencies of HLA-DRB1*04 allele and HLA-A*03-B*44-DRB1*04 haplotype, and decreased frequency of HLA-B*15 were associated with better response to IFN-β treatment. CONCLUSION The possibility of genetic screening particularly HLA typing prior to starting IFN-β therapy for MS may permit the identification of likely responders or nonresponders.

RAR-related orphan receptor A (RORA): A new susceptibility gene for multiple sclerosis.

Retinoic acid receptor-related orphan receptor alpha (RORA) is proposed to promote Th17 cells differentiation that play a crucial role in many inflammatory diseases, including multiple sclerosis (MS). The gene is also involved in regulation of inflammatory responses and neuronal cell development. The aim of the present study is to determine if any relation exists between RORA rs11639084 and rs4774388 gene polymorphisms on the individual susceptibility of multiple sclerosis. 410 patients with clinically definite MS and 500 ethnically-matched healthy controls participated in this study. Genotyping was performed using tetra primer-amplification refractory mutation system-PCR (4P-ARMS-PCR) method for the mentioned polymorphisms in the RORA gene. Both variants showed significant differences in allele and genotype distributions between the studied groups. Genotypes were risk associated in additive (P-value of 0.0003 and odds ratio equal to 1.7 (95% CI: 1.27-2.26)), dominant (P-value of <0.0001 and odds ratio equal to 0.55 (95% CI: 0.41-0.73)) and recessive (P-value of 0.04 and odds ratio equal to 0.33 (95% CI: (0.12-0.96)) models for rs11639084. However, the rs4774388 genotypes were risk associated in recessive model with a P-value of 0.036 and an odds ratio of 0.62 (95% CI: (0.4-0.97)). To the best of our knowledge this is the first report concerning the association between RORΑ gene polymorphisms and MS. The further study of RORΑ related pathways and gene networks might result in the better understanding of the pathophysiology of MS and related symptoms.

Glutamate receptor, metabotropic 7 (GRM7) gene variations and susceptibility to autism: A case–control study

Autism spectrum disorder (ASD) as a synaptopathy is revealed to be pertained to aberrant glutamatergic neurotransmission. Glutamate receptor, metabotropic 7 (GRM7), a receptor coding gene of this pathway, is a new candidate gene for autism. The aim of this study was to examine if there is a relationship between genetic variants rs779867 and rs6782011 of GRM7 with ASD. The present research was designed as a population‐based, case–control study including 518 ASD patients versus 472 control individuals. The results showed that the frequency of rs779867 G/G genotype was significantly higher in ASD patients compared to healthy controls (P = 0.0001). Also, the G allele of this SNP was found to be significantly more frequent in the patients than control group (P = 0.0001). Haplotype analysis exhibited significant association of two estimated block of rs6782011/rs779867 in ASD patients versus control group. We found higher significant frequency of GT haplotype and lower frequencies of AT and AC haplotypes in the patients group compared to healthy controls (P = 0.001, P = 0.006, and P = 0.05, respectively). Our study indicated that the rs779867 polymorphism is associated with ASD; thus, results of this study provide supportive evidence of association of the GRM7 gene with ASD. Autism Res 2016, 9: 1161–1168.

HOTAIR genetic variants are associated with prostate cancer and benign prostate hyperplasia in an Iranian population

Prostate cancer and benign prostate hyperplasia (BPH) are heterogeneous disorders with a wide array of clinical presentations and high prevalence among men. Several protein coding genes as well as non-coding genes have been shown to contribute in prostate cancer and BPH risk. Among non-coding genes whose contribution in tumorigenesis has been identified is HOX transcript antisense RNA (HOTAIR). In the present study we aimed at identification of the associations between three HOTAIR polymorphisms (rs12826786, rs1899663 and rs4759314) and risk of prostate cancer and BPH by the means of tetra-primer ARMS-PCR in a population of 128 Iranian prostate cancer patients, 143 BPH patients and 250 normal male controls. The study showed that rs1899663 T allele was associated with BPH risk. Comparison between prostate cancer and BPH groups showed that rs1899663 is associated with cancer risk in co-dominant, dominant and recessive inheritance models. The rs12826786 T allele was significantly more presented in both BPH and prostate cancer groups compared with healthy subjects. This SNP was associated with both BPH and prostate cancer risk in co-dominant and recessive models. However, rs4759314 showed no significant difference in allele or genotype frequencies between three mentioned groups. In addition, some haplotypes within this gene were associated with increased prostate cancer and BPH risk. Consequently, HOTAIR can be suggested as a risk locus for prostate cancer and BPH in Iranian population.

Up regulation of MMP9 gene expression in female patients with multiple sclerosis

BACKGROUND Multiple sclerosis (MS) is an inflammatory, immune-mediated, demyelinating disease of the central nervous system which disturbs cerebral vascular permeability. OBJECTIVE Matrix metalloproteinase can increase capillary permeability and are involved in neurological diseases. METHODS The study compared the expression level of MMP9 gene in RRMS samples with normal individuals in Iran. RNA from the buffy coat of 50 RRMS patients and 50 normal controls were extracted. All patients were HLA-DRB1*15 negative and were responders to interferon-beta with a normal vitamin D level. The level of MMP9 gene expression was measured using quantitative RT-PCR. RESULTS The RRMS patients manifested a higher expression level of MMP9 than their normal counterparts (P= 0.02). Age-wise, there was no correlation between different age groups (> 30, 30-40, 40 <). In terms of sex, only the female patients manifested a statistically significant increase in MMP9 (p value = 0.037). Besides, there was no linear correlation between MMP9 expression level and risk of Expanded Disability Status Scale of Kurtzke (EDSS); nor were there any significant correlation between expression status of MMP9 and duration of the disease. CONCLUSION Up regulation of MMP9 gene expression would happen in RRMS IFN-B responders, but the level of increase in female patients is significantly more than males.

FOXP3 gene variations and susceptibility to autism: A case–control study

Autism Spectrum Disorders (ASD) are a group of heterogeneous neurodevelopmental disorders associated with immune system dysregulation. There are supporting evidences for the role of Forkhead Box P3 (FOXP3) gene as a lineage specification factor of regulatory T cells in the pathogenesis of ASD. The aim of this study was to explore possible relationship between genetic variants rs2232365 and rs3761548 of FOXP3 and ASD in 523 ASD patients versus 472 control individuals. Allele frequency analyses showed significant overpresentation of rs2232365-G allele in cases versus controls. In addition, rs2232365 GG genotype was associated with ASD in dominant inheritance model. Haplotype analysis revealed no significant association of any estimated block of rs2232365/rs3761548 with ASD. Our study indicated that rs2232365 is associated with ASD.

Determination of cytokine levels in multiple sclerosis patients and their relevance with patients' response to Cinnovex

HighlightsWe compared cytokine levels in IFN‐&bgr; responders and non‐responders multiple sclerosis patients.Comparison of cytokine levels revealed higher IFN‐&ggr; levels in HLA‐DRB1*04 positive patients compared with HLA‐DRB1*04 negative patients.IL‐17A levels tend to be higher in responder patients who were positive for HLA‐DRB1*04 compared with those were negative for the same allele. Abstract Multiple sclerosis (MS) is a heterogeneous chronic immune‐mediated disorder of the central nervous system (CNS) with several environmental and genetic factors participating in its development and disease course. Interferon (IFN)‐&bgr; therapy is considered as the first line treatment in this disorder. The present study enrolled 231 relapsing‐remitting MS patients who were diagnosed as IFN‐&bgr; responders (n = 146) and non‐responders (n = 85). Serum cytokine levels were analyzed by commercially available ELISA kits in distinct groups based on HLA‐A, ‐B and ‐DRB1 alleles. IFN‐&ggr; levels were significantly higher in responders compared with non‐responders, whereas IL‐17A and IL‐6 had the opposite trend. The levels of IL‐10 and IL‐4 were not significantly different between two groups. IFN‐&ggr; and IL‐17A levels were associated with response to IFN‐&bgr;. Comparison of cytokine levels revealed higher IFN‐&ggr; levels in HLA‐DRB1*04 positive patients (n = 72) compared with HLA‐DRB1*04 negative patients (n = 159). In responder group, patients who were positive for HLA‐DRB1*15 had significantly higher levels of IL‐6 compared to HLA‐DRB1*15 negative patients. IL‐17A levels tend to be higher in responder patients who were positive for HLA‐DRB1*04 compared with those were negative for the same allele. This study suggests that the serum levels of pro‐ and anti‐inflammatory cytokines are different among IFN‐&bgr; responders and non‐responders. Future studies are needed to confirm their efficiency in determination of response to IFN‐&bgr; in MS patients.

Increased expression ratio of matrix metalloproteinase-9 (MMP9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) RNA levels in Iranian multiple sclerosis patients

OBJECTIVES Multiple sclerosis (MS) is an autoimmune disease involving the central nervous system (CNS) with unknown immunopathogenic mechanisms. Matrix metalloproteinase-9 (MMP-9) facilitates T-cell migration into the CNS while the tissue inhibitor matrix metalloproteinase-1 (TIMP-1) inhibits MMP-9 actions. The aim of this study was to evaluate the expression of TIMP-1 RNA and MMP-9/TIMP-1 RNA ratio in blood cells of Iranian patients with relapsing-remitting multiple sclerosis (RRMS) treated with IFNb. MATERIAL AND METHODS The study compared the expression level of TIMP-1 gene in RRMS samples with normal individuals in Iran and the results were compared using a ratio of MMP-9 to TIMP-1. All patients were HLA-DRB1*15 negative and were responders to interferon-beta with a normal vitamin D level. RESULTS The RRMS patients manifested a lower expression level of TIMP-1 RNA than their normal counterparts although the result was not significant (P= 0.06). Also, the ratio of MMP-9 to TIMP-1 RNA increased significantly (P= 0.009). There was no linear correlation between TIMP-1 expression level and risk of Expanded Disability Status Scale of Kurtzke (EDSS); nor was there any significant correlation between expression status of TIMP-1 and duration of the disease. Although there was no significant decrease in TIMP-1 expression level, the MMP-9/TIMP-1 RNA ratio in RRMS was significantly higher than normal subjects. CONCLUSION Further studies are recommended to compare MMP-9/TIMP-1 RNA ratio in patients before and after taking IFN-beta in order to find out if MMP-9/TIMP-1 RNA ratio can function as a proper marker of the bio efficacy of IFN-beta treatment of MS.

Frequency of viral infections and environmental factors in multiple sclerosis.

OBJECTIVES Multiple sclerosis (MS) is a complicated disease which occurs due to relationship between genes and environmental factors that causes tissue damage by autoimmune mechanisms.We investigated and illustrated the hypotheses correlated to the evidence of several putative environmental risk factors for MS onset and progression in this part of Iran. MATERIALS AND METHODS Univariate logistic regression was used to detect the effects of environmental factors on the risk of MS. Data were analyzed using SPSS version 16. RESULTS The childhood history of patients with rubella, measles and chickenpox increased the risk of MS significantly. Moreover, low consumption of dairy products, avoidance of seafood consumption, cigarette smoking and exposure to tobacco smoke, stress, anxiety disorders, depress and disturbing thoughts, negative and disturbing thoughts, developing a sudden shock upon hearing bad news, having obsessive-compulsive and being depressed increased the risk of MS significantly. CONCLUSIONS The results of the current research partially solved the puzzling question of complex interplay between environmental factors and MS disease in this part of Iran. Incorporating these factors enables more powerful and accurate detection of novel risk factors with diagnostic and prognostic methods.

Dominant and Protective Role of the CYTH4 Primate-Specific GTTT-Repeat Longer Alleles Against Neurodegeneration.

Primate-specific genes and regulatory mechanisms could provide insight into human brain functioning and disease. In a genome-scale analysis of the entire protein-coding genes listed in the GeneCards database, we have recently reported human genes that contain “exceptionally long” short tandem repeats (STRs) in their core promoter, which may be of adaptive/selective evolutionary advantage in this species. The longest tetra-nucleotide repeat identified in a human gene core promoter belongs to the CYTH4 gene. This GTTT-repeat is specific to Hominidae and Old World monkeys, and the shortest allele of this repeat, (GTTT)6, is linked with neural dysfunction and type I bipolar disorder in human. In the present study, we sought a possibly broader role for the CYTH4 gene core promoter GTTT-repeat in neural functioning and investigated its allelic distribution in a total of 949 human subjects, consisting of two neurodegenerative disorders, multiple sclerosis (MS) (n = 272) and Alzheimer’s disease (AD) (n = 257), and controls (n = 420). The range of the alleles of this GTTT-repeat in the human sample studied was between 6- and 9-repeats. The shortest allele, (GTTT)6, was significantly in excess in the MS and AD patients in comparison with the controls (p < 0.004). The 6/6, 6/7, and 7/7 genotypes were in excess in the MS and AD patients, whereas the overall frequency of all other genotypes (consisting of at least one longer allele, i.e., 8- or 9-repeat) was higher in the controls (p < 0.005), indicating a dominant and protective effect for the longer alleles against neurodegeneration. This is the first indication of the involvement of a primate-specific STR in neurodegeneration in humans. We propose an adaptive evolutionary role for the expansion of the CYTH4 gene core promoter GTTT-repeat in the human brain, which is supported by a link between the shortest allele of this repeat with neuropsychiatric disorders.