Genomewide association analysis of coronary artery disease

Background - Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. Methods - We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Results - Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10–14 and P=3.40x10–6, respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). Conclusions - We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease

Classification of Rhinoentomophthoromycosis into Atypical, Early, Intermediate, and Late Disease: A Proposal

<div><p>Background</p><p>Rhinoentomophthoromycosis, or rhino-facial conidiobolomycosis, is a rare, grossly disfiguring disease due to an infection with entomophthoralean fungi. We report a case of rhinoentomophthoromycosis from Gabon and suggest a staging system, which provides information on the prognosis and duration of antifungal therapy.</p><p>Methods</p><p>We present a case of rhinoentomophthoromycosis including the histopathology, mycology, and course of disease. For the suggested staging system, all cases on confirmed rhinoentomophthoromycosis published in the literature without language restriction were eligible. Exclusion criteria were missing data on (i) duration of disease before correct diagnosis, (ii) outcome, and (iii) confirmation of entomophthoralean fungus infection by histopathology and/or mycology. We classified cases into atypical (orbital cellulitis, severe pain, fever, dissemination), early, intermediate, and late disease based on the duration of symptoms before diagnosis. The outcome was evaluated for each stage of disease.</p><p>Findings</p><p>The literature search of the Medpilot database was conducted on January 13, 2014, (updated on January 18, 2015). The search yielded 8,333 results including 198 cases from 117 papers; of these, 145 met our inclusion criteria and were included in the final analysis. Median duration of treatment was 4, 3, 4, and 5 months in atypical, early, intermediate, and late disease, respectively. Cure rates were clearly associated with stage of disease and were 57%, 100%, 82%, and 43% in atypical, early, intermediate, and late disease, respectively.</p><p>Conclusion</p><p>We suggest a clinical staging system that underlines the benefit of early case detection and may guide the duration of antifungal treatment. The scientific value of this classification is its capacity to structure and harmonize the clinical and research approach towards rhinoentomophthoromycosis.</p></div

Histopathology.

<p>Histopathological picture of hyphae of Entomophthorales after KOH-staining (A), after hematoxylin eosin stain (HE-stain) (B and C), and after Grocott-Gomori's methenamine silver stain (GMS-stain) (D). The pauci-septated, right-angled branching fungal hyphae have an irregular diameter of 5–12 μm with drumstick-like distended ends (A). The “Splendore-Hoeppli phenomenon” is characterized by a peri-hyphal amorphous eosinophilic material (B). Fungal hyphae are visible in transversal (C) or longitudinal cuts (D).</p

Portrait of the patient before, during and after treatment.

<p>(A) The patient is shown as a healthy young adult. (B) Before treatment (month 0). (C) After treatment with fluconazole and terbinafine (month 18). (D) After 14 months without therapy (month 32).</p

Typical course of rhinoentomophthoromycosis.

<p>(A) In early disease (cure rate: 100%) patients complain about rhinitis, intermittent epistaxis, nasal obstruction, or sinus pain. A nodule at the nostrils indicates invasion into the subcutaneous fat. Tissue invasion follows anatomical barriers causing facial tumefaction. (B) History of the disease of not more than 12 months is classified as intermediate disease (cure rate: 82%). (C) In late disease, patients present with facial deformity (cure rate: 43%). Patients with facial elephantiasis, as defined by Choon et al., might have an even poorer prognosis (cure rate: 37.5%) [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003984#pntd.0003984.ref002" target="_blank">2</a>].</p

Suggested staging system of rhinoentomophthoromycosis.

<p>^a The duration of disease can overlap between early and intermediate disease. See <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003984#pntd.0003984.g004" target="_blank">Fig 4</a> for the definite association of a case to the corresponding stage.</p><p>^b Cure rates in atypical disease could be misleading. The lethality rate (43%) might be more conclusive.</p><p>Suggested staging system of rhinoentomophthoromycosis.</p

Characteristics of the study population.

<p>^a Homogeneity was tested using one-way analysis of variance for continuous variables and Chi-square test for categorical variables.</p><p>^b The distribution of age (p = 0.86), mean number of antifungal drugs (p = 0.35), and all pathogens (p = 0.29) among early, intermediate, and late disease (excluding atypical disease) showed homogeneity.</p><p>Characteristics of the study population.</p