Dysregulated Genes and Signaling Pathways in the Formation and Rupture of Intracranial Aneurysm.

Intracranial aneurysm (IA) has the potential to rupture. Despite scientific advances, we are still not in a position to screen patients for IA and identify those at risk of rupture. It is critical to comprehend the molecular basis of disease to facilitate the development of novel diagnostic strategies. We used transcriptomics to identify the dysregulated genes and understand their role in the disease biology. In particular, RNA-Seq was performed in tissue samples of controls, unruptured IA, and ruptured IA. Dysregulated genes (DGs) were identified and analyzed to understand the functional aspects of molecules. Subsequently, candidate genes were validated at both transcript and protein level. There were 314 DGs in patients with unruptured IA when compared to control samples. Out of these, SPARC and OSM were validated as candidate molecules in unruptured IA. PI3K-AKT signaling pathway was found to be an important pathway for the formation of IA. Similarly, 301 DGs were identified in the samples of ruptured IA when compared with unruptured IAs. CTSL was found to be a key candidate molecule which along with Hippo signaling pathway may be involved in the rupture of IA. We conclude that activation of PI3K-AKT signaling pathway by OSM along with up-regulation of SPARC is important for the formation of IA. Further, regulation of Hippo pathway through PI3K-AKT signaling results in the down-regulation of YAP1 gene. This along with up-regulation of CTSL leads to further weakening of aneurysm wall and its subsequent rupture.

Association Between CYP2C19 Genotypes With Clinical Phenotypes and Adipokine Levels Among Ischemic Stroke Patients: A Prospective Observational Study.

Background Cytochrome P450 system is implicated in vascular pathologies, including stroke. Besides its role as a drug metabolizer, it also plays an important role in the metabolism of several endogenous substances like fatty acids, arachidonic acid, etc., which have pro-inflammatory effects. On the other hand, leptin and adiponectin are two of the most common adipose tissue-derived cytokines (adipokines), which are pro-inflammatory and anti-inflammatory in nature, respectively. Both of them are implicated in the pathogenesis of stroke. Methods We prospectively recruited ischemic stroke patients (within three months of occurrence of an attack of stroke). The occurrence of composite outcome (recurrence of transient ischemic attack/ischemic stroke or death) was evaluated for association with genetic variants of CYP2C19 (allele *2, *17, *3, and *4, i.e., single nucleotide polymorphism (SNP) 1/2/3/4, identified using TaqMan assays and DNA sequencing). Adiponectin and leptin levels were determined using an enzyme-linked immunosorbent assay. Comparisons were made between stroke vs. control patients and between CYP2C19 intermediate metabolizer (IM)/poor metabolizer (PM) vs. extensive metabolizer (EM)/ultra metabolizer (UM) (PM: *2/*2; IM: *1/*2 vs. EM: *1/*1; UM: *1/*17). P < 0.05 was taken as the threshold for statistical significance. Results A total of 204 patients and 101 controls were recruited. With regard to the occurrence of stroke, SNP2 showed a significant positive association. Haplotypes (SNP1/SNP2) AC (OR = 1.75 (1.08-2.83), p = 0.024) and GT (OR = 3.33 (1.53-7.22), p = 0.0026) were strongly associated with the occurrence of ischemic stroke even after adjustment for age and sex (global haplotype association p-value: 0.0062). Haplotype phenotype gender interaction was evident. Among stroke patients, with regard to composite outcome, only SNP1 showed a positive association. The AC haplotype was significantly associated with the occurrence of composite outcome (OR = 2.27 (1.17-4.41), p = 0.016). Among stroke patients, a significant positive association was seen between death and SNP1 (OR = 2.35 (1.13-4.90), p = 0.021) and AC haplotype (OR = 2.73 (1.20-6.22), p = 0.018). However, none of the SNPs or haplotypes showed any association with recurrence. Significant higher leptin and lower adiponectin levels were observed among stroke patients compared to controls. Leptin levels were higher in IM/PM group. IM/PM phenotypes showed a higher incidence of occurrence of composite outcome (hazard ratio = 2.07 (0.96-4.47), p = 0.056). Conclusion CYP2C19 polymorphisms may play a significant role in the pathogenesis of stroke. Leptin could serve as a prominent biomarker of atherosclerosis and inflammation in the early post-stroke period; however, further study is warranted with a larger sample size.

Oxidative stress in metabolic diseases: current scenario and therapeutic relevance.

The metabolic syndrome is a clustering condition of increased abdominal obesity in concert with hyperglycemia, insulin resistance, hypertension, and dyslipidemia. It confers higher risk of metabolic diseases such as diabetes and ischemic heart disease and has been observed to be associated with high morbidity and mortality. It is a progressive pathological process for diabetes-induced complications and appears to be multifactorial in origin. Several preclinical, clinical, and epidemiological reports have shown a persistent link between the metabolic syndrome and oxidative stress. There is pronounced imbalance between pro-oxidants and anti-oxidants with increased production of oxidizing molecules, depletion of anti-oxidants, and consequently accumulation of protein and lipid oxidation products in the cell in metabolic syndrome. The increased cellular pro-oxidant activity also results in altered molecular pathways, mitochondrial dysfunction, deregulation in cell cycle control, chromosomal aberrations, inflammation, and overall decreased biological activity as well as impairment of the antioxidant systems. Here, the focus of our review article will be on the formation of oxidative species, the interplay between metabolic syndrome and oxidative stress, and its potential implications in therapeutic approaches.

Genotyping Indian patients with primary cardiomyopathies-analysis of database.

INTRODUCTION: Each population has its own unique genotype. Genotyping data on Indian cardiomyopathy patients is lacking. METHODS: We aimed to create and analyse a database of sequence variations in Indian patients with primary cardiomyopathies. This included all data of the cardiomyopathy cohort at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh. In addition, all published papers in Pubmed containing sequence variations in Indian cardiomyopathy patients till December 2020 using specific search terms were included. Affected genes and sequence variations, methodologies and quality of clinical data was analysed. Novel sequence variations were documented. RESULTS: A database of 493 datasets including 417 different sequence variations was created. Of these, the PGIMER database had 137 datasets consisting of 94 different variants. Only 63 publications included genotyping data of Indian cardiomyopathy cohort from 2000 to 2020 reporting 335 sequence variations. Five (7.9%) studies were from institutions abroad. Of published variations, 35.1% were novel. Most studies carried out selective genotyping. Comprehensive genotyping using cardiomyopathy panels or whole exome sequencing was reported in only 9 (14.3%) publications. CONCLUSION: Database of 417 different sequence variations in Indian cardiomyopathy patients was analysed. Over a third of all reported sequence variations in Indians were novel.

A common Matrix metalloproteinase 8 promoter haplotype enhances the risk for hypertension via diminished interactions with nuclear factor kappa B.

OBJECTIVES: Matrix metalloproteinase 8 (MMP8) has a prominent role in collagen turnover in blood vessels and vascular remodeling. The contribution of regulatory single nucleotide polymorphisms in MMP8 to cardiovascular diseases is unclear. We aimed to delineate the influence of MMP8 promoter variations on hypertension. METHODS: A case-control study in unrelated individuals ( n  = 2565) was carried out. Resequencing of the MMP8 proximal promoter, linkage disequilibrium analysis, genotyping of variants and regression analyses were performed. MMP8 promoter-reporter constructs were generated and expressed in human vascular endothelial cells under various conditions. RESULTS: We identified four single nucleotide polymorphisms (SNPs) in the promoter region of MMP8 : -1089A/G (rs17099452), -815G/T (rs17099451), -795C/T (rs11225395), -763A/T (rs35308160); these SNPs form three major haplotypes. Hap3 (viz., GTTT haplotype) carriers showed significant associations with hypertension in two geographically distinct human populations (e.g., Chennai: odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.16-1.86, P  = 2 × 10 -3 ; Chandigarh: OR = 1.85, 95% CI = 1.21-2.81, P  = 4 × 10 -3 ). Hap3 carriers also displayed elevated systolic blood pressure, diastolic blood pressure and mean arterial pressure levels. Hap3 promoter-reporter construct showed lower promoter activity than the wild-type (Hap1) construct. In silico analysis and molecular dynamics studies predicted diminished binding of the transcription factor nuclear factor kappa B (NF-κB) to the functional -815T allele of Hap3 compared to the -815G wild-type allele; this prediction was validated by in-vitro experiments. Hap3 displayed impaired response to tumor necrosis factor-alpha treatment, possibly due to weaker binding of NF-κB. Notably, MMP8 promoter haplotypes were identified as independent predictors of plasma MMP8 and endothelial dysfunction markers (von Willebrand factor and endothelin-1) levels. CONCLUSION: MMP8 promoter GTTT haplotype has a functional role in reducing MMP8 expression during inflammation via diminished interaction with NF-κB and in enhancing the risk of hypertension.

MN/CA9 gene expression as a potential tumor marker for renal cell carcinoma.

MN/CA9 is a cell surface glycoprotein and a tumor-associated antigen. It plays a crucial role in the regulation of cell proliferation and oncogenesis. There is no ideal tumor marker currently available for renal cell carcinoma (RCC) with sufficient sensitivity and specificity. Therefore, we studied MN/CA9 gene expression in the tumor tissue, apparently normal kidney tissue, preoperative blood, and urine samples of patients with RCC. We included thirty cases of renal tumors (26 RCC and 4 benign tumors) in the study. We applied an RT-PCR assay for MN/CA9 gene expression to 26 RCC kidney tumor samples and four benign kidney tumor tissue samples. We also evaluated MN/CA9 gene expression in preoperative blood and urine samples of 15 of these cases. Additionally, thirty-five grossly normal renal tissue samples, including 21 from kidneys with RCC, were also evaluated for gene expression. The RT-PCR analysis revealed that twenty-one out of 26 RCC tissue samples showed MN/CA9 gene expression compared to three out of 35 non-malignant renal tissue samples (p < 0.05). Two out of four benign renal tissue samples also expressed this gene. We also observed MN/CA9 gene expression in nine out of 15 blood samples and four out of 15 urine samples. All patients with urinary MN/CA9 gene expression showed expression in blood and tumor tissue samples. We found a correlation in terms of MN/CA9 expression between blood and tumor tissue samples of RCC patients as those who exhibit MN/CA9 expression in blood were also positive at the tumor tissue levels. The difference in MN/CA9 gene expression in tumor tissue, blood, and urine samples in relation to the stage of the disease, nuclear grade, and histological cell-type was not statistically significant. However, all the three patients who had metastatic RCC had MN/CA9 gene expression in their blood. The existence of a tumor-associated antigen such as MN/CA9 may present a possible target for molecular diagnosis and management of RCC.

Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin Is a Novel Risk Factor for Cardiometabolic Disorders.

Pancreastatin (PST), a chromogranin A-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a nonsynonymous functional PST variant (p.Gly297Ser; rs9658664) that occurs in a large section of human populations. Association analysis of this single nucleotide polymorphism with cardiovascular/metabolic disease states in Indian populations (n = 4,300 subjects) displays elevated plasma glucose, glycosylated hemoglobin, diastolic blood pressure, and catecholamines in Gly/Ser subjects as compared with wild-type individuals (Gly/Gly). Consistently, the 297Ser allele confers an increased risk (∼1.3-1.6-fold) for type 2 diabetes/hypertension/coronary artery disease/metabolic syndrome. In corroboration, the variant peptide (PST-297S) displays gain-of-potency in several cellular events relevant for cardiometabolic disorders (e.g., increased expression of gluconeogenic genes, increased catecholamine secretion, and greater inhibition of insulin-stimulated glucose uptake) than the wild-type peptide. Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78) and insulin receptor than the wild-type peptide, providing a mechanistic basis for the enhanced activity of the variant peptide. In vitro binding assays validate these in silico predictions of PST peptides binding to GRP78 and insulin receptor. In conclusion, the PST 297Ser allele influences cardiovascular/metabolic phenotypes and emerges as a novel risk factor for type 2 diabetes/hypertension/coronary artery disease in human populations.

Structural and mechanistic insights into the inhibition of amyloid-ß aggregation by Aß39-42 fragment derived synthetic peptides.

The inhibition of amyloid-ß (Aß) aggregation is a promising approach towards therapeutic intervention for Alzheimer's disease (AD). Thirty eight tetrapeptides based upon Aß39-42C-terminus fragment of the parent Aß peptide were synthesized. The sequential replacement/modification employing unnatural amino acids imparted scaffold diversity, augmented activity, enhanced blood brain barrier permeability and offered proteolytic stability to the synthetic peptides. Several peptides exhibited promising protection against Aß aggregation-mediated-neurotoxicity in PC-12 cells at doses ranged between 10 µM and 0.1 µM, further confirmed by the thioflavin-T fluorescence assay. CD study illustrate that these peptides restrict the ß-sheet formation, and the non-appearance of Aß42 fibrillar structures in the electron microscopy confirm the inhibition of Aß42 aggregation. HRMS and ANS fluorescence spectroscopic analysis provided additional mechanistic insights. Two selected lead peptides 5 and 16 depicted enhanced blood-brain penetration and stability against serum and proteolytic enzyme. Structural insights into ligand-Aß interactions on the monomeric and proto-fibrillar units of Aß were computationally studied. Promising inhibitory potential and short sequence of the lead peptides offers new avenues for the advancement of peptide-derived therapeutics for AD.

Molecular Mechanisms and Epigenetic Regulation in Diabetic Cardiomyopathy.

Diabetes mellitus (DM) is an important lifestyle disease. Type 2 diabetes is one of the prime contributors to cardiovascular diseases (CVD) and diabetic cardiomyopathy (DbCM) and leads to increased morbidity and mortality in patients with DM. DbCM is a typical cardiac disease, characterized by cardiac remodeling in the presence of DM and in the absence of other comorbidities such as hypertension, valvular diseases, and coronary artery disease. DbCM is associated with defective cardiac metabolism, altered mitochondrial structure and function, and other physiological and pathophysiological signaling mechanisms such as oxidative stress, inflammation, myocardial apoptosis, and autophagy. Epigenetic modifiers are crucial players in the pathogenesis of DbCM. Thus, it is important to explore the role of epigenetic modifiers or modifications in regulating molecular pathways associated with DbCM. In this review, we have discussed the role of various epigenetic mechanisms such as histone modifications (acetylation and methylation), DNA methylation and non-coding RNAs in modulating molecular pathways involved in the pathophysiology of the DbCM.

Presence of allele CYP3A4*16 does not have any bearing on carbamazepine-induced adverse drug reactions in North Indian people with epilepsy.

OBJECTIVES: The objectives of this study were to determine the relationship between genetic polymorphisms in gene encodings for CYP3A4 and carbamazepine (CBZ)-induced dose-related side effects in North Indian people with epilepsy. PATIENTS AND METHODS: The current prospective study included 37 patients with CBZ-induced dose-related side effects and 102 patients who did not experience side effects while on CBZ. The genotyping for CYP3A4 allele (CYP3A4*16) was done using real-time polymerase chain reaction (RT-PCR) in Applied Biosystems 7500 RT-PCR System (USA). CBZ was administered in all patients at a dose varying from 15 to 20 mg/kg daily. RESULTS: Various demographic variables were comparable between the groups except that control of seizures was far better in controls. After testing, it was found that none of our patients had the presence of CYP3A4*16 allele. CONCLUSION: CYP3A4*16 allele is not represented significantly in North Indian people with CBZ-induced dose-related side effects.

Stage-specific expression analysis ofMMP-2 & MMP-9 in laryngeal carcinoma.

AIM OF THE STUDY: Both matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) is involved in degradation of extracellular matrix and found to stimulate invasion and metastasis in cancer patients. However, studies on the stage-specific expression of MMPs at different stages of larynx carcinoma are still lacking. In the present study, we compare the expression level of MMP-2 and MMP-9 at different stages of laryngeal carcinoma. MATERIAL AND METHODS: Tumor tissues samples were taken from larynx cancer patients by deep biopsy during direct laryngoscopy. Gene expression for MMP-2 and MMP-9 was analyzed using RT-PCR. RESULTS: Significantly high expression of MMP-2 was observed compared to the MMP-9 at stage IV compared to the less advanced stages of the disease. CONCLUSION: Present study concluded that the MMP-2 expressed with a greater magnitude as compared to the MMP-9 in advance stages of laryngeal carcinoma.

Clopidogrel response in ischemic stroke patients: Is polymorphism or gender more important? Results of the CRISP study.

Clopidogrel (CLP) is a second generation thienopyridine drug commonly used in secondary prevention of ischemic stroke (IS). Its antiplatelet response maybe variable due to genetic and non-genetic factors. Adipokines may affect platelet aggregation through ADP mediated platelet signalling. However, the combined effect of CYP genetic variants and adipokines on antiplatelet response of clopidogrel is unclear. Patients of IS/Transient ischemic attack (TIAs) within 3 months were prospectively screened following clopidogrel treatment. Major exclusions were cardioembolic and non atherosclerotic strokes. Antiplatelet effect of clopidogrel along with adipokine (Leptin and adiponectin) levels and genotyping of CYP, P2Y12 gene were investigated. Rare genetic variants were confirmed by DNA sequencing. 204 patients with ischemic stroke/TIAs were screened and 163 were recruited. 85 (52.1%) patients were poor responders to clopidogrel. Antiplatelet response to clopidogrel was weaker in females [Median 8.0 (IQR: 3.0-14.0)] compared to males [Median 5.0 (IQR: 2.0-10.0)]. In female subgroup analysis, association was found among high leptin levels and PPI (+) usage in poor responders. None of the genetic variants (CYP2C19*2,*3,*4*, CYP2C9*3, CYP2B6 and P2Y12) were found to influence the antiplatelet effects (p > 0.05). On multivariable logistic regression, a poor clopidogrel response was associated with female gender (Adjusted OR 2.55, 95% CI: 1.05-6.18) and PPI usage (Adjusted OR 2.42, 95% CI: 1.09-5.34). Despite a high prevalence of clopidogrel resistance in the North Indian stroke patients, female gender rather than genetic polymorphisms of CYP and P2Y12 genes may influence its antiplatelet effect. Further research may ascertain the role of gender on clopidogrel response.

Brain natriuretic peptide in pregnant women with heart disease.

BACKGROUND: Plasma brain natriuretic peptide levels were prospectively studied in pregnant women with heart disease. METHODS: Fifty pregnant women with heart disease and 25 controls were evaluated at 24 weeks or under, 30-32 weeks, 34 weeks or more of gestation, and 6 weeks postpartum. Adverse maternal cardiac events were hospitalization for worsening heart failure, stroke, and death. RESULTS: Thirty-eight (76%) women had rheumatic heart disease. Plasma brain natriuretic peptide levels were (in cases and controls) 118.3 ± 46.5 pg/ml and 66.3 ± 15.9 pg/ml (at 24 weeks or under), 124.8 ± 30.4 pg/ml and 68.4 ± 16.5 pg/ml (30-32 weeks), 135.8 ± 34.9 pg/ml and 68.6 ± 15.6 pg/ml (34 weeks or more), and 110.1 ± 21.9 pg/ml and 65.0 ± 16.1 pg/ml (6 weeks postpartum) (p = .0001). Eighteen women had adverse events. Of these, only 1 had a level less than 100 pg/ml, 12 were between 100 and 200 pg/ml, and 5 more than 200 pg/ml. CONCLUSIONS: Plasma brain natriuretic peptide levels were higher in women with heart disease at all periods of gestation as well as six weeks postpartum. No woman with a plasma brain natriuretic peptide levels of 98 pg/ml or less had an adverse event.

Effect of C-terminus amidation of Aß39-42 fragment derived peptides as potential inhibitors of Aß aggregation.

The C-terminus fragment (Val-Val-Ile-Ala) of amyloid-ß is reported to inhibit the aggregation of the parent peptide. In an attempt to investigate the effect of sequential amino-acid scan and C-terminus amidation on the biological profile of the lead sequence, a series of tetrapeptides were synthesized using MW-SPPS. Peptide D-Phe-Val-Ile-Ala-NH2 (12c) exhibited high protection against ß-amyloid-mediated-neurotoxicity by inhibiting Aß aggregation in the MTT cell viability and ThT-fluorescence assay. Circular dichroism studies illustrate the inability of Aß42 to form ß-sheet in the presence of 12c, further confirmed by the absence of Aß42 fibrils in electron microscopy experiments. The peptide exhibits enhanced BBB permeation, no cytotoxicity along with prolonged proteolytic stability. In silico studies show that the peptide interacts with the key amino acids in Aß, which potentiate its fibrillation, thereby arresting aggregation propensity. This structural class of designed scaffolds provides impetus towards the rational development of peptide-based-therapeutics for Alzheimer's disease (AD).

A Common Tag Nucleotide Variant in MMP7 Promoter Increases Risk for Hypertension via Enhanced Interactions With CREB (Cyclic AMP Response Element-Binding Protein) Transcription Factor.

MMP (matrix metalloproteinase)-7-a potent extracellular matrix degrading enzyme-is emerging as a new regulator of cardiovascular diseases. However, potential contributions of MMP7 genetic variations to hypertension remain unknown. In this study, we probed for the association of a tag single-nucleotide polymorphism in the MMP7 promoter (-181A/G; rs11568818) with hypertension in an urban South Indian population (n=1501). The heterozygous AG genotype significantly increased risk for hypertension as compared with the wild-type AA genotype (odds ratio, 1.60 [95% CI, 1.25-2.06]; P=2.4×10-4); AG genotype carriers also displayed significantly higher diastolic blood pressure and mean arterial pressure than wild-type AA individuals. The study was replicated in a North Indian population (n=949) (odds ratio, 1.52 [95% CI, 1.11-2.09]; P=0.01). Transient transfection experiments using MMP7 promoter-luciferase reporter constructs revealed that the variant -181G allele conferred greater promoter activity than the -181A allele. Computational prediction and structure-based conformational and molecular dynamics simulation studies suggested higher binding affinity for the CREB (cyclic AMP response element-binding protein) to the -181G promoter. In corroboration, overexpression/downregulation of CREB and chromatin immunoprecipitation experiments provided convincing evidence for stronger binding of CREB with the -181G promoter. The -181G promoter also displayed enhanced responses to hypoxia and epinephrine treatment. The higher promoter activity of -181G allele translated to increased MMP7 protein level, and MMP7-181AG heterozygous individuals displayed elevated plasma MMP7 levels, which positively correlated with blood pressure. In conclusion, the MMP7 A-181G promoter polymorphism increased MMP7 expression under pathophysiological conditions (hypoxic stress and catecholamine excess) via increased interactions with CREB and enhanced the risk for hypertension in its carriers.

Myocardin ablation in a cardiac-renal rat model.

Cardiorenal syndrome is defined by primary heart failure conditions influencing or leading to renal injury or dysfunction. Dilated cardiomyopathy (DCM) is a major co-existing form of heart failure (HF) with renal diseases. Myocardin (MYOCD), a cardiac-specific co-activator of serum response factor (SRF), is increased in DCM porcine and patient cardiac tissues and plays a crucial role in the pathophysiology of DCM. Inhibiting the increased MYOCD has shown to be partially rescuing the DCM phenotype in porcine model. However, expression levels of MYOCD in the cardiac tissues of the cardiorenal syndromic patients and the effect of inhibiting MYOCD in a cardiorenal syndrome model remains to be explored. Here, we analyzed the expression levels of MYOCD in the DCM patients with and without renal diseases. We also explored, whether cardiac specific silencing of MYOCD expression could ameliorate the cardiac remodeling and improve cardiac function in a renal artery ligated rat model (RAL). We observed an increase in MYOCD levels in the endomyocardial biopsies of DCM patients associated with renal failure compared to DCM alone. Silencing of MYOCD in RAL rats by a cardiac homing peptide conjugated MYOCD siRNA resulted in attenuation of cardiac hypertrophy, fibrosis and restoration of the left ventricular functions. Our data suggest hyper-activation of MYOCD in the pathogenesis of the cardiorenal failure cases. Also, MYOCD silencing showed beneficial effects by rescuing cardiac hypertrophy, fibrosis, size and function in a cardiorenal rat model.

Mitochondrial genome variations in idiopathic dilated cardiomyopathy.

Idiopathic dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. The aim of this study was to assess the role of mitochondrial DNA (mtDNA) variations and haplogroups in Indian DCM patients. Whole mtDNA analysis of 221 DCM patients revealed 48 novel, 42 disease-associated and 97 private variations. The frequency of reported variations associated with hearing impairment, DEAF, SNHL and LHON are significantly high in DCM patients than controls. Haplogroups H and HV were over represented in DCM than controls. Functional analysis of two private variations (m.8812A>G & m.10320G>A) showed decrease in mitochondrial functions, suggesting the role of mtDNA variations in DCM.

Lack of association between lysyl oxidase-like 1 polymorphism in pseudoexfoliation syndrome and pseudoexfoliation glaucoma in North Indian population.

INTRODUCTION: Pseudoexfoliation syndrome is commonly associated with pseudoexfoliation glaucoma. The two nonsynonymous single-nucleotide polymorphisms rs1048661 (R141L) and rs3825942 (G153D) within exon 1 of LOXL1 gene have been found to confer risk of pseudoexfoliation syndrome and pseudoexfoliation glaucoma in different geographical populations. This study aims to find association between two nonsynonymous single-nucleotide polymorphisms with pseudoexfoliation syndrome and pseudoexfoliation glaucoma in North Indian population. METHODS: North Indian subjects clinically diagnosed with pseudoexfoliation syndrome/pseudoexfoliation glaucoma and normal age-matched control were enrolled in the study. Genomic DNA was extracted and the two single-nucleotide polymorphisms of LOXL1 gene were genotyped by polymerase chain reaction and sequencing. The association between single-nucleotide polymorphisms with pseudoexfoliation syndrome/pseudoexfoliation glaucoma was evaluated by chi-square test. RESULTS: A total of 30 pseudoexfoliation glaucoma, 27 pseudoexfoliation syndrome and 61 control subjects were enrolled in the study. Patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma did not show any genetic association with either single-nucleotide polymorphism rs1048661 or rs3825942. CONCLUSION: The study shows lack of association between LOXL1 single-nucleotide polymorphisms and pseudoexfoliation in North Indian population.

Correction to: ACE2, CALM3 and TNNI3K polymorphisms as potential disease modifiers in hypertrophic and dilated cardiomyopathies.

In the original publication of the article, the location and rs number of TNNI3K mouse SNP (3784 C>T) (rs49812611) has been mentioned inadvertently in place of its human homologue. The correct information for human SNP is rs760769780 located at position 74436534, resulting in (G>A) change in human TNNI3K gene.

The Big Entity of New RNA World: Long Non-Coding RNAs in Microvascular Complications of Diabetes.

A major part of the genome is known to be transcribed into non-protein coding RNAs (ncRNAs), such as microRNA and long non-coding RNA (lncRNA). The importance of ncRNAs is being increasingly recognized in physiological and pathological processes. lncRNAs are a novel class of ncRNAs that do not code for proteins and are important regulators of gene expression. In the past, these molecules were thought to be transcriptional "noise" with low levels of evolutionary conservation. However, recent studies provide strong evidence indicating that lncRNAs are (i) regulated during various cellular processes, (ii) exhibit cell type-specific expression, (iii) localize to specific organelles, and (iv) associated with human diseases. Emerging evidence indicates an aberrant expression of lncRNAs in diabetes and diabetes-related microvascular complications. In the present review, we discuss the current state of knowledge of lncRNAs, their genesis from genome, and the mechanism of action of individual lncRNAs in the pathogenesis of microvascular complications of diabetes and therapeutic approaches.