Changes in Expression Profiles of Energy Metabolism and Cellular Calcium Balance Genes in the Mammalian Inner Ear During Development

The incurable and devastating disease of age-related hearing loss (ARHL) affects a majority of the elderly worldwide. As humans age, their cells of the inner ear, which are responsible for hearing, undergo degenerative aging, as well as apoptosis (programmed cell death). Scientists believe that ARHL may be associated with specific cell types of the inner ear known to be high in mitochondrial concentration. These sensorineural tissues as well as the specific neurons, namely hair cells, spiral ganglion neurons, and cells of stria vascularis, are susceptible to irreversible cellular damage. A decline of mitochondrial function is common in various age-dependent neurodegenerative diseases. Mitochondrial health is tightly regulated by Ca2+signals, which plays an important role in ARHL. Calcium and other cations enters via mechanotransduction channels when a sound from the outside environment comes in the inner ear that cause the hair cell bundles to deflect to one side with sound frequencies. Thus, the goal of this study was to reveal the intrinsic mechanisms that relate to energy metabolism and cellular calcium balance genes expression levels in the mammalian inner ear from early development. Changes in expression of energy metabolism genes in the inner ear cells were examined in mouse models, comparing these gene expression profiles in mice ranging from embryonic day 16 to adult age of up to 4 months. Mouse models are widely used to study mammalian hearing and comprehensive databases are available. Here, databases were used to compare with preliminary data that was obtained in Dr. Ruben Stepanyan’s laboratory that had indicated the expression of mitochondrial metabolism genes can alter with age, possible affecting hearing. Once this data was obtained, it was compared on a spreadsheet and graphed using Excel. The following graphs of expression levels were made: fluorescence activated cell sorting (FACS) of all genes studied, spiral and vestibular ganglion neurons, inner and outer hair cells, and fluorescence activated cell sorting (FACS) of all the individual genes. In doing so, we were able to identify mitochondrial metabolism and cellular calcium balance-related genes that can undergo changes in expression levels in the mammalian inner ear, thus providing their importance in hearing.https://commons.case.edu/intersections-fa20/1026/thumbnail.jp

Association of APOE polymorphism with chronic kidney disease in a nationally representative sample: a Third National Health and Nutrition Examination Survey (NHANES III) Genetic Study

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein E polymorphisms (<it>APOE</it>) have been associated with lowered glomerular filtration rate (GFR) and chronic kidney disease (CKD) with e2 allele conferring risk and e4 providing protection. However, few data are available in non-European ethnic groups or in a population-based cohort.</p> <p>Methods</p> <p>The authors analyzed 5,583 individuals from the Third National Health and Nutrition Examination Survey (NHANES III) to determine association with estimated GFR by the Modification of Diet in Renal Disease (MDRD) equation and low-GFR cases. Low-GFR cases were defined as GFR <75 ml/min/1.73 m²; additionally, GFR was analyzed continuously.</p> <p>Results</p> <p>In univariate analysis, the e4 allele was negatively associated with low-GFR cases in non-Hispanic whites, odds ratio (OR): 0.76, 95% confidence interval (CI): 0.60, 0.97. In whites, there was a significant association between increasing <it>APOE </it>score (indicating greater number of e2 alleles) and higher prevalence of low-GFR cases (OR: 1.21, 95%CI: 1.01, 1.45). Analysis of continuous GFR in whites found the e4 allele was associated with higher levels of continuous GFR (β-coefficient: 2.57 ml/min/1.73 m², 95%CI: 0.005, 5.14); in non-Hispanic blacks the e2 allele was associated with lower levels of continuous GFR (β-coefficient: -3.73 ml/min/1.73 m², 95%CI: -6.61, -0.84). <it>APOE </it>e2 and e4 alleles were rare and not associated with low-GFR cases or continuous GFR in Mexican Americans.</p> <p>Conclusion</p> <p>In conclusion, the authors observed a weak association between the <it>APOE </it>e4 allele and low-GFR cases and continuous GFR in non-Hispanic whites, and the <it>APOE </it>e2 allele and continuous GFR in non-Hispanic blacks, but found no association with either measure of kidney function in Mexican Americans. Larger studies including multiethnic groups are needed to determine the significance of this association.</p

Psychological Determinants of Consumer Acceptance of Personalised Nutrition in 9 European Countries

YesObjective: To develop a model of the psychological factors which predict people’s intention to adopt personalised nutrition. Potential determinants of adoption included perceived risk and benefit, perceived self-efficacy, internal locus of control and health commitment. Methods: A questionnaire, developed from exploratory study data and the existing theoretical literature, and including validated psychological scales was administered to N = 9381 participants from 9 European countries (Germany, Greece, Ireland, Poland, Portugal, Spain, the Netherlands, the UK, and Norway). Results: Structural equation modelling indicated that the greater participants’ perceived benefits to be associated with personalised nutrition, the more positive their attitudes were towards personalised nutrition, and the greater their intention to adopt it. Higher levels of nutrition self-efficacy were related to more positive attitudes towards, and a greater expressed intention to adopt, personalised nutrition. Other constructs positively impacting attitudes towards personalised nutrition included more positive perceptions of the efficacy of regulatory control to protect consumers (e.g. in relation to personal data protection), higher self-reported internal health locus of control, and health commitment. Although higher perceived risk had a negative relationship with attitude and an inverse relationship with perceived benefit, its effects on attitude and intention to adopt personalised nutrition was less influential than perceived benefit. The model was stable across the different European countries, suggesting that psychological factors determining adoption of personalised nutrition have generic applicability across different European countries. Conclusion: The results suggest that transparent provision of information about potential benefits, and protection of consumers’ personal data is important for adoption, delivery of public health benefits, and commercialisation of personalised nutrition.This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n u 265494 (http://cordis.europa.eu/fp7/home_en.html). Food4Me is the acronym of the project ‘‘Personalised nutrition: an integrated analysis of opportunities and challenges’’ (http://www.food4me.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4-2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in genera

Genome-wide association and functional follow-up reveals new loci for kidney function

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Abstract: Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk