Selenoprotein P in a Rodent Model of Exercise; Theorizing Its Interaction with Brain Reward Dysregulation, Addictive Behavior, and Aging.

Exercise promotes health and wellness, including its operation as a protective factor against a variety of psychological, neurological, and chronic diseases. Selenium and its biomarker, selenoprotein P (SEPP1), have been implicated in health, including cancer prevention, neurological function, and dopamine signaling. SEPP1 blood serum levels were compared with a one-way ANOVA between sedentary (SED), moderately exercised (MOD) [10 m/min starting at 10 min, increasing to 60 min], and high-intensity interval training (HIIT) exercised rats [30 min in intervals of 2-min followed by a 1-min break, speed progressively increased from 10 to 21 m/min]. HIIT rats showed significantly higher serum SEPP1 concentrations compared to MOD and SED. More specifically, HIIT exercise showed an 84% increase in SEPP1 levels compared to sedentary controls. MOD rats had greater serum SEPP1 concentrations compared to SED, a 33% increase. The results indicated that increased exercise intensity increases SEPP1 levels. Exercise-induced increases in SEPP1 may indicate an adaptive response to the heightened oxidative stress. Previous studies found a significant increase in dopamine D2 receptor (D2R) binding in these same rats, suggesting a potential association between SEPP1 and dopamine signaling during exercise. Modulating antioxidants like SEPP1 through personalized therapies, including exercise, has broad implications for health, disease, and addiction.

A Pharmacogenomics-Based In Silico Investigation of Opioid Prescribing in Post-operative Spine Pain Management and Personalized Therapy.

Considering the variability in individual responses to opioids and the growing concerns about opioid addiction, prescribing opioids for postoperative pain management after spine surgery presents significant challenges. Therefore, this study undertook a novel pharmacogenomics-based in silico investigation of FDA-approved opioid medications. The DrugBank database was employed to identify all FDA-approved opioids. Subsequently, the PharmGKB database was utilized to filter through all variant annotations associated with the relevant genes. In addition, the dpSNP ( https://www.ncbi.nlm.nih.gov/snp/ ), a publicly accessible repository, was used. Additional analyses were conducted using STRING-MODEL (version 12), Cytoscape (version 3.10.1), miRTargetLink.2, and NetworkAnalyst (version 3). The study identified 125 target genes of FDA-approved opioids, encompassing 7019 variant annotations. Of these, 3088 annotations were significant and pertained to 78 genes. During variant annotation assessments (VAA), 672 variants remained after filtration. Further in-depth filtration based on variant functions yielded 302 final filtered variants across 56 genes. The Monoamine GPCRs pathway emerged as the most significant signaling pathway. Protein-protein interaction (PPI) analysis revealed a fully connected network comprising 55 genes. Gene-miRNA Interaction (GMI) analysis of these 55 candidate genes identified miR-16-5p as a pivotal miRNA in this network. Protein-Drug Interaction (PDI) assessment showed that multiple drugs, including Ibuprofen, Nicotine, Tramadol, Haloperidol, Ketamine, L-Glutamic Acid, Caffeine, Citalopram, and Naloxone, had more than one interaction. Furthermore, Protein-Chemical Interaction (PCI) analysis highlighted that ABCB1, BCL2, CYP1A2, KCNH2, PTGS2, and DRD2 were key targets of the proposed chemicals. Notably, 10 chemicals, including carbamylhydrazine, tetrahydropalmatine, Terazosin, beta-methylcholine, rubimaillin, and quinelorane, demonstrated dual interactions with the aforementioned target genes. This comprehensive review offers multiple strong, evidence-based in silico findings regarding opioid prescribing in spine pain management, introducing 55 potential genes. The insights from this report can be applied in exome analysis as a pharmacogenomics (PGx) panel for pain susceptibility, facilitating individualized opioid prescribing through genotyping of related variants. The article also points out that African Americans represent an important group that displays a high catabolism of opioids and suggest the need for a personalized therapeutic approach based on genetic information.

Summary Document Research on RDS Anti-addiction Modeling: Annotated Bibliography.

Annotated bibliography of genetic addiction risk severity (GARS) publications, pro-dopamine regulation in nutraceuticals (KB220 nutraceutical variants), and policy documents. Further research is required to encourage the field to consider "Reward Deficiency Syndrome (RDS) Anti-addiction Modeling" which involves early risk identification by means of genetic assessment similar to GARS, followed by induction of dopamine homeostasis by means of genetically guided pro-dopamine regulation similar to KB220. These results suggest that genetically based treatments may be a missing piece in the treatment of substance use disorder (SUD).

A Mutation in the CACNA1F Gene Found by Whole Exome Sequencing (WES) and In Silico Analysis in an Iranian Family with Consanguineous Relationships.

BACKGROUND: X-linked mutations are highly important in clinical diagnosis, and at least 533 disorders are related to the genes located on the X chromosome. CASE PRESENTATION: A 21-year-old Caucasian woman with a 24-year-old Caucasian man as her fiancé referred Clinical genetic lab for premarital genetic counseling (carrier screening). None of them had any abnormal manifestations. Following genetic counseling, Whole Exome Sequencing (WES) test performed to find the possible pathogenic mutations. Also, after drawing the couple's pedigree, candidate mutations were examined in the woman's parents as well as her uncles. Additionally, in silico investigations were performed through SWISS-MODEL, MolProbity, ProSA, Py- Mol, and FATCAT tools. The most important mutation diagnosed in the woman (R1362Q in the 35th exon of CACNA1F), was observed in her mother and her two uncles. The mutation was also screened in both her father and her fiancé, but they had no mutations. After medical examinations of carriers, there was no sign of any eye impairment. Other mutations were TCTN2 (c.1613-2A>G), TARS (p.K319E), SPEG (p.E3020K), CPS1 (p.A1180V), MYO3A (p.I736M), NNT (p.R968Q), MED23 (p.K406T). Bioinformatics analyses indicated no alteration in the mutant structure of CACNA1F (Q1362) compared with the normal structure (R1362). CONCLUSION: Conclusively, the current study emphasizes the non-pathogenic effect of missense mutation R1362Q in the 35th exon of CACNA1F in association with ocular diseases. This will ensure the reports of this mutation as healthy instead of uncertain in the literature and databanks.

Haplotype-based association study of TCF7L2 gene variants with the development of diabetic retinopathy in an Iranian population.

BACKGROUND: Diabetic retinopathy (DR) is recognized as one of the most prevalent complications of diabetes and a major cause of morbidity. Transcription factor 7-like 2 (TCF7L2), a pivotal component in the Wnt-signaling pathway, plays a significant role in ß-cell development, blood-glucose homeostasis, cell survival, cell migration, and cell proliferation. Thus, this study aimed to assess the association between TCF7L2 variants (rs7903146, rs11196205, and rs12255372) with DR in a population-based association study. MATERIALS AND METHODS: DNA was extracted from whole blood of all subjects by salting-out procedure. Total 524 T2DM patients including 234 T2DM individuals without DR and 290 T2DM individuals with DR were genotyped by TaqMan assay technology. Clinical characteristics of subjects were conducted to evaluate the plausible association between TCF7L2 variants and DR with univariate linear regression analysis. RESULTS: Demographic analysis between case and control groups revealed significant differences in FBS, HbA1c, lipidemia, heart disease, and family history of T2DM (p < 0.05). No significant difference was observed in either genotypes distribution or allele frequency (p > 0.05) between T2DM individuals with and without DR in any models of inheritance. Genotype-phenotype association showed no significant association. Result of analysis indicated that HbAlc with adjusted OR of 1.8 (p < 0.0001) and first-degree relatives of family history with adjusted OR of 3.04 (p < 0.0001) were significantly associated with DR. Finally, haplotype analysis showed no noticeable association. CONCLUSION: In conclusion, there was no significant genetic association between rs7903146, rs11196205, and rs12255372 with DR among T2DM Iranians; however, these variants may play unknown roles in other populations.

A Novel Mutation (Lys31Arg) in the DMD Gene Impacts on Neuromuscular Dysfunctions found by Whole Exome Sequencing and In Silico Analyses in an Iranian Family.

BACKGROUND: Duchene Muscular Disorder (DMD) is a severe X-linked recessive neuromuscular disease. Previous reports predicted that one-third of cases with a fatal X-linked recessive disease will be caused by a novel mutation, and the mutation rate for DMD seems to be higher in males. OBJECTIVE: A novel mutation in the DMD gene DMD (NM_004006.3):c.92A>G (p.Lys31Arg) is suggested for males because of their heterozygous mothers carrying the mutant alleles. METHOD: Whole Exome Sequencing (WES) was done for a 25-year-old female followed by the screening of the novel mutation in her parents and her brother by the Sanger sequencing technique. Some in silico analyses were run to find the putative alterations in wild-type and mutant structures by PolyPhen-2 and Mupro. Notably, SWISS-MODEL was performed to build a reliable model for the mutant allele based on the PDB ID: 1DXX structure. Also, superimposition was done by PyMol. RESULTS: WES analysis revealed three novel mutations including DLD (exon13:c.G1382A:p. G461E), ABCA3 (exon12:c.G1404C:p.W468C), and DMD (exon2:c.A92G:p.K31R) in the case. Focusing on DMD mutation, Sanger sequencing of the patient's parents and brother indicated no mutant allele in her mother and brother but a mutant allele in her father as a hemizygous pattern. In silico analyses showed no considerable change regarding pathogenic impact. CONCLUSION: In conclusion, our findings revealed no pathogenic effect of the new mutation (K31R) of the DMD gene in an Iranian 25-year-old woman. Because of the DMD importance in preclinical diagnosis, these data may shed a light on the diagnosis of this mutation in future pregnancies.

A Novel Arg120Pro Mutation in the RP2 Gene in an Iranian Family with X-linked Retinitis Pigmentosa: A Case Report.

As the most common type of inherited retinal degenerative disease, retinitis pigmentosa (RP) has taken clinical and prenatal attention. Considering the clinical importance of consanguineous marriages, new mutations in this type of pregnancy have a high risk and increase the importance of Prenatal Diagnosis (PND). In vitro analysis was done through Whole Exome Sequencing (WES) for a 36-year-old woman who was referred to a genetic laboratory in Kermanshah in 2021 for PND. The woman had consanguineous marriage and was pregnant with twins (a boy and a girl). Mutation confirmation tests were also performed on her husband and both fetuses to find mutations. Moreover, in silico analyses were performed by SWISS-MODEL, ProSA, Molprobity, Swiss-Pdb Viewer, and ERRAT. The WES analysis showed a novel mutation of the RP2 gene (exon2:c. 359G>C: p.R120P) in the 36-year-old pregnant woman. Mutations identified in her husband and her twins revealed changes in protein conformations. Further modeling and validation evaluations showed the replacement of Arg by Pro at the 120th residue site of the cognate protein. For the first time, our report introduced a novel missense mutation in the RP2 gene associated with severe signs of RP in an Iranian family based on an X-linked recessive pattern of genetic inheritance. These findings may pave the way for a better diagnosis of RP in genetic counseling and PND.

Network-Based In Silico Analysis of New Combinations of Modern Drug Targets with Methotrexate for Response-Based Treatment of Rheumatoid Arthritis.

BACKGROUND: Methotrexate (MTX), sulfonamides, hydroxychloroquine, and leflunomide have consistently resulted in remission with relatively mild to moderate adverse effects in patients with rheumatoid arthritis (RA). Modern medications outperform traditional treatments in that they target the pathological processes that underlie the development of RA. METHODS: Following PRISMA guidelines, the authors accomplished a systematic review of the clinical efficacy of RA drugs, including the biologics such as Tumor Necrosis Factor-alpha inhibitors (TNF-α i) like Etanercept, Infliximab, Golimumab, and Adalimumab, kinase inhibitors (JAK inhibitors including Baricitinib and Tofacitanib), SyK inhibitors like Fos-tamatinib, MAPK inhibitors such as Talmapimod, T-cell inhibitors (Abatacept), IL6 blockers (Tocilizumab), and B cells depleters (Rituximab). These drugs have been found to increase remission rates when combined with MTX. A bioinformatics-based network was designed applying STRING-MODEL and the DrugBank database for the aforementioned drugs and MTX and, finally, employed for this systematic review. RESULTS: Current research demonstrates that non-TNF-α inhibitor biologicals are particularly helpful in treating patients who did not respond well to conventional medications and TNF-α inhibitors. Despite being effective, these innovative drugs have a higher chance of producing hazardous side effects. The in silico investigations suggested an uncovered molecular interaction in combining MTX with other biological drugs. The STRING-MODEL showed that DHFR, TYMS, and ATIC, as the receptors of MTX, interact with each other but are not connected to the major interacted receptors. CONCLUSIONS: New game-changing drugs including Mavrilimumab, Iguratimod, Upadacitinib, Fenebrutinib, and nanoparticles may be crucial in controlling symptoms in poorly managed RA patients. Emerging therapeutic targets like Toll-like 4 receptors, NLRP3 inflammasome complexes, and mesenchymal stem cells can further transform RA therapy.

Personalized Medicine in Cancer Pain Management.

BACKGROUND: Previous studies have documented pain as an important concern for quality of life (QoL) and one of the most challenging manifestations for cancer patients. Thus, cancer pain management (CPM) plays a key role in treating pain related to cancer. The aim of this systematic review was to investigate CPM, with an emphasis on personalized medicine, and introduce new pharmacogenomics-based procedures for detecting and treating cancer pain patients. METHODS: This study systematically reviewed PubMed from 1990 to 2023 using keywords such as cancer, pain, and personalized medicine. A total of 597 publications were found, and after multiple filtering processes, 75 papers were included. In silico analyses were performed using the GeneCards, STRING-MODEL, miRTargetLink2, and PharmGKB databases. RESULTS: The results reveal that recent reports have mainly focused on personalized medicine strategies for CPM, and pharmacogenomics-based data are rapidly being introduced. The literature review of the 75 highly relevant publications, combined with the bioinformatics results, identified a list of 57 evidence-based genes as the primary gene list for further personalized medicine approaches. The most frequently mentioned genes were CYP2D6, COMT, and OPRM1. Moreover, among the 127 variants identified through both the literature review and data mining in the PharmGKB database, 21 variants remain as potential candidates for whole-exome sequencing (WES) analysis. Interestingly, hsa-miR-34a-5p and hsa-miR-146a-5p were suggested as putative circulating biomarkers for cancer pain prognosis and diagnosis. CONCLUSIONS: In conclusion, this study highlights personalized medicine as the most promising strategy in CPM, utilizing pharmacogenomics-based approaches to alleviate cancer pain.

Transesophageal Echocardiogram Before Cardioversion in Atrial Fibrillation Patients.

Transesophageal echocardiography (TEE) offers an invaluable, non-invasive avenue for diagnosing and managing various cardiac conditions, including atrial fibrillation (AF). As the most common cardiac arrhythmia, AF affects millions and can lead to severe complications. Cardioversion, a procedure to restore the heart's normal rhythm, is frequently conducted on AF patients resistant to medication. Due to inconclusive data, TEE's utility prior to cardioversion in AF patients remains ambiguous. Understanding TEE's potential benefits and limitations in this population could significantly influence clinical practice. This review aims to scrutinize the current literature on the use of TEE before cardioversion in AF patients. The principal objective is to understand TEE's potential benefits and limitations comprehensively. The study seeks to offer a clear understanding and practical recommendations for clinical practice, thereby improving the management of AF patients before cardioversion using TEE. A literature search of databases was conducted using the keywords "Atrial Fibrillation," "Cardioversion" and "Transesophageal echocardiography," resulting in 640 articles. These were narrowed to 103 following title and abstract reviews. After applying exclusion and inclusion criteria with a quality assessment, 20 papers were included: seven retrospective studies, 12 prospective observational studies, and one randomized controlled trial (RCT). Stroke risk associated with direct-current cardioversion (DCC) potentially results from post-cardioversion atrial stunning. Thromboembolic events occur post cardioversion, with or without prior atrial thrombus or cardioversion complications. Generally, cardiac thrombus localizes in the left atrial appendage (LAA), a clear contraindication to cardioversion. Atrial sludge without LAA thrombus in TEE is a relative contraindication. TEE before electrical cardioversion (ECV) in anticoagulated AF individuals is uncommon. In AF patients planned for cardioversion, contrast enhancement facilitates thrombus exclusion in TEE images, reducing embolic events. Left atrial thrombus (LAT) frequently occurs in AF patients, necessitating TEE examination. Despite the increased use of pre-cardioversion TEE, thromboembolic events persist. Notably, patients with post-DCC thromboembolic events had no LA thrombus or LAA sludge. The use of TEE-guided DCC has grown due to its ability to detect atrial thrombi pre-cardioversion, aiding risk stratification. Thrombus in the left atrium also signals an elevated risk of future thromboembolic events in AF patients. While atrial stunning post cardioversion detected by TEE is a significant risk factor for future thromboembolic events, further evidence is required. Therapeutic anticoagulation is essential during and post cardioversion, even if no atrial thrombus is detected. Current data recommends cardioversion guided by TEE, particularly in outpatient settings.

A Review of Biomarkers in Delirium Superimposed on Dementia (DSD) and Their Clinical Application to Personalized Treatment and Management.

Delirium superimposed on dementia (DSD) occurs when patients with pre-existing dementia develop delirium. This complication causes patients to become impaired, posing safety concerns for both hospital staff and patients. Furthermore, there is an increased risk of worsening functional disability and death. Despite medical advances, DSD provides both diagnostic and therapeutic challenges to providers. Identifying at-risk patients and providing personalized medicine and patient care can decrease disease burden in a time-efficient manner. This review delves into bioinformatics-based studies of DSD in order to design and implement a personalized medicine-based approach. Our findings suggest alternative medical treatment methods based on gene-gene interactions, gene-microRNA (miRNA) interactions, gene-drug interactions, and pharmacogenetic variants involved in dementia and psychiatric disorders. We identify 17 genes commonly associated with both dementia and delirium including apolipoprotein E (ApoE), brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT), butyrylcholinesterase (BChE), acetylcholinesterase (AChE), DNA methyltransferase 1 (DNMT1), prion protein (PrP), tumor necrosis factor (TNF), serine palmitoyltransferase long chain base subunit 1 (SPTLC1), microtubule-associated protein tau (MAPT), alpha-synuclein (αS), superoxide dismutase 1 (SOD1), amyloid beta precursor protein (APP), neurofilament light (NFL), neurofilament heavy, 5-hydroxytryptamine receptor 2A (HTR2A), and serpin family A member 3 (ERAP3). In addition, we identify six main genes that form an inner concentric model, as well as their associated miRNA. The FDA-approved medications that were found to be effective against the six main genes were identified. Furthermore, the PharmGKB database was used to identify variants of these six genes in order to suggest future treatment options. We also looked at previous research and evidence on biomarkers that could be used to detect DSD. According to research, there are three types of biomarkers that can be used depending on the stage of delirium. The pathological mechanisms underlying delirium are also discussed. This review will identify treatment and diagnostic options for personalized DSD management.

A study on methylation of two CpG islands of MAOA gene promoter among opium-addicted males undergoing methadone treatment.

The association between methylation of MAOA gene promoter and alcohol and nicotine dependence has been demonstrated in women but not in men yet. Antisocial personality disorder (ASPD) and substance use disorders (SUD) are two types of disorders that could highly be influenced by methylation-induced changes in MAOA function. The aim of the current study is to investigate the effect of opioid addiction on methylation of MAOA gene promoter in males. DNA was extracted from the whole blood of all samples (29 opium-addicted individuals undergoing methadone treatment and 28 healthy people) according to the extraction protocol, followed by treating these samples with bisulfite kits. The investigated region including two CpG islands in the promoter region of MAOA gene contained 35 CpG dinucleotides investigated through Sanger sequencing method. The frequency of methylation at two CpG islands of MAOA gene promoter regions was equal to zero among addicted individuals undergoing methadone treatment and healthy peoples. Then, comparing methylation levels among the study group is not applicable. In conclusion, there was no association between opium addiction and methylation of the MAOA promoter regions in opium-addicted male undergoing methadone treatment.

Identification of miR-195-5p as a novel prognostic biomarker for colorectal cancer.

BACKGROUND: Recent evidence indicated that transcription patterns of microRNAs could be used as promising biomarkers for numerous cancers. It is stated that miR-195-5p could be used as a tumor suppressor in colorectal cancer (CRC). The purpose of the current work was to explore the transcription level of miR-195-5p and its clinical relevance in CRC patients. METHODS AND RESULTS: We used quantitative real-time polymerase chain reaction (qRT-PCR) to assess the tumor tissue sample of 140 CRC cases compared with normal adjacent tissue for the transcription of miR-195-5p and the clinicopathological relevance was statistically evaluated. We showed that tumor tissue miR-195-5p transcription was statistically downregulated in patients with CRC (median expression value 0.23, range 0.03-6.62) compared to normal adjacent tissue (median expression value 0.98, range 0.092-29.6, p < 0.001). The median transcription of miR-195-5p divided the CRC patients into miR-195-5p low-transcription (miR-195-5plow) and miR-195-5p high-transcription (miR-195-5phigh) groups. Furthermore, low miR-195-5p transcription level was statistically related with TNM stage, lymph node metastasis and tumor differentiation in CRC patients (all p-value < 0.05). Moreover, our results indicated that CRC cases with a decreased transcription level of miR-195-5p displayed a statistically shorter overall survival (OS) (p = 0.001) compared to higher miR-195-5p transcription. CONCLUSION: In conclusion, the finding proposes that miR-195-5p might be a valuable biomarker and a prognostic factor for CRC in the future.

Association Study of Opioid Receptor Delta-Type 1 (OPRD1) Gene Variants with Nicotine Dependence in an Iranian Population.

Twins studies indicate that many individual factors are associated with genetic polymorphisms in tobacco use, dependence vulnerability, and the ability to quit smoking. Opioid receptor delta-type 1 (OPRD1) is one of the most important genes in the opioid pathway. Therefore, the current study aimed to investigate the association of variants located in the intron 1 of the OPRD1 gene, including rs2236857, rs2236855, and rs760589, with susceptibility to nicotine dependence among northern Iranians. DNA of 426 individuals, including 224 smokers and 202 healthy people, were extracted with the salting-out standard technique, qualified with Agarose gel, then quantified with Nanodrop, and finally genotyped by Amplification Refractory Mutation System (ARMS) PCR. All statistical analyses were performed by SNPAlyze version 8.1 and SPSS version 20. Results revealed no significant association of all three studied variants with the susceptibility to nicotine dependence in any models of inheritance. However, there were five haplotypes with an overall frequency higher than 0.05; no significant impact of any of them on nicotine dependence was observed. Altogether, rs2236857, rs2236855, and rs760589 were not associated with nicotine dependence among northern Iranians.

Single locus and haplotype association of ENPP1 gene variants with the development of retinopathy among type 2 diabetic patients.

PURPOSE: The present study was designed to investigate the associations of ENPP1 variants (rs997509, rs1799774, rs1044498 (K121Q), and rs7754561) with diabetic retinopathy (DR) derived from type 2 diabetes mellitus (T2DM). METHODS: Total 501 T2DM patients with and without DR were studied as the case and control group, respectively. All four variants were genotyped by TaqMan assay. Statistical analyses were performed through SNPAlyze and SPSS software. RESULTS: The statistical analysis of clinical characteristics represented significant differences of HbA1c, and fasting blood sugar between two study groups. The results indicated that among four studied variants, rs997509 and rs7754561 were significantly associated with DR under recessive (P = 0.01) and dominant (P = 0.01) models of inheritance, respectively. One haplotype (T-A-T-A) with a frequency higher than 0.05 was associated with the increased risk of DR (P = 0.04). Genotype-phenotype sub-analysis of rs997509 and rs7754561 showed that only rs7754561 had significant associations with systolic and diastolic blood pressures (P = 0.03 and P = 0.01, respectively); more specifically, A allele carriers of rs7754561 were in a higher risk of blood pressures. CONCLUSIONS: This study suggested that rs997509 and rs7754561 were associated with the increased risk of DR among Iranians with T2DM and rs7754561 might be a potential genetic marker for prognosis and diagnosis of DR.

Haplotype-Based Association and In Silico Studies of OPRM1 Gene Variants with Susceptibility to Opioid Dependence Among Addicted Iranians Undergoing Methadone Treatment.

The associations of OPRM1 gene variants with opioid dependence have been demonstrated. This study investigated the association of rs495491, rs1799971 (A118G), rs589046, and rs10457090 variants of OPRM1 gene with opium dependence and their haplotypes among addicted individuals undergoing methadone treatment. Moreover, we investigated whether any of these variants were associated with libido dysfunction or insomnia among addicted people. A total of 404 individuals were genotyped by amplification refractory mutation system (ARMS) PCR. In silico studies were designed through homology modeling of A118G structures (N40 and D40) and docked with 41 FDA-approved drugs of OPRM1 protein by SWISS-MODEL, COACH, MolProbity, ProSA, Errat, Glide XP, and Autodock 4. Results revealed that rs495491, A118G, rs589046, and rs10457090 were significantly associated with opium dependence under recessive (P = 6.66E-10), dominant (P = 0.017), co-dominant (P = 0.001), and recessive (P = 9.28E-6) models of inheritance, respectively. Further analyses indicated three significant haplotypes including A-A-A-C (P-permutation < 1E-9), G-G-A-C (P-permutation = 0.04), and G-A-G-C (P-permutation = 8.69E-4). Genotype-phenotype associations of OPRM1 variants with insomnia and libido dysfunction showed no significant association. Docking showed the higher binding affinity of N40 rather than D40 model; however, methadone and morphine were bonded with D40 structure more powerful. Consequently, rs495491, A118G, rs589046, and rs10457090 were associated with opioid dependence among Iranians; also, A118G might be the most remarkable marker of OPRM1 owing to its vital structural roles.

Association of FSHR missense mutations with female infertility, in silico investigation of their molecular significance and exploration of possible treatments using virtual screening and molecular dynamics.

This study investigated the association of A419T (rs121909661) and T449I (rs28928870) with infertility among Iranian women and possible treatments by agonizing the mutated receptor. 151 women were genotyped at A419T and T449I sites. Homology modeling, pharmacophore modeling, virtual screening, docking and molecular dynamics (MD) were performed. A419T and T449I indicated a significant and a weak association with infertility among Iranian women (P = 0.005 and P = 0.03, respectively). Significant differences found among three genotypes of A419T with FSH (P = 0.01) and LH (P < 0.0001). G-allele carriers of A419T had susceptibility to display higher FSH and LH serum levels. In silico results revealed the most potent agonists among 3041 similar compounds and MD supported this finding. Altogether, genotyping of A419T and T449I as potential markers might be helpful in prognosis and treatment of infertility. Also, a new series of potent FSHR agonists were identified for future drug development and treatment of infertility related to FSHR dysfunction.

Association of PARP1 rs4653734, rs907187 and rs1136410 variants with breast cancer risk among Iranian women.

BACKGROUND: Breast cancer (BC) is the highest cause of mortality among female cancer patients. In some cases, BC is due to Poly [ADP-ribose] polymerase 1 (PARP1) gene dysregulation, which has been involved in various important cellular processes. Among Iranian women, the association between PARP1 polymorphisms and BC was never studied before so in this case-control study, the genetic association of three SNPs (rs1136410, rs907187 and rs4653734) was analyzed with susceptibility to BC. METHODS: The study subjects were 386 Iranian females divided into 186 patients and 200 healthy controls. The genotypes of PARP1 variants were detected using ARMS and a combined ARMS-RFLP PCR method. RESULTS: The results showed that Carriers of CG and GG genotypes of the variant rs4653734 were at higher risk of BC compared with wild-type carriers (CC) and this variant was statistically significant under a recessive model of inheritance. Moreover, rs907187 was related to increased BC risk in the CC and GG genotypes under dominant and recessive models of inheritance. The G allele frequency of rs4653734 and rs907187 was higher in breast cancer patients than in normal subjects. No association was detected between rs1136410 and susceptibility to BC among studied groups. Furthermore, A-G-C haplotype was linked to an increased BC risk, whereas A-C-C and A-C-G haplotypes were related to a decreased risk of BC. In Silico predictions suggested that rs907187 affects E2F and E2F-4 transcription factors binding site. CONCLUSIONS: The current study suggests that rs907187 and rs4653734 have remarkable associations with BC risk among Iranian women.

Association and in silico investigations of miR-302c insertion/deletion variant as a novel biomarker with susceptibility to gastric cancer.

Gastric cancer (GC) is the fifth most prevalent malignant tumor and the third most frequent cause of cancer mortality worldwide. rs199971565 is an insertion/deletion (INDEL) located in microRNA-302c (miR-302c) seed site, which may affect its function and biogenesis. There is no genetic association study investigating this INDEL with any disease till now. Thus, the current study was conducted to investigate the association of rs199971565 with susceptibility to GC in an Iranian population. In addition, in silico studies were performed to reveal the possible functional significance of this INDEL. A total of 378 subjects were genotyped through amplification refractory mutation system PCR (ARMS-PCR) after DNA extraction from peripheral blood by the salting out procedure. Also, in silico analyses were performed through databases and web tools including MiRNASNP V2.0, miRWalk V2.0, miRTarBase, DAVID V6.8, RNAfold, PHDcleave, miRmap, and STarMir. Results revealed that there was an association between rs199971565 and the incidence risk of GC under a recessive (P = .04, odds ratio [OR] = 18.73; 95% confidence interval [CI] = 1.07-326.95) model of inheritance. Also, compared to the Ins allele, the Del allele significantly increased the risk of GC (P = .01, OR = 2.02; 95% CI = 1.11-3.66). Further analyses showed no significant association in age and sex between two study groups (P = .216 and P = .798, respectively). In conclusion, for the first time, this study indicated the association and in silico investigations of rs199971565 and suggested it as a novel INDEL biomarker located in the seed site of miR-302c, which may have crucial roles in the susceptibility to GC and its incidence risk.