Rhinoviruses: The Quest for a Cure

Rhinoviruses, also known as Human Rhinovirus, abbreviated HRV, are one of the many causes of the common cold. In fact, around 50 percent of all cold are caused by rhinoviruses, with the other major candidates being coronaviruses, influenza A or B virus, and minor causative agents like parainfluenza virus, respiratory syncytial virus, adenovirus, and enterovirus (Makela and Puhakka, 1997). However, due to the complex molecular structure of rhinoviruses, a cure for the common cold caused by HRV is still in the making. Several new treatments have been discovered, impacting the virus as different stages of its life, hopefully to prevent those colds that are cause by HRV. Most are still in the process of development, and some have adverse effects. Hopefully, in the near future, a cure will be developed, saving millions of people per year from that annual plague. (Greenberg, 2003)

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Identifying X-Chromosome Variants Associated with Age-Related Macular Degeneration

PurposeIn genome-wide association studies (GWAS), X chromosome (ChrX) variants are often not investigated. Sex-specific effects and ChrX-specific quality control (QC) are needed to examine these effects. Previous analyses identified 52 autosomal variants associated with age-related macular degeneration (AMD) via the International AMD Genomics Consortium (IAMDGC), but did not analyze ChrX. Therefore, our goal was to investigate ChrX variants for association with AMD. MethodsWe genotyped 29,629 non-Hispanic White (NHW) individuals (M/F:10,404/18,865; AMD12,087/14723) via a custom chip and imputed after ChrX-specific QC (XWAS 3.0) using the Michigan Imputation Server. Imputation generated 1,221,623 variants on ChrX. Age, informative PCs, and subphenotyeps were covariates for logistic association analyses with Fishers correction. Gene/pathway analyses were performed with VEGAS, GSEASNP, ICSNPathway, DAVID, and mirPath. ResultsLogistic association on NHW individuals with sex correction, identified variants in/near the genes SLITRK4, ARHGAP6, FGF13 and DMD associated with AMD (P<1x10 -6 ,Fishers combined-corrected). Via association testing of subphenotypes of choroidal neovascularization and geographic atrophy (GA), variants in DMD associated with GA (P<1x10 -6 , Fishers combined-corrected). Via gene-based analysis with VEGAS, several genes were associated with AMD (P<0.05, both truncated tail strength/truncated product P) including SLITRK4 and BHLHB9 . Pathway analysis using GSEASNP and DAVID showed genes associated with nervous system development (FDR: P:0.02), and blood coagulation (FDR: P:0.03). Variants in the region of a microRNA (miR) were associated with AMD (P<0.05, truncated tail strength/truncated product P). Via DIANA mirPath analysis, downstream targets of miRs show association with brain disorders and fatty acid elongation (P<0.05). A long-non coding RNA on ChrX near the DMD locus was also associated with AMD (P=4x10 -7 ). Epistatic analysis (t-statistic) for a quantitative trait of AMD vs control including covariates found a suggestive association in the XG gene (P=2x10^-5). ConclusionsAnalysis of ChrX variants demonstrates association with AMD and these variants may be linked to novel pathways. Further analysis is needed to confirm results and to understand their biological significance and relationship with AMD development in worldwide populations

Degeneration Modulates Retinal Response to Transient Exogenous Oxidative Injury

<div><p>Purpose</p><p>Oxidative injury is involved in retinal and macular degeneration. We aim to assess if retinal degeneration associated with genetic defect modulates the retinal threshold for encountering additional oxidative challenges.</p><p>Methods</p><p>Retinal oxidative injury was induced in degenerating retinas (rd10) and in control mice (WT) by intravitreal injections of paraquat (PQ). Retinal function and structure was evaluated by electroretinogram (ERG) and histology, respectively. Oxidative injury was assessed by immunohistochemistry for 4-Hydroxy-2-nonenal (HNE), and by Thiobarbituric Acid Reactive Substances (TBARS) and protein carbonyl content (PCC) assays. Anti-oxidant mechanism was assessed by quantitative real time PCR (QPCR) for mRNA of antioxidant genes and genes related to iron metabolism, and by catalase activity assay.</p><p>Results</p><p>Three days following PQ injections (1 µl of 0.25, 0.75, and 2 mM) the average ERG amplitudes decreased more in the WT mice compared with the rd10 mice. For example, following 2 mM PQ injection, ERG amplitudes reduced 1.84-fold more in WT compared with rd10 mice (p = 0.02). Injection of 4 mM PQ resulted in retinal destruction. Altered retina morphology associated with PQ was substantially more severe in WT eyes compared with rd10 eyes. Oxidative injury according to HNE staining and TBARS assay increased 1.3-fold and 2.1-fold more, respectively, in WT compared with rd10 mice. At baseline, prior to PQ injection, mRNA levels of antioxidant genes (<i>Superoxide Dismutase1, Glutathione Peroxidase1, Catalase</i>) and of <i>Transferrin</i> measured by quantitative PCR were 2.1–7.8-fold higher in rd10 compared with WT mice (p<0.01 each), and catalase activity was 1.7-fold higher in rd10 (p = 0.0006).</p><p>Conclusions</p><p>This data suggests that degenerating rd10 retinas encounter a relatively lower degree of damage in response to oxidative injury compared with normal retinas. Constitutive up-regulation of the oxidative defense mechanism in degenerating retinas may confer such relative protection from oxidative injury.</p></div

Pathway Analysis Integrating Genome-Wide and Functional Data Identifies PLCG2 as a Candidate Gene for Age-Related Macular Degeneration

PURPOSE. Age-related macular degeneration (AMD) is the worldwide leading cause of blindness among the elderly. Although genome-wide association studies (GWAS) have identified AMD risk variants, their roles in disease etiology are not well-characterized, and they only explain a portion of AMD heritability. METHODS. We performed pathway analyses using summary statistics from the International AMD Genomics Consortium's 2016 GWAS and multiple pathway databases to identify biological pathways wherein genetic association signals for AMD may be aggregating. We determined which genes contributed most to significant pathway signals across the databases. We characterized these genes by constructing protein-protein interaction networks and performing motif analysis. RESULTS. We determined that eight genes (C2, C3, LIPC, MICA, NOTCH4, PLCG2, PPARA, and RAD51B) "drive'' the statistical signals observed across pathways curated in the Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Gene Ontology (GO) databases. We further refined our definition of statistical driver gene to identify PLCG2 as a candidate gene for AMD due to its significant gene-level signals (P < 0.0001) across KEGG, Reactome, GO, and NetPath pathways. CONCLUSIONS. We performed pathway analyses on the largest available collection of advanced AMD cases and controls in the world. Eight genes strongly contributed to significant pathways from the three larger databases, and one gene (PLCG2) was central to significant pathways from all four databases. This is, to our knowledge, the first study to identify PLCG2 as a candidate gene for AMD based solely on genetic burden. Our findings reinforce the utility of integrating in silico genetic and biological pathway data to investigate the genetic architecture of AMD

H&E staining of formalin-fixed paraffin-embedded retina sections from rd10 and WT mice injected with 1 µl of 2 mM or 4 mM PQ or PBS.

<p>Normal retina morphology was seen in WT mice (A), while the retina appeared disrupted in these mice following PQ injection (C, E). Arrow indicates wavy appearance of nuclear layers and photoreceptor inner and outer segments in WT retina injected with PQ. This wavy appearance appear extreme following injection of 4 mM PQ. Retinas of rd10 mice, already undergoing retinal degeneration, are typically thinner, due to loss of photoreceptors (B). PQ injection in rd10 mice was not associated with structural alterations similar to the one observed in WT mice (D, F). GCL =  ganglion cell layer, INL = inner nuclear layer, ONL = outer nuclear layer, RPE =  retinal pigmented epithelium.</p

HNE staining of retina sections for assessment of oxidative injury following PQ injection.

<p>Retinas of rd10 and WT mice injected with 1 µl of 2 mM PQ or PBS were labeled with anti-HNE antibody (<i>red</i>; A). GCL =  ganglion cell layer, INL = inner nuclear layer, ONL = outer nuclear layer, RPE =  retinal pigmented epithelium. (B) Quantification of HNE staining intensity showed marked oxidative injury following PQ injection in WT and the rd10 mice (*p<0.05 as compared to PBS injected eyes of same strain. † p = 0.0002 comparing control (PBS) eyes between the strains; n = 5 in each group).</p

Measurements of TBARS level in mice retinas following PQ injection.

<p>TBARS level (nmol MDA per mg protein) indicates the extent of oxidative injury to lipids. TBARS were measured in retinas of rd10 and WT mice following 2 mM paraquat or PBS injections. *p≤0.004 as compared to PBS injected eyes of same strain. † p = 0.001 comparing control (PBS) eyes between the strains (n = 5 in each group).</p

Protein carbonyl content (PCC) in mice retinas following PQ injection.

<p>Protein carbonylation was measured to assess oxidative retinal injury to proteins. It was assessed in retinas of rd10 and WT mice injected with 1 µl of 2 mM PQ or PBS. In both strains PQ injections caused an insignificant 1.35 fold increase of PCC. *p = 0.009 comparing control (PBS) rd10 with WT retinas (n = 5 in each group).</p