👤 Kannaki T Ramasamy

The present study explored for the first time the blood-based proteomic signature that could potentially distinguish older adults with and without cognitive frailty (CF). The participants were recruited under the Malaysian Elders Longitudinal Research (MELoR) study. Cognition and physical frailty were determined using the Montreal Cognitive Assessment (MoCA) and Fried's criteria, respectively. The differential protein expression in the blood samples (38 CF vs 40 robust) were then determined using the Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH) analysis. A total of 294 proteins were found to be differentially expressed in the CF group as opposed to the robust group. Considering proteins with fold change (FC) ≥  ± 2 and p-values < 0.05, 13 proteins were significantly upregulated and nine proteins significantly downregulated in the CF group when compared to the robust group. Subsequent correlation analysis identified nine dysregulated proteins, namely APOA1, APOA2, APOA4, APOC1, APOE, GPX3, RBP4, SERPINC1 and TTR, to exhibit significantly and moderately strong correlations with parameters of cognitive and/or frailty assessments. These proteins could potentially serve as useful proteomic signature of CF given their sensitivity > 78%, specificity > 75%, accuracy > 80% and area under the curve (AUC) > 0.8. The major biological pathways that could be potentially dysregulated by the nine proteins were associated with lipid metabolism and the retinoid system. The present findings warrant further validation in future studies that involve a larger cohort. Show less

The poultry industry is significantly impacted by viral infections, particularly Newcastle Disease Virus (NDV), which leads to substantial economic losses. It is essential to comprehend how the sequence of development affects biological pathways and how early exposure to infections might affect immune responses. This study employed transcriptome analysis to investigate host-pathogen interactions by analyzing gene expression changes in NDV-infected chicken embryos' lungs. RNA-Seq reads were aligned with the chicken reference genome (Galgal7), revealing 594 differentially expressed genes: 264 upregulated and 330 downregulated. The most overexpressed genes, with logFC between 8.15 and 8.75, included C8A, FGG, PIT54, FETUB, APOC3, and FGA. Notably, downregulated genes included BPIFB3 (-4.46 logFC) and TRIM39.1 (-4.26 logFC). The analysis also identified 29 novel transcripts and 20 lncRNAs that were upregulated. Gene Ontology and KEGG pathways' analyses revealed significant alterations in gene expression related to immune function, metabolism, cell cycle, nucleic acid processes, and mitochondrial activity due to NDV infection. Key metabolic genes, such as ALDOB (3.27 logFC), PRPS2 (2.66 logFC), and XDH (2.15 logFC), exhibited altered expression patterns, while DCK2 (-1.99 logFC) and TK1 (-2.11 logFC) were also affected. Several immune-related genes showed significant upregulation in infected lung samples, including ALB (6.15 logFC), TLR4 (1.86 logFC), TLR2 (2.79 logFC), and interleukin receptors, such as IL1R2 (3.15 logFC) and IL22RA2 (1.37 logFC). Conversely, genes such as CXCR4 (-1.49 logFC), CXCL14 (-2.57 logFC), GATA3 (-1.51 logFC), and IL17REL (-2.93 logFC) were downregulated. The higher expression of HSP genes underscores their vital role in immune responses. Comprehension of these genes' interactions is essential for regulating viral replication and immune responses during infections, potentially aiding in the identification of candidate genes for poultry breed improvement amidst NDV challenges. Show less

Dyslipidemia is a commonly encountered clinical condition and is an important determinant of cardiovascular disease. Although secondary factors play a role in clinical expression, dyslipidemias have a strong genetic component. Familial hypercholesterolemia is usually due to loss-of-function mutations in LDLR, the gene coding for low density lipoprotein receptor and genes encoding for proteins that interact with the receptor: APOB, PCSK9 and LDLRAP1. Monogenic hypertriglyceridemia is the result of mutations in genes that regulate the metabolism of triglyceride rich lipoproteins (eg LPL, APOC2, APOA5, LMF1, GPIHBP1). Conversely familial hypobetalipoproteinemia is caused by inactivation of the PCSK9 gene which increases the number of LDL receptors and decreases plasma cholesterol. Mutations in the genes APOB, and ANGPTL3 and ANGPTL4 (that encode angiopoietin-like proteins which inhibit lipoprotein lipase activity) can further cause low levels of apoB containing lipoproteins. Abetalipoproteinemia and chylomicron retention disease are due to mutations in the microsomal transfer protein and Sar1b-GTPase genes, which affect the secretion of apoB containing lipoproteins. Dysbetalipoproteinemia stems from dysfunctional apoE and is characterized by the accumulation of remnants of chylomicrons and very low density lipoproteins. ApoE deficiency can cause a similar phenotype or rarely mutations in apoE can be associated with lipoprotein glomerulopathy. Low HDL can result from mutations in a number of genes regulating HDL production or catabolism; apoAI, lecithin: cholesterol acyltransferase and the ATP-binding cassette transporter ABCA1. Patients with cholesteryl ester transfer protein deficiency have markedly increased HDL cholesterol. Both common and rare genetic variants contribute to susceptibility to dyslipidemias. In contrast to rare familial syndromes, in most patients, dyslipidemias have a complex genetic etiology consisting of multiple genetic variants as established by genome wide association studies. Secondary factors, obesity, metabolic syndrome, diabetes, renal disease, estrogen and antipsychotics can increase the likelihood of clinical presentation of an individual with predisposed genetic susceptibility to hyperlipoproteinemia. The genetic profiles studied are far from complete and there is room for further characterization of genes influencing lipid levels. Genetic assessment can help identify patients at risk for developing dyslipidemias and for treatment decisions based on 'risk allele' profiles. This review will present the current information on the genetics and pathophysiology of disorders that cause dyslipidemias. Show less

Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p<5 × 10(-8). UK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50,008 unique samples: 10,002 individuals with low FEV1, 10,000 with average FEV1, and 5002 with high FEV1 from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV1 between heavy smokers and never smokers (p=2.29 × 10(-16)) and between individuals with and without doctor-diagnosed asthma (p=6.06 × 10(-11)). We discovered six novel genome-wide significant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5' end of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV1. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect on expression of NCAM1 in brain tissue. By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease. Medical Research Council. Show less

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease. Show less