Pathway-Based Analysis of a Melanoma Genome-Wide Association Study: Analysis of Genes Related to Tumour-Immunosuppression

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele

Metapopulation Dynamics Enable Persistence of Influenza A, Including A/H5N1, in Poultry

Thanks to K. Sturm-Ramirez, C. Jessup, J. Rosenthal and the staff of EcoHealth Alliance for feedback. Disclaimer: The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government.Conceived and designed the experiments: PRH TF RH DZ CSA AG MJM XX TB PD. Performed the experiments: PRH. Analyzed the data: PRH. Contributed reagents/materials/analysis tools: PRH TF RH DZ CSA AG MJM XX TB JHJ PD. Wrote the paper: PRH TF RH DZ CSA AG MJM XX TB JHJ PD.Highly pathogenic influenza A/H5N1 has persistently but sporadically caused human illness and death since 1997. Yet it is still unclear how this pathogen is able to persist globally. While wild birds seem to be a genetic reservoir for influenza A, they do not seem to be the main source of human illness. Here, we highlight the role that domestic poultry may play in maintaining A/H5N1 globally, using theoretical models of spatial population structure in poultry populations. We find that a metapopulation of moderately sized poultry flocks can sustain the pathogen in a finite poultry population for over two years. Our results suggest that it is possible that moderately intensive backyard farms could sustain the pathogen indefinitely in real systems. This fits a pattern that has been observed from many empirical systems. Rather than just employing standard culling procedures to control the disease, our model suggests ways that poultry production systems may be modified.Yeshttp://www.plosone.org/static/editorial#pee

LOW-DOSE APROTININ IN INTERNAL MAMMARY ARTERY BYPASS OPERATIONS CONTRIBUTES TO IMPORTANT BLOOD SAVING

The effect on postoperative blood loss and blood use of blood-saving treatment with or without 280 mg of low-dose aprotinin (2 million kallikrein inactivator units) was studied in 200 consecutive patients undergoing either unilateral or bilateral internal mammary artery bypass grafting. Postoperative blood loss and total units of homologous blood products were similar in patients having either bypass procedure without aprotinin treatment. In patients given aprotinin, postoperative blood loss and use of homologous blood products were significantly lower (p <0.05). The use of any donor blood product was prevented in 78% of the patients given aprotinin versus only 45% of patients treated without aprotinin. None of the aprotinin-treated patients underwent repeat thoracotomy for excessive bleeding; repeat thoracotomy was indicated in 8% of the patients having bilateral internal mammary artery grafting without aprotinin treatment. These results demonstrate that low-dose aprotinin reduces blood loss and blood use significantly and prevents excessive bleeding

PREOPERATIVE THERAPY OF LOW-DOSE ASPIRIN IN INTERNAL MAMMARY ARTERY BYPASS OPERATIONS WITH AND WITHOUT LOW-DOSE APROTININ

The effect of preoperative low-dose aspirin (1 mg/kg of body weight) and intraoperative low-dose aprotinin (2 million kallikrein inactivator units) treatment on perioperative blood loss and blood requirements in patients who undergo internal mammary artery bypass operations is unknown. Therefore, we retrospectively studied 75 matching patients who underwent internal mammary artery operations, and they were allocated to one of three groups: low-dose aspirin and aprotinin treatment (group 1, n = 25), low-dose aspirin treatment without aprotinin (group 2, n = 25), and neither aspirin nor aprotinin treatment (group 3, n = 25). Although the perioperative blood loss was similar, the blood requirements tended to be higher (p = 0.09) in the patients who were treated with aspirin (group 2) than in the control patients (group 3). When aprotinin was added to the priming solution in patients who were treated with aspirin (group 1), blood loss was significantly lower (p <0.05) than that of group 2 patients but not of control patients. Blood requirements were significantly lower (p <0.01) than those of patients in groups 2 and 3. Blood products were needed in 29 %, 62 %, and 75 % of patients in groups 1, 2, and 3, respectively