Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Functional Characterization of the Small Heat Shock Protein Hsp12p from Candida albicans

Hsp12p is considered to be a small heat shock protein and conserved among fungal species. To investigate the expression of this heat shock protein in the fungal pathogen Candida albicans we developed an anti-CaHsp12p antibody. We show that this protein is induced during stationary phase growth and under stress conditions including heat shock, osmotic, oxidative and heavy metal stress. Furthermore, we find that CaHsp12p expression is influenced by the quorum sensing molecule farnesol, the change of CO2 concentration and pH. Notably we show that the key transcription factor Efg1p acts as a positive regulator of CaHsp12p in response to heat shock and oxidative stress and demonstrate that CaHsp12p expression is additionally modulated by Hog1p and the cAMP-PKA signaling pathway. To study the function of Hsp12p in C. albicans we generated a null mutant, in which all four CaHSP12 genes have been deleted. Phenotypic analysis of the strain shows that CaHSP12 is not essential for stress resistance, morphogenesis or virulence when tested in a Drosophila model of infection. However, when overexpressed, CaHSP12 significantly enhanced cell-cell adhesion, germ tube formation and susceptibility to azole antifungal agents whilst desensitizing C. albicans to the quorum sensing molecule farnesol

Molecular and functional characterisation of HSP 12 in fungal pathogen Candida albicans

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The Diverse Roles of Monocytes in Cryptococcosis

Monocytes are considered to play a central role in the pathogenesis of Cryptococcus neoformans infection. Monocytes and monocyte-derived macrophages and dendritic cells are key components for the control of infection, but paradoxically they can also contribute to detrimental host responses and may even support fungal proliferation and dissemination. Simultaneously, the C. neoformans polysaccharide capsule can impair the functions of monocytes. Although monocytes are often seen as simple precursor cells, they also function as independent immune effector cells. In this review, we summarize these monocyte-specific functions during cryptococcal infection and the influence of C. neoformans on monocyte responses. We also cover the most recent findings on the functional and phenotypic heterogeneity of monocytes and discuss how new advanced technologies provide a platform to address outstanding questions in the field

The ‘Amoeboid Predator-Fungal Animal Virulence’ Hypothesis

The observation that some aspects of amoeba-fungal interactions resemble animal phagocytic cell-fungal interactions, together with the finding that amoeba passage can enhance the virulence of some pathogenic fungi, has stimulated interest in the amoeba as a model system for the study of fungal virulence. Amoeba provide a relatively easy and cheap model system where multiple variables can be controlled for the study of fungi-protozoal (amoeba) interactions. Consequently, there have been significant efforts to study fungal⁻amoeba interactions in the laboratory, which have already provided new insights into the origin of fungal virulence as well as suggested new avenues for experimentation. In this essay we review the available literature, which highlights the varied nature of amoeba-fungal interactions and suggests some unsolved questions that are potential areas for future investigation. Overall, results from multiple independent groups support the ‘amoeboid predator⁻fungal animal virulence hypothesis’, which posits that fungal cell predation by amoeba can select for traits that also function during animal infection to promote their survival and thus contribute to virulence

<i>HSP12</i> differs among yeast species.

<p>(A) Two Ca<i>HSP12</i> genes have been identified in <i>C. albicans</i> SC5314 and five clinical isolates by Southern blot. (B) Both alleles of Ca<i>HSP12</i> are transcriptionally expressed. The transcription level of Ca<i>HSP12</i> is assessed by qRT-PCR of total RNA obtained from the strain with absence of one Ca<i>HSP12</i> gene (HSP12KO2) and its parental strain (BWP17). The error bars represent the S.D. of triplicate independent reactions. <i>P</i> value<0.01, two-sided unpaired student t-test. (<b>C</b>) 5′ RACE analysis of Ca<i>HSP12</i>. Two DNA bands (band 1 and band 2) with the expected size above 250 bp were sequenced. The sequencing shows that the 5′ untranslated region (in lowercase) contains 29 bp nucleotides and only the second start codon (underlined) of <i>CaHSP12</i> can be identified. M: 1 kb DNA ladder; -ve: negative control of PCR without template; <i>HSP12</i>: 5′RLM-RACE PCR product of <i>CaHSP12</i>.</p

Overexpression of Ca<i>HSP12</i> in <i>C. albicans</i>.

<p>(A) qRT-PCR analysis of the <i>CaHSP12</i> transcripts in HSP12OE. The level of transcripts was normalized to <i>ACT1</i>. The error bars represent the S.D. of triplicate independent reactions (B) Overexpression of Ca<i>HSP12</i> induced cell clumping. The control CAI4+pFM2 and HSP12OE were grown at pH 7. (C) Overexpression of <i>CaHSP12</i> promoted cell aggregation which was independent from filamentation. CAI4+pFM2 and HSP12OE were grown at pH 4 for 4 h. Aggregation was then measured. The graphs were plotted by the percentage of cells sedimented against time. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042894#s3" target="_blank">Results</a> represent the means of three biological replicates with S.D. *<i>P</i> value<0.05, versus control strain, two-sided unpaired student t-test. (D) Overexpression of Ca<i>HSP12</i> enhanced cell adhesion at pH 4 or pH 7. HSP12OE and CAI4+pFM2 were grown on the flat-bottomed 96-well polystyrene plates and incubated at 37°C for 24 h. The adherent cells were quantified using the XTT reduction assay. The error bars were calculated from the S.D. of the triplicates. *<i>P</i> value<0.01, versus control strain, two-sided unpaired student t-test. (E) Overexpression of Ca<i>HSP12</i> promoted filamentation at pH 7. The percentage of the germ tube formation was counted every 30 min. The results presented are the means of three biological replicates with the S.D. **<i>P</i> value<0.01, * <i>P</i> value>0.05 versus control strains, two-sided unpaired student t-test. (F) Overexpression of Ca<i>HSP12</i> impacts on farnesol susceptibility. Cells were spotted onto 5% serum YEPD plates supplemented with or without 100 µm farnesol. Scale bar, 200 µm. (G) CAI4+pFM2 and HSP12OE were incubated in YNB supplemented with 5% serum with or without 100 µM farnesol. Germ tube formation was quantified every 30 min. The error bars were calculated from the S.D. of the triplicates. **<i>P</i> value<0.01, *<i>P</i> value>0.05 versus control strains, two-sided unpaired student t-test. (G) Overexpression of Ca<i>HSP12</i> increases susceptibility to azole antifungal drugs. 10-fold dilutions were spotted onto YNB plates containing 4 µg ml⁻¹ itraconazole, ketoconazole and fluconzaole. YNB plates supplemented with 1% chloroform, methanol and DMSO act as control.</p