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DeLorenze G.N.,Kaiser Permanente | Nelson C.L.,Duke Clinical Research Institute | Scott W.K.,John P Hussman Institute For Human Genomics | Scott W.K.,University of Miami | And 6 more authors.
Journal of Infectious Diseases | Year: 2016

Background. Staphylococcus aureus can cause life-threatening infections. Human susceptibility to S. aureus infection may be influenced by host genetic variation. Methods. A genome-wide association study (GWAS) in a large health plan-based cohort included biologic specimens from 4701 culture-confirmed S. aureus cases and 45 344 matched controls; 584 535 single-nucleotide polymorphisms (SNPs) were genotyped on an array specific to individuals of European ancestry. Coverage was increased by imputation of >25 million common SNPs, using the 1000 Genomes Reference panel. In addition, human leukocyte antigen (HLA) serotypes were also imputed. Results. Logistic regression analysis, performed under the assumption of an additive genetic model, revealed several imputed SNPs (eg, rs115231074: odds ratio [OR], 1.22 [P = 1.3 × 10-10]; rs35079132: OR, 1.24 [P = 3.8 × 10-8]) achieving genome-wide significance on chromosome 6 in the HLA class II region. One adjacent genotyped SNP was nearly genome-wide significant (rs4321864: OR, 1.13; P = 8.8 × 10-8). These polymorphisms are located near the genes encoding HLA-DRA and HLA-DRB1. Results of further logistic regression analysis, in which the most significant GWAS SNPs were conditioned on HLA-DRB1∗04 serotype, showed additional support for the strength of association between HLA class II genetic variants and S. aureus infection. Conclusions. Our study results are the first reported evidence of human genetic susceptibility to S. aureus infection. © The Author 2015. Source

Gunes N.,Istanbul University | Cengiz F.B.,Ankara University | Duman D.,Ankara University | Dervisoglu S.,Istanbul University | And 3 more authors.
Genetic Counseling | Year: 2014

We present an 18-day old boy with bilateral cervical cutaneous defect in the retroauricular region, low-set and posteriorly rotated ears, bilateral microphtalmia and bilateral pseudocleft of the upper lip. Histopathological evaluation of cervical cutaneous defect showed ulceration on the surface and ectopic thymus tissue in the deep dermis with cortex, medulla and Hassal's corpuscles. Clinical findings led to the diagnosis of Branchio-oculo-facial syndrome, characterized by branchial defects (erythematous cutaneous defects in cervical region), ocular anomalies (microphthalmia, anophthalmia, lacrimal duct obstruction, coloboma, cataract, ptosis) and facial defects (cleft lip and/or palate, pseudocleft or abnormal philtrum). DNA sequencing showed a novel heterozygous mutation, c.731T>C (p.L244P), in TFAP2A gene confirming the diagnosis of this rare autosomal dominant developmental disorder with variable clinical findings. Source

Jahic A.,Jena University Hospital | Khundadze M.,Jena University Hospital | Jaenisch N.,Jena University Hospital | Schule R.,University of Tubingen | And 12 more authors.
Orphanet Journal of Rare Diseases | Year: 2015

Background: The hereditary spastic paraplegias (HSPs) are rare neurodegenerative gait disorders which are genetically highly heterogeneous. For each single form, eventual consideration of therapeutic strategies requires an understanding of the mechanism by which mutations confer pathogenicity. SPG8 is a dominantly inherited HSP, and associated with rather early onset and rapid progression. A total of nine mutations in KIAA0196, which encodes the WASH regulatory complex (SHRC) member strumpellin, have been reported in SPG8 patients so far. Based on biochemical and cell biological approaches, they have been suggested to act via loss of function-mediated haploinsufficiency. Methods: We generated a deletion-based knockout allele for E430025E21Rik, i.e. the murine homologue of KIAA0196. The consequences on mRNA and protein levels were analyzed by qPCR and Western-blotting, respectively. Motor performance was evaluated by the foot-base angle paradigm. Axon outgrowth and relevant organelle compartments were investigated in primary neuron cultures and primary fibroblast cultures, respectively. A homemade multiplex ligation-dependent probe amplification assay enabling identification of large inactivating KIAA0196 deletion alleles was applied to DNA from 240 HSP index patients. Results: Homozygous but not heterozygous mice showed early embryonic lethality. No transcripts from the knockout allele were detected, and the previously suggested compensation by the wild-type allele upon heterozygosity was disproven. mRNA expression of genes encoding other SHRC members was unaltered, while there was evidence for reduced SHRC abundance at protein level. We did, however, neither observe HSP-related in vivo and ex vivo phenotypes, nor alterations affecting endosomal, lysosomal, or autophagic compartments. KIAA0196 copy number screening excluded large inactivating deletion mutations in HSP patients. The consequences of monoallelic KIAA0196/E430025E21Rik activation thus differ from those observed for dominant HSP genes for which a loss-of-function mechanism is well established. Conclusions: Our data do not support the current view that heterozygous loss of strumpellin/SHRC function leads to haploinsufficiency and, in turn, to HSP. The lethality of homozygous knockout mice, i.e. the effect of complete loss of function, also argues against a dominant negative effect of mutant on wild-type strumpellin in patients. Toxic gain-of-function represents a potential alternative explanation. Confirmation of this therapeutically relevant hypothesis in vivo, however, will require availability of appropriate knockin models. © 2016 Jahic et al. Source

Rosentul D.C.,Radboud University Nijmegen | Plantinga T.S.,Radboud University Nijmegen | Farcas M.,Radboud University Nijmegen | Farcas M.,University of Medicine and Pharmacy, Cluj-Napoca | And 14 more authors.
Medical Mycology | Year: 2014

Candida albicans can cause candidemia in neutropenic and critically ill patients and oropharyngeal candidiasis in human immunodeficiency virus (HIV)-positive patients with low CD4+ counts. Because all patients at risk do not develop Candida infections, it is possible that a patient's genetic background might play a role in his or her susceptibility to infection. Autophagy mediates pathogen clearance andmodulation of inflammation. Our aim was to assess the effect of genetic variations in the ATG16L1 and IRGM autophagy genes on the susceptibility of patients with candidemia and oropharyngeal candidiasis. We assessed genetic variations in the ATG16L1 and IRGM genes in a cohort of candidemia patients of both African and European origin. In addition, we evaluated the effect of these polymorphisms on the susceptibility to oropharyngeal candidiasis of an HIV-positive cohort from Tanzania. Functional studies have been performed to assess the effect of the ATG16L1 and IRGM genetic variants on both in vitro and in vivo cytokine production. The results indicate that ATG16L1 variants modulate production of tumor necrosis factor-alpha, but not other cytokines, while no effects were seen in the presence of IRGM polymorphisms. In addition, no significant associations between the singlenucleotide polymorphisms in the ATG16L1 and IRGM genetic variants and the incidence of candidemia or oropharyngeal candidiasis were identified. Despite moderate effects on the modulation of proinflammatory cytokine production, genetic variation in the autophagy genes ATG16L1 and IRGM has a minor impact on the susceptibility to both mucosal and systemic Candida infections. © The Author 2014. Source

Kohli M.A.,John P Hussman Institute For Human Genomics | Kohli M.A.,Max Planck Institute of Psychiatry | Salyakina D.,John P Hussman Institute For Human Genomics | Salyakina D.,Max Planck Institute of Psychiatry | And 13 more authors.
Archives of General Psychiatry | Year: 2010

Context: A consistent body of evidence supports a role of reduced neurotrophic signaling in the pathophysiology of major depressive disorder (MDD) and suicidal behavior. Especially in suicide victims, lower postmortem brain messenger RNA and protein levels of neurotrophins and their receptors have been reported. Objective: To determine whether the brain-derived neurotrophic factor (BDNF) gene or its high-affinity receptor gene, receptor tyrosine kinase 2 (NTRK2), confer risk for suicide attempt (SA) and MDD by investigating common genetic variants in these loci. Design: Eighty-three tagging single-nucleotide polymorphisms (SNPs) covering the genetic variability of these loci in European populations were assessed in a casecontrol association design. Setting: Inpatients and screened control subjects. Participants: The discovery sample consisted of 394 depressed patients, of whom 113 had SA, and 366 matched healthy control subjects. The replication studies comprised 744 German patients with MDD and 921 African American nonpsychiatric clinic patients, of whom 152 and 119 were positive for SA, respectively. Interventions: Blood or saliva samples were collected from each participant for DNA extraction and genotyping. Main Outcome Measures: Associations of SNPs in BDNF and NTRK2 with SA and MDD. Results: Independent SNPs within NTRK2 were associated with SA among depressed patients of the discovery sample that could be confirmed in both the German and African American replication samples. Multilocus interaction analysis revealed that single SNP associations within this locus contribute to the risk of SA in a multiplicative and interactive fashion (P=4.7 × 10 -7 for a 3-SNP model in the combined German sample). The effect size was 4.5 (95% confidence interval, 2.1-9.8) when patients carrying risk genotypes in all 3 markers were compared with those without any of the 3 risk genotypes. Conclusions: Our results suggest that a combination of several independent risk alleles within the NTRK2 locus is associated with SA in depressed patients, further supporting a role of neurotrophins in the pathophysiology of suicide. ©2010 American Medical Association. All rights reserved. Source

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