Diabetes has become a pandemic as the number of diabetic people continues to rise globally. Being a heterogeneous disease, it has different manifestations and associated complications in different individuals like diabetic nephropathy, neuropathy, retinopathy, and others. With the advent of science and technology, this era desperately requires increasing the pace of embracing precision medicine and tailoring of drug treatment based on the genetic composition of individuals. It has been previously established that response to antidiabetic drugs, like biguanides, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and others, depending on variations in their transporter genes, metabolizing genes, genes involved in their action, etc. Responsiveness of these drugs also relies on epigenetic factors, including histone modifications, miRNAs, and DNA methylation, as well as environmental factors and the lifestyle of an individual. For precision medicine to make its way into clinical procedures and come into execution, all these factors must be reckoned with. This review provides an insight into several factors oscillating around the idea of precision medicine in type-2 diabetes mellitus.
Prenatal testing provides crucial information about the health status of fetuses as well as recommending better treatment. For the past decades, prenatal testing using chorionic villus sampling and amniocentesis were the two majorly used forms of invasive prenatal diagnostic approaches. However, to facilitate prenatal testing without causing any danger to the fetus, the noninvasive prenatal diagnostic method, which uses circulating cell-free deoxyribonucleic acid (DNA), has become a suitable method of prenatal diagnosis. This review discusses the recent bioinformatics approaches used for analyzing fetal DNA concentration.
The development of tooth is a highly complex procedure and mastered by specific genetic programs. Genetic alterations, environmental factors, and developmental timing can disturb the execution of these programs, and result in various dental anomalies like hypodontia/oligodontia, and supernumerary teeth, which are commonly seen in our clinical practice. Advances in molecular research enabled the identification of various genes involved in the pathogenesis of dental anomalies. In the near future, it will help provide a more accurate diagnosis and biological-based treatment for these anomalies. In this article, we present the molecular phenomenon of tooth development and the genetics of various dental anomalies.
Psoriasis is an erythematous-squamous dermatosis with a polygenic inheritance history. Both environmental and genetic factors play a role in the etiology of the disease. Over the past two decades, numerous linkage analyzes and genome-wide association studies have been conducted to investigate the role of genetic variation in disease pathogenesis and progression. To date, >70 psoriasis susceptibility loci have been identified, including HLA-Cw6, IL12B, IL23R, and LCE3B/3C. Some genetic markers are used in clinical diagnosis, prognosis, treatment, and personalized new drug development that can further explain the pathogenesis of psoriasis. This review summarizes the immunological mechanisms involved in the etiopathogenesis of psoriasis and recent advances in susceptibility genes and highlights new potential targets for therapeutic intervention.
Tuberculosis (TB) continues to be a major infectious disease affecting individuals worldwide. Current TB treatment strategy recommends the standard short-course chemotherapy regimen containing first-line drug, i.e., isoniazid, rifampicin, pyrazinamide, and ethambutol to treat patients suffering from drug-susceptible TB. Although Mycobacterium tuberculosis, the causing agent, is susceptible to drugs, some patients do not respond to the treatment or treatment may result in serious adverse reactions. Many studies revealed that anti-TB drug-related toxicity is associated with genetic variations, and these variations may also influence attaining maximum drug concentration. Thus, inter-individual diversities play a characteristic role by influencing the genes involved in drug metabolism pathways. The development of pharmacogenomics could bring a revolution in the field of treatment, and the understanding of germline variants may give rise to optimized targeted treatments and refine the response to standard therapy. In this review, we briefly introduced the field of pharmacogenomics with the evolution in genetics and discussed the pharmacogenetic impact of genetic variations on genes involved in the activities, such as anti-TB drug transportation, metabolism, and gene regulation.
Background Dendritic cell (DC) tumor vaccine has been extensively utilized in preclinical and clinical studies; however, this technique has encountered many difficulties, particularly in late-stage tumor patients. For those, ex vivo-induced DCs are actuallymyeloid-derived suppressive cells-derived DCs (MDSC-DCs). MDSCs with immunosuppressive activity, but not monocytes, became the major DC precursor. Thus, how to enhance antitumor activity of MDSC-DCs is urgent need to address.
Methods We utilized 4T1 and MC38 tumor-bearing both wildtype and CC chemokine ligand 5-/- (CCL5-/-) mice as animal models. MDSC-DCs were induced from splenocytes of these mice by granulocyte macrophage-colony stimulating factor/interleukin-4 with or without all-trans-retinoic acid (ATRA) in vitro for 7 days, then incubated with tumor-cell-lysis to treat mouse models for total three doses. For human MDSC-DCs, peripheral bloods from colorectal cancer patients were induced in vitro as murine cells with or without T- lymphocytes depletion to get rid of CCL5.
Results Flow cytometry analysis showed that MDSCs from CCL5 -/- mice could be induced into a new type of CD24+ MDSC-DCs in the presence of ATRA, which had more antitumor activity than control. Antibody blocking and adoptive transfer experiments demonstrated that downregulation of regulatory T cells (Tregs) mediated the inhibition of CD24+ MDSC-DCs on tumor growth. Mechanically, CD24+ MDSC-DCs inhibited Tregs' polarization by secreting cytokine or coactivators' expression. What's important, decreasing CCL5 protein levels by T- lymphocytes depletion during both murine and human MDSC-DCs in vitro induction could also acquire CD24+ MDSC-DCs.
Conclusion Knockdown of CCL5 protein during MDSC-DCs culture might provide a promising method to acquire DC-based tumor vaccines with high antitumor activity.
Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by a devastating decline in cognitive activities among all types of dementia, and it severely affects the quality of life. Late-onset AD (LOAD) occurs after the age of 65 years and develops sporadically. Although aging comes first along the main risk factors underlying LOAD, disease-causing susceptibility genes have been associated with disease pathogenesis. In our study, we included the genes PARP1, POLB, HTRA2, SLC1A2, HS1BP3, and DRD3 to be investigated in LOAD patients based on their expression levels. Within this framework, we aimed to determine the possible functions of these genes in the pathophysiology of the disease. We investigated whether the utilization of these genes as biomarkers in the early diagnosis of LOAD may help the treatment scheme to be applied in the clinic. We involved 50 individuals in the study and collected peripheral blood samples from the patients and control groups for molecular genetic analysis. Subsequently, RNA was extracted from the peripheral blood samples, and expression analyzes were performed using qualitative reverse transcription polymerase chain reaction. The results obtained were evaluated by using proper statistical methods. Our results demonstrated that there was no difference between patient and control groups in terms of HTRA2, DRD3, HS1BP3, and POLB genes. The expression levels of the SLC1A2 and PARP1 genes were significantly lower in the patient group compared with the control group. In conclusion, we presume that the PARP1 and SLC1A2 genes can be utilized as molecular biomarkers for LOAD.
Acinetobacter baumannii is a bacterium found in most places, especially in clinics and hospitals, and an important agent of nosocomial infections. The presence of class D enzymes such as OXA-type carbapenemases in A. baumannii is proven to have a key function in resistance to carbapenem. The aim of the current study is to determine the blaOXA-type carbapenemase genes and antimicrobial resistance among clinically isolated samples of A. baumannii. We assessed 100 clinically isolated specimens of A. baumannii from patients in intensive care units of educational hospitals of Hamadan, West of Iran. The A. baumannii isolates' susceptibility to antibiotics was performed employing disk diffusion method. Multiplex polymerase chain reaction was used to identify the blaOXA-24-like , blaOXA-23-like , blaOXA-58-like , and blaOXA-51-like genes. The blaOXA-23-like , blaOXA-24-like , and blaOXA-58-like genes' prevalence were found to be 84, 58, and 3%, respectively. The highest coexistence of the genes was for blaOXA-51/23 (84%) followed by blaOXA-51/24-like (58%). The blaOXA-51/23- like pattern of genes is a sort of dominant gene in resistance in A. baumannii from Hamadan hospitals. The highest resistance to piperacillin (83%) and ciprofloxacin (81%) has been observed in positive isolates of blaOXA-23-like . The A. baumannii isolates with blaOXA-58-like genes did not show much resistance to antibiotics. Based on the results of the phylogenetic tree analysis, all isolates have shown a high degree of similarity. This study showed the high frequency of OXA-type carbapenemase genes among A. baumannii isolates from Hamadan hospitals, Iran. Thus, applying an appropriate strategy to limit the spreading of these strains and also performing new treatment regimens are necessary.
Sterile α motif domain-containing protein 9 (SAMD9) is a regulatory protein centrally involved in cell proliferation and apoptosis. Mapped to 7p21.2, variants in SAMD9 have been reported in <50 pediatric cases worldwide, typically with early lethality. Germline gain-of-function SAMD9 variants are associated with MIRAGE syndrome (myelodysplasia, infection, restricted growth, adrenal hypoplasia, genital anomalies, and enteropathy). Spalt like transcription factor 1 (SALL1) is a zinc finger transcriptional repressor located at 16q12.1 where only two transcript variants in SALL1 are known. RUNX2 (6p21.1) encodes a nuclear protein with a Runt DNA-binding domain critical for osteoblastic differentiation, skeletal morphogenesis, and serves as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. RUNX2 and SALL1 are thus both “master regulators” of tissue organization and embryo development. Here, we describe exome sequencing and copy number variants in two previously unknown mutations—R824Q in SAMD9, and Q253H in SALL1. A multiexon 3′ terminal duplication of RUNX2 not previously encountered is also reported. This is the first known phenotype assessment for an intersection of all three variants in a healthy 46,XX adult. Focusing on developmental progress, ultrastructural renal anatomy, and selected reproductive aspects, we describe this unique genotype diagnosed incidentally during coronavirus disease 2019 (COVID-19) illness. Individually, disruption in SAMD9, RUNX2, or SALL1 would be expected to give a bleak prognosis. However, this variant convergence appears to dampen severe pathology perhaps by cross-gene silencing of effects normally deleterious when such changes occur alone.
Objectives Cervical cancer (CC) is one of the most destructive disease caused by persistent HPV infection which affects women worldwide, especially in developing countries. The genetic basis of host immune response especially cytokine function has been shown to influence CC susceptibility. Studies have demonstrated that IL-10 gene polymorphism have been associated with numerous malignancies, but in context to CC results were inconclusive. Though, aim of our study to investigate the association between IL-10 -1082A/G and -819C/T promoter polymorphism and CC susceptibility.
Material and Methods This study comprised 192 women with CC and 200 controls. HPV detection was done by RT-PCR and genotyping was assessed through PCR-RFLP method. Serum concentration of IL-10 measured by ELISA.
Results Women with AG and AG+GG genotypes of IL-10 -1082A/G had two-fold increased risk of CC [OR, 2.35 (95% CI, 1.54-3.58), p = 0.005], [OR, 2.03 (95% CI, 1.36-3.04), p = 0.0005] compared to controls. Women with G allele of -1082A/G polymorphism had linked with CC susceptibility [OR, 1.39 (95% CI, 1.02-1.88), p = 0.036] compared to controls. No significant difference was found between patients and controls in the genotype or allele frequencies of IL-10 -819C/T polymorphism [OR, 1.00 (95% CI, 0.63-1.58), p = 0.99]. The level of serum concentration of IL-10 was significantly higher in cases compared to controls.
Conclusion These findings help to understand that polymorphism of IL-10 -1082A/G gene is associated with increased risk of CC development and can serve as a marker of genetic susceptibility to CC.
Background Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm with features of the myelodysplastic syndromes (MDSs) and myeloproliferative neoplasm presenting with peripheral blood monocytosis and an inherent risk for transformation to acute myeloid leukemia, while the abnormal DNA methylation plays a critical role in the pathogenesis of MDS, which is a disease of disordered differentiation. Recently, with the rapid development of molecular biology, hypomethylating agents (HMAs) for the treatment of MDS has gradually become a research focus. The objective of this study was to evaluate the benefits and risks of HMAs for patients with CMML.
Materials and Methods PubMed, Embase, the Cochrane Library, and three Chinese databases were searched for studies published before November 2020 that used HMAs in CMML.
Results The pooled objective response rate (ORR), complete response (CR), and partial response (PR) were 50.0, 21.0, and 2.0%, respectively. The proportion of patients with minor response (MR) was significantly higher for decitabine (DAC) than for azacitidine (AZA). There was no significant difference in hematologic improvement, ORR, CR, and PR rates between the DAC and AZA groups. Hematological toxicity included neutropenia grade 3/4 (14.0%), anemia grade 3/4 (17.0%), and thrombocytopenia grade 3/4 (22.0%).
Conclusion This study showed that HMAs were effective and safe in the treatment of CMML, but large multicenter study would be needed to confirm the efficacy of HMAs for the treatment of CMML with different risk level and genetic abnormality, to support individualization treatment theoretically.
Objective The goal of this research was to investigate the gap junction beta 2 (GJB2) gene mutations associated with nonsyndromic hearing loss individuals in North Karnataka, India.
Materials and Methods For this study, patients with sensorineural genetic hearing abnormalities and a family history of deafness were included. A total of 35 patients from 20 families have been included in the study. The patient's DNA was isolated from peripheral blood samples. The GJB2 gene coding region was analyzed through Sanger sequencing.
Results There is no changes in the first exon of the GJB2 gene. Nine different variants were recorded in second exon of the targeted gene. W24X and W77X are two nonsense mutations and three polymorphisms viz. R127H, V153I, and I33T were reported along with four 3′-UTR variants. A total (9/20) of 45% of families have been identified with mutations in the targeted gene.
Conclusion GJB2 mutations were identified in 19 deaf-mute patients (19/35), and 13 patients were homozygous for the mutations identified in our study cohort. In our study, W24X mutation was found to be the pathogenic with a high percentage, prompting further evaluation of the other genes, along with the study of additional genetic or external causes in the families, which is essential.
Statement of Problem Prosthodontic planning in patients with temporomandibular joint disorders (TMDs) is a challenge for the clinicians.
Purpose A differential biomarker identification could aid in developing methods for early detection and confirmation of TMD from other related conditions.
Materials and Methods The present study identified candidate genes with possible association with TMDs. The observational study delineates genes from three datasets retrieved from DisGeNET database. The convergence of datasets identifies potential genes related to TMDs with associated complication such as osteoarthritis. Gene ontology analysis was also performed to identify the potential pathways associated with the genes belonging to each of the datasets.
Results The preliminary analysis revealed vascular endothelial growth factor A (VEGFA), interleukin 1 β (IL1B, and estrogen receptor 1 (ESR1) as the common genes associated with all three phenotypes assessed. The gene ontology analysis revealed functional pathways in which the genes of each dataset were clustered. The chemokine and cytokine signaling pathway, gonadotropin-releasing hormone receptor pathway, cholecystokinin receptors (CCKR) signaling, and tumor growth factor (TGF)-β signaling pathway were the pathways most commonly associated with the phenotypes. The genes CCL2, IL6, and IL1B were found to be the common genes across temporomandibular joint (TMJ) and TMJ + osteoarthritis (TMJ-OA) datasets.
Conclusion Analysis through computational approach has revealed IL1B as the crucial candidate gene which could have a strong association with bone disorders. Nevertheless, several immunological pathways have also identified numerous genes showing putative association with TMJ and other related diseases. These genes have to be further validated using experimental approaches to acquire clarity on the mechanisms related to the pathogenesis.
Background Cytogenomic analyses have been used to detect pathogenic copy number variants. Patients with deletions at 6q26-q27 present variable clinical features. We reported clinical and cytogenomic findings of eight unrelated patients with a deletion of 6q26-q27. A systematic review of the literature found 28 patients with a deletion of 6q26-q27 from 2010 to 2020.
Results For these 36 patients, the sex ratio showed equal occurrence between males and females; 29 patients (81%) had a terminal deletion and seven patients (19%) had a proximal or distal interstitial deletion. Of the 22 patients with parental studies, deletions of de novo, maternal, paternal, and bi-parental inheritance accounted for 64, 18, 14, and 4% of patients, respectively. The most common clinical findings were brain abnormalities (100%) in fetuses observed by ultrasonography followed by developmental delay and intellectual disability (81%), brain abnormalities (72%), facial dysmorphism (66%), hypotonia (63%), learning difficulty or language delay (50%), and seizures (47%) in pediatric and adult patients. Anti-epilepsy treatment showed the effect on controlling seizures in these patients. Cytogenomic mapping defined one proximal critical region at 6q26 containing the putative haploinsufficient gene PRKN and one distal critical region at 6q27 containing two haploinsufficient genes DLL1 and TBP. Deletions involving the PRKN gene could associate with early-onset Parkinson disease and autism spectrum disorder; deletions involving the DLL1 gene correlate with the 6q terminal deletion syndrome.
Conclusion The genotype-phenotype correlations for putative haploinsufficient genes in deletions of 6q26-q27 provided evidence for precise diagnostic interpretation, genetic counseling, and clinical management of patients with a deletion of 6q26-q27.
Geroderma osteodysplasticum (GO; MIM 231070) is characterized by a typical progeroid facial appearance, wrinkled, lax skin, joint laxity, skeletal abnormalities with variable degree of osteopenia, frequent fractures, scoliosis, bowed long bones, vertebral collapse, and hyperextensible fingers. The disorder results from mutations in the GORAB—golgin, RAB6 interacting. This gene encodes a member of the golgin family, a group of coiled-coil proteins on golgin that maps to chromosome 1q24. The encoded protein has a function in the secretory pathway, was identified by terminal kinase-like protein, and thus, it may function in mitosis. Mutations in this gene have been associated with GO. Herein, we describe the clinical presentation of one young male patient from related Saudi parents. Mutations, a homozygous frameshift mutation (c.306dup p.(pro 103 Thrfs*20)). Interestingly, phenotypic variability was observed in this patient with GO features that were more atypical than the cases reported in the literature as he looks tall stature where most of the cases reported were short and arachnodactyly fingers which mimic other syndromes.
The frequency of 18p deletion syndrome is estimated to be ∼1/50,000 live births and is more commonly associated with certain clinical features including short stature, intellectual disability, and facial dysmorphism. Physical examination of our patient revealed a short stature, intellectual disability, facial dysmorphism (microcephaly, ptosis, epicanthus, low nasal bridge, protruding ears, long philtrum, and thin lips), and clinodactyly of the fifth finger. The peripheral karyotype was 46, XX, del (18) (p11.32p11.2). DNA microarray analysis revealed a de novo 13.9-Mb deletion at 18p11.32p.11.21. Echocardiography revealed asymmetric septal hypertrophy. Congenital cardiac abnormalities are present very rarely in this syndrome. This finding suggests that one locus or loci that play a role in cardiac development is located in this chromosomal region. Although rare, cardiac hypertrophies should be kept in mind when evaluating a patient with phenotypic anomalies and genetic results compatible with an 18p deletion syndrome.
This study shows that oligonucleotide sequences are shared between the human genome and primers that have been proposed/used for SARS-CoV-2 detection by polymerase chain reaction (PCR). The high level of sharing (namely, up to 19mer with a maximum number of gaps equal to 2) might bear implications for the diagnostic validity of SARS-CoV-2 detection by PCR.
Mannose-binding lectin 2 (MBL2) is a serine protease which is believed to be an important factor in the inherited immune system. In this article, we present a coronavirus disease 2019 (COVID-19) family of five patients: a 56-year-old father, a 51-year-old mother, two sons aged 23 and 21 years, and a 15-year-old daughter. According to the results of MBL2 rs1800450 variant analysis performed, the father had homozygous mutant, the mother had homozygous normal, and the three children had heterozygous mutant genotype. When we compared the clinical parameters and genotypes, MBL2 gene polymorphism plays a very important role in COVID-19 susceptibility and severe disease. The family, which makes up our study, is the proof of this situation, and it contains important implications for host factors and COVID-19.