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1. Plasma cell but not CD20-mediated B-cell depletion protects from bleomycin-induced lung fibrosis.

Author: Prêle, CM, Miles, T, Pearce, DR, O'Donoghue, RJ, Grainge, C, Barrett, L, Birnie, K, Lucas, AD, Baltic, S, Ernst, M, Rinaldi, C, Laurent, GJ, Knight, DA, Fear, M, Hoyne, G, McAnulty, RJ, Mutsaers, SE, Prêle, CM, Miles, T, Pearce, DR, O'Donoghue, RJ, Grainge, C, Barrett, L, Birnie, K, Lucas, AD, Baltic, S, Ernst, M, Rinaldi, C, Laurent, GJ, Knight, DA, Fear, M, Hoyne, G, McAnulty, RJ, and Mutsaers, SE
Abstract: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease associated with chronic inflammation and tissue remodelling leading to fibrosis, reduced pulmonary function, respiratory failure and death. Bleomycin (Blm)-induced lung fibrosis in mice replicates several clinical features of human IPF, including prominent lymphoid aggregates of predominantly B-cells that accumulate in the lung adjacent to areas of active fibrosis. We have shown previously a requirement for B-cells in the development of Blm-induced lung fibrosis in mice. To determine the therapeutic potential of inhibiting B-cell function in pulmonary fibrosis, we examined the effects of anti-CD20 B-cell ablation therapy to selectively remove mature B-cells from the immune system and inhibit Blm-induced lung fibrosis. Anti-CD20 B-cell ablation did not reduce fibrosis in this model; however, immune phenotyping of peripheral blood and lung resident cells revealed that anti-CD20-treated mice retained a high frequency of CD19+ CD138+ plasma cells. Interestingly, high levels of CD138+ cells were also identified in the lung tissue of patients with IPF, consistent with the mouse model. Treatment of mice with bortezomib, which depletes plasma cells, reduced the level of Blm-induced lung fibrosis, implicating plasma cells as important effector cells in the development and progression of pulmonary fibrosis.
Published: 2022

2. Genome-wide association study to identify genetic determinants of severe asthma

Author: Wan, Y I, Shrine, N R G, Soler Artigas, M, Wain, L V, Blakey, J D, Moffatt, M F, Bush, A, Chung, K F, Cookson, W O C M, Strachan, D P, Heaney, L, Al-Momani, B A H, Mansur, A H, Manney, S, Thomson, N C, Chaudhuri, R, Brightling, C E, Bafadhel, M, Singapuri, A, Niven, R, Simpson, A, Holloway, J W, Howarth, P H, Hui, J, Musk, A W, James, A L, Brown, M A, Baltic, S, Ferreira, M A R, Thompson, P J, Tobin, M D, Sayers, I, and Hall, I P
Published: 2012
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3. A-SYNUCLEIN AFFECTS DENDRITIC CELL DIFFERENTIATION: TP 067

Author: BALTIC, S, THOMPSON, P, and FOGEL-PETROVIC, M
Published: 2009

4. α-SYNUCLEIN PROMOTES MIGRATION AND APOPTOSIS OF HUMAN MONOCYTE-DERIVED DENDRITIC CELLS (HMODC): TO 05

Author: BALTIC, S, THOMPSON, P J, and FOGEL-PETROVIC, M
Published: 2008

5. Resequencing study confirms that host defense and cell senescence gene variants contribute to the risk of idiopathic pulmonary fibrosis

Author: Moore, C., Blumhagen, R.Z., Yang, I.V., Walts, A., Powers, J., Walker, T., Bishop, M., Russell, P., Vestal, B., Cardwell, J., Markin, C.R., Mathai, S.K., Schwarz, M.I., Steele, M.P., Lee, J., Brown, K.K., Loyd, J.E., Crapo, J.D., Silverman, E.K., Cho, M.H., James, J.A., Guthridge, J.M., Cogan, J.D., Kropski, J.A., Swigris, J.J., Bair, C., Kim, D.S., Ji, W., Kim, H., Song, J.W., Maier, L.A., Pacheco, K.A., Hirani, N., Poon, A.S., Li, F., Jenkins, R.G., Braybrooke, R., Saini, G., Maher, T.M., Molyneaux, P.L., Saunders, P., Zhang, Y., Gibson, K.F., Kass, D.J., Rojas, M., Sembrat, J., Wolters, P.J., Collard, H.R., Sundy, J.S., O’Riordan, T., Strek, M.E., Noth, I., Ma, S-F, Porteous, M.K., Kreider, M.E., Patel, N.B., Inoue, Y., Hirose, M., Arai, T., Akagawa, S., Eickelberg, O., Fernandez, I.E., Behr, J., Mogulkoc, N., Corte, T.J., Glaspole, I., Tomassetti, S., Ravaglia, C., Poletti, V., Crestani, B., Borie, R., Kannengiesser, C., Parfrey, H., Fiddler, C., Rassl, D., Molina-Molina, M., Machahua, C., Worboys, A.M., Gudmundsson, G., Isaksson, H.J., Lederer, D.J., Podolanczuk, A.J., Montesi, S.B., Bendstrup, E., Danchel, V., Selman, M., Pardo, A., Henry, M.T., Keane, M.P., Doran, P., Vašáková, M., Sterclova, M., Ryerson, C.J., Wilcox, P.G., Okamoto, T., Furusawa, H., Miyazaki, Y., Laurent, G., Baltic, S., Prêle, C., Moodley, Y., Shea, B.S., Ohta, K., Suzukawa, M., Narumoto, O., Nathan, S.D., Venuto, D.C., Woldehanna, M.L., Kokturk, N., de Andrade, J.A., Luckhardt, T., Kulkarni, T., Bonella, F., Donnelly, S.C., McElroy, A., Armstong, M.E., Aranda, A., Carbone, R.G., Puppo, F., Beckman, K.B., Nickerson, D.A., Fingerlin, T.E., Schwartz, D.A., Moore, C., Blumhagen, R.Z., Yang, I.V., Walts, A., Powers, J., Walker, T., Bishop, M., Russell, P., Vestal, B., Cardwell, J., Markin, C.R., Mathai, S.K., Schwarz, M.I., Steele, M.P., Lee, J., Brown, K.K., Loyd, J.E., Crapo, J.D., Silverman, E.K., Cho, M.H., James, J.A., Guthridge, J.M., Cogan, J.D., Kropski, J.A., Swigris, J.J., Bair, C., Kim, D.S., Ji, W., Kim, H., Song, J.W., Maier, L.A., Pacheco, K.A., Hirani, N., Poon, A.S., Li, F., Jenkins, R.G., Braybrooke, R., Saini, G., Maher, T.M., Molyneaux, P.L., Saunders, P., Zhang, Y., Gibson, K.F., Kass, D.J., Rojas, M., Sembrat, J., Wolters, P.J., Collard, H.R., Sundy, J.S., O’Riordan, T., Strek, M.E., Noth, I., Ma, S-F, Porteous, M.K., Kreider, M.E., Patel, N.B., Inoue, Y., Hirose, M., Arai, T., Akagawa, S., Eickelberg, O., Fernandez, I.E., Behr, J., Mogulkoc, N., Corte, T.J., Glaspole, I., Tomassetti, S., Ravaglia, C., Poletti, V., Crestani, B., Borie, R., Kannengiesser, C., Parfrey, H., Fiddler, C., Rassl, D., Molina-Molina, M., Machahua, C., Worboys, A.M., Gudmundsson, G., Isaksson, H.J., Lederer, D.J., Podolanczuk, A.J., Montesi, S.B., Bendstrup, E., Danchel, V., Selman, M., Pardo, A., Henry, M.T., Keane, M.P., Doran, P., Vašáková, M., Sterclova, M., Ryerson, C.J., Wilcox, P.G., Okamoto, T., Furusawa, H., Miyazaki, Y., Laurent, G., Baltic, S., Prêle, C., Moodley, Y., Shea, B.S., Ohta, K., Suzukawa, M., Narumoto, O., Nathan, S.D., Venuto, D.C., Woldehanna, M.L., Kokturk, N., de Andrade, J.A., Luckhardt, T., Kulkarni, T., Bonella, F., Donnelly, S.C., McElroy, A., Armstong, M.E., Aranda, A., Carbone, R.G., Puppo, F., Beckman, K.B., Nickerson, D.A., Fingerlin, T.E., and Schwartz, D.A.
Abstract: Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91–6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34–26.17) for two copies of the risk allele (P = 9.60 × 10−295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.
Published: 2019

6. Polymorphisms in P2X4R and CAMKK2 may affect TNFα production: Implications for a role in HIV-associated sensory neuropathy

Author: Gaff, Jessica, Halstrom, S., Temple, S., Baltic, S., Kamerman, P., Price, Patricia, Gaff, Jessica, Halstrom, S., Temple, S., Baltic, S., Kamerman, P., and Price, Patricia
Abstract: Polymorphisms in P2X4R and CAMKK2 associate with susceptibility to HIV-associated sensory neuropathy (HIV-SN) - a condition likely mediated by TNFα. As single nucleotide polymorphisms (SNPs) and haplotypes of CAMKK2, and a neighbouring gene P2X4R, mark susceptibility to HIV-SN in South Africans living with HIV, we examined the relationship between P2X4R and CAMKK2 genotypes and TNFα production. Peripheral blood mononuclear cells from 129 healthy donors were stimulated with killed Escherichia coli, and concentrations of soluble TNFa were assessed. Their DNA was genotyped for 22 SNPs in P2X4R and CAMKK2. Three SNPs within P2X4R and two SNPs within CAMKK2 influenced concentrations of TNFα, but these SNP did not associate with risk for HIV-SN. This incongruence may reflect differences in P2X4R haplotypes present in Africans and Europeans. However some CAMKK2 haplotypes were found in both populations, so CAMKK2 polymorphisms may impact upon HIV-SN via effects of the protein on pathways other than TNFα.
Published: 2018

7. Characterisation of B cell subsets in the blood and lung of patients with idiopathic pulmonary fibrosis

Author: Prêle, C., Lucas, A., Barrett, L., Baltic, S., Fear, M., Knight, D., Laurent, G., McAnulty, R., Mutsaers, S., Hoyne, G., Prêle, C., Lucas, A., Barrett, L., Baltic, S., Fear, M., Knight, D., Laurent, G., McAnulty, R., Mutsaers, S., and Hoyne, G.
Abstract: Idiopathic pulmonary fibrosis is the most common of the idiopathic interstitial pneumonias and is typically associated with prominent lymphoid aggregates of CD3+ T cells and CD20+ B cells within the lung tissue that are located near sites of active fibrosis. The presence of lymphoid aggregates outside of primary and secondary lymphoid tissues is a prominent feature of many autoimmune diseases and the presence of lymphoid foci can precede the onset of clinical disease. We have examined the B cell profile of IPF patients and aged matched healthy controls using multicolour flow cytometry and analysed the serum for the presence of B cell cytokines BAFF and April, and CXCL13 a chemokine that promotes B cell migration to lung tissue. In contrast to healthy controls IPF patients show an accumulation of plasma B cells in the peripheral blood and a subset of patients show a rise in CD5+ CD23+ transitional B cells. Immunohistochemical staining of lung tissue from IPF patients revealed synchronous accumulation of CD138+ plasma cells and CD5+ B cells within the lymphoid aggregates of IPF patients. IPF patients showed a trend toward increased serum levels of BAFF, April and CXCL13. The presence of plasma cells and CD5+ B cells in the blood and lung tissue of IPF patients raises the important question as to the role of B cells in IPF disease pathogenesis. Grant Support This work is funded by NHMRC Project Grant GNT1067511 and British Lung Foundation Grant PPRG15-10.
Published: 2018

8. A haplotype spanning P2X7R, P2X4R and CAMKK2 may mark susceptibility to pulmonary non-tuberculous mycobacterial disease

Author: Halstrom, S., Cherry, C.L., Black, M., Thomson, R., Goullee, H., Baltic, S., Allcock, R., Temple, S.E.L., Price, P., Halstrom, S., Cherry, C.L., Black, M., Thomson, R., Goullee, H., Baltic, S., Allcock, R., Temple, S.E.L., and Price, P.
Abstract: Despite widespread exposure to potentially pathogenic mycobacteria present in the soil and in domestic water supplies, it is not clear why only a small proportion of individuals contract pulmonary nontuberculous mycobacterial (NTM) infections. Here, we explore the impact of polymorphisms within three genes: P2X ligand gated ion channel 7 (P2X7R), P2X ligand gated ion channel 4 (P2X4R) and calcium/calmodulin-dependent protein kinase kinase 2 beta (CAMKK2) on susceptibility. Thirty single nucleotide polymorphisms (SNPs) were genotyped in NTM patients (n = 124) and healthy controls (n = 229). Weak associations were found between individual alleles in P2X7R and disease but were not significant in multivariate analyses adjusted to account for gender. Haplotypes spanning the three genes were derived using the fastPHASE algorithm. This yielded 27 haplotypes with frequencies >1% and accounting for 63.3% of the combined cohort. In univariate analyses, seven of these haplotypes displayed associations with NTM disease above our preliminary cut-off (p ≤ 0.20). When these were carried forward in a logistic regression model, gender and one haplotype (SH95) were independently associated with the disease (model p < 0.0001; R2 = 0.05). Examination of individual alleles within these haplotypes implicated P2X7R and CAMKK2 in pathways affecting pulmonary NTM disease.
Published: 2017

9. Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling

Author: Ferreira, M.A.R., Jansen, R., Willemsen, G., Penninx, B.W.J.H., Bain, L.M., Vicente, C.T., Revez, J.A., Matheson, M.C., Hui, J., Tung, J.Y., Baltic, S., Le Souëf, P., Montgomery, G.W., Martin, N.G., Robertson, C.F., James, A., Thompson, P.J., Boomsma, D.I., Hopper, J.L., Hinds, D.A., Werder, R.B., Phipps, S., Ferreira, M.A.R., Jansen, R., Willemsen, G., Penninx, B.W.J.H., Bain, L.M., Vicente, C.T., Revez, J.A., Matheson, M.C., Hui, J., Tung, J.Y., Baltic, S., Le Souëf, P., Montgomery, G.W., Martin, N.G., Robertson, C.F., James, A., Thompson, P.J., Boomsma, D.I., Hopper, J.L., Hinds, D.A., Werder, R.B., and Phipps, S.
Abstract: Background: Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed. Objective: We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes. Methods: We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both . cis- and . trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations. Results: We tested the association between asthma and 17,190 genes that were found to have . cis- and/or . trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, . LIMS1, . TINF2, and . SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: . B4GALT3, . USMG5, . P2RY13, and . P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltrati
Published: 2017
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10. Susceptibility to non-tuberculous mycobacterial disease is influenced by rs1518111 in IL10

Author: Halstrom, S., Thomson, R., Goullee, H., Baltic, S., Allcock, R., Temple, S., Price, Patricia, Halstrom, S., Thomson, R., Goullee, H., Baltic, S., Allcock, R., Temple, S., and Price, Patricia
Abstract: Although exposure to potentially pathogenic nontuberculous mycobacteria (NTM) via soil and domestic water supplies is common, pulmonary infection and disease are confined to a small proportion of older individuals. Previously, alleles of a polymorphism in IL10 (rs1800896) were associated with NTM disease and we demonstrated elevated production of IL-10 by blood leukocytes from patients with pulmonary NTM. Here seven additional polymorphisms in IL10 were investigated in a larger cohort of Caucasian controls and patients with pulmonary NTM disease. This demonstrated a significant association between pulmonary NTM disease and one polymorphism (rs1518111) in strong linkage disequilibrium with rs1800896.
Published: 2017

11. Genome-wide association study unravels genetic determinants of the atopic march

Author: Marenholz, Ingo, Esparza-Gordillo, J., Rueschendorf, F., Strachan, D. P., Spycher, B. D., Baurecht, H., Margaritte-Jeannin, P., Saeaef, A., Kerkhof, M., Ege, M., Baltic, S., Matheson, M. C., Li, J., Ang, W. Q., McArdle, W., Homuth, G., Bouzigon, E., Pershagen, G., Postma, D. S., Braun-Fahrlaender, C., Duffy, D. L., Marks, G. B., Robertson, C. F., Martin, N. G., James, A., Sleiman, P., Foelster-Holst, R., Lieb, W., Gieger, C., Rietschel, E., Keil, T., Noethen, M. M., Sly, P. D., Schmidt, C. O., Matanovic, A., Holt, Pg P. G., Lau, S., Kabesch, M., Weidinger, S., Hakonarson, H., Ferreira, M. A. R., Laprise, C., Freidin, M. B., Genuneit, J., Koppelman, G. H., Melen, E., Dizier, M-H, Henderson, A. J., Lee, Y-A, and Groningen Research Institute for Asthma and COPD (GRIAC)
Published: 2016

12. Genome-wide association study unravels genetic determinants of the atopic march

Author: Marenholz, I, Esparza-Gordillo, J., Rueschendorf, F., Strachan, D. P., Spycher, B. D., Baurecht, H., Margaritte-Jeannin, P., Saeaef, A., Kerkhof, M., Ege, M., Baltic, S., Matheson, M. C., Li, J., Michel, S., Ang, W. Q., McArdle, W., Homuth, G., Bouzigon, E., Pershagen, G., Postma, D. S., Braun-Fahrlaender, C., Duffy, D. L., Marks, G. B., Robertson, C. F., Martin, N. G., James, A., Sleiman, P., Foelster-Holst, R., Lieb, W., Gieger, C., Rietschel, E., Keil, T., Noethen, M. M., Sly, P. D., Schmidt, C. O., Matanovic, A., Holt, Pg P. G., Lau, S., Kabesch, M., Weidinger, S., Hakonarson, H., Ferreira, M. A. R., Laprise, C., Freidin, M. B., Genuneit, J., Koppelman, G. H., Melen, E., Dizier, M-H, Henderson, A. J., Lee, Y-A, Marenholz, I, Esparza-Gordillo, J., Rueschendorf, F., Strachan, D. P., Spycher, B. D., Baurecht, H., Margaritte-Jeannin, P., Saeaef, A., Kerkhof, M., Ege, M., Baltic, S., Matheson, M. C., Li, J., Michel, S., Ang, W. Q., McArdle, W., Homuth, G., Bouzigon, E., Pershagen, G., Postma, D. S., Braun-Fahrlaender, C., Duffy, D. L., Marks, G. B., Robertson, C. F., Martin, N. G., James, A., Sleiman, P., Foelster-Holst, R., Lieb, W., Gieger, C., Rietschel, E., Keil, T., Noethen, M. M., Sly, P. D., Schmidt, C. O., Matanovic, A., Holt, Pg P. G., Lau, S., Kabesch, M., Weidinger, S., Hakonarson, H., Ferreira, M. A. R., Laprise, C., Freidin, M. B., Genuneit, J., Koppelman, G. H., Melen, E., Dizier, M-H, Henderson, A. J., and Lee, Y-A
Published: 2016

13. Identification of STOML2 as a putative novel asthma risk gene associated with IL6R

Author: Revez, JA, Matheson, MC, Hui, J, Baltic, S, James, A, Upham, JW, Dharmage, S, Thompson, PJ, Martin, NG, Hopper, JL, Ferreira, MAR, Revez, JA, Matheson, MC, Hui, J, Baltic, S, James, A, Upham, JW, Dharmage, S, Thompson, PJ, Martin, NG, Hopper, JL, and Ferreira, MAR
Abstract: BACKGROUND: Functional variants in the interleukin-6 receptor gene (IL6R) are associated with asthma risk. We hypothesized that genes co-expressed with IL6R might also be regulated by genetic polymorphisms that are associated with asthma risk. The aim of this study was to identify such genes. METHODS: To identify genes whose expression was correlated with that of IL6R, we analyzed gene expression levels generated for 373 human lymphoblastoid cell lines by the Geuvadis consortium and for 38 hematopoietic cell types by the Differentiation Map Portal (DMAP) project. Genes correlated with IL6R were then screened for nearby single nucleotide polymorphisms (SNPs) that were significantly associated with both variation in gene expression levels (eSNPs) and asthma risk. RESULTS: We identified 90 genes with expression levels correlated with those of IL6R and that also had a nearby eSNP associated with disease risk in a published asthma GWAS (N = 20 776). For 16 (18%) genes, the association between the eSNP and asthma risk replicated with the same direction of effect in a further independent published asthma GWAS (N = 27 378). Among the top replicated associations (FDR < 0.05) were eSNPs for four known (IL18R1, IL18RAP, BCL6, and STAT6) and one putative novel asthma risk gene, stomatin-like protein 2 (STOML2). The expression of STOML2 was negatively correlated with IL6R, while eSNPs that increased the expression of STOML2 were associated with an increased asthma risk. CONCLUSION: The expression of STOML2, a gene that plays a key role in mitochondrial function and T-cell activation, is associated with both IL-6 signaling and asthma risk.
Published: 2016

14. Meta-analysis identifies seven susceptibility loci involved in the atopic March

Author: Marenholz, I, Esparza-Gordillo, J, Rüschendorf, F, Bauerfeind, A, Strachan, DP, Spycher, BD, Baurecht, H, Margaritte-Jeannin, P, Sääf, A, Kerkhof, M, Ege, M, Baltic, S, Matheson, MC, Li, J, Michel, S, Ang, WQ, McArdle, W, Arnold, A, Homuth, G, Demenais, F, Bouzigon, E, Söderhäll, C, Pershagen, G, De Jongste, JC, Postma, DS, Braun-Fahrländer, C, Horak, E, Ogorodova, LM, Puzyrev, VP, Bragina, EY, Hudson, TJ, Morin, C, Duffy, DL, Marks, GB, Robertson, CF, Montgomery, GW, Musk, B, Thompson, PJ, Martin, NG, James, A, Sleiman, P, Toskala, E, Rodriguez, E, Fölster-Holst, R, Franke, A, Lieb, W, Gieger, C, Heinzmann, A, Rietschel, E, Keil, T, Cichon, S, Nöthen, MM, Pennell, CE, Sly, PD, Schmidt, CO, Matanovic, A, Schneider, V, Heinig, M, Hübner, N, Holt, PG, Lau, S, Kabesch, M, Weidinger, S, Hakonarson, H, Ferreira, MAR, Laprise, C, Freidin, MB, Genuneit, J, Koppelman, GH, Melén, E, Dizier, MH, Henderson, AJ, Lee, YA, Marenholz, I, Esparza-Gordillo, J, Rüschendorf, F, Bauerfeind, A, Strachan, DP, Spycher, BD, Baurecht, H, Margaritte-Jeannin, P, Sääf, A, Kerkhof, M, Ege, M, Baltic, S, Matheson, MC, Li, J, Michel, S, Ang, WQ, McArdle, W, Arnold, A, Homuth, G, Demenais, F, Bouzigon, E, Söderhäll, C, Pershagen, G, De Jongste, JC, Postma, DS, Braun-Fahrländer, C, Horak, E, Ogorodova, LM, Puzyrev, VP, Bragina, EY, Hudson, TJ, Morin, C, Duffy, DL, Marks, GB, Robertson, CF, Montgomery, GW, Musk, B, Thompson, PJ, Martin, NG, James, A, Sleiman, P, Toskala, E, Rodriguez, E, Fölster-Holst, R, Franke, A, Lieb, W, Gieger, C, Heinzmann, A, Rietschel, E, Keil, T, Cichon, S, Nöthen, MM, Pennell, CE, Sly, PD, Schmidt, CO, Matanovic, A, Schneider, V, Heinig, M, Hübner, N, Holt, PG, Lau, S, Kabesch, M, Weidinger, S, Hakonarson, H, Ferreira, MAR, Laprise, C, Freidin, MB, Genuneit, J, Koppelman, GH, Melén, E, Dizier, MH, Henderson, AJ, and Lee, YA
Abstract: Eczema often precedes the development of asthma in a disease course called the a € atopic marcha €. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.
Published: 2015

15. Meta-analysis identifies seven susceptibility loci involved in the atopic March

Author: Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Rüschendorf, F. (Franz), Bauerfeind, A. (Anja), Strachan, D.P. (David P.), Spycher, B.D. (Ben D.), Baurecht, H. (Hansjörg), Margaritte-Jeannin, P. (Patricia), Sääf, A. (Annika), Kerkhof, M. (Marjan), Ege, M. (Markus), Baltic, S. (Svetlana), Matheson, J., Li, J. (Jin), Michel, S. (Sven), Ang, W.Q. (Wei Q.), McArdle, W.L. (Wendy), Homuth, G. (Georg), Demenais, F. (Florence), Bouzigon, E. (Emmanuelle), Söderhäll, C. (Cilla), Pershagen, G. (Göran), Jongste, J.C. (Johan) de, Postma, D.S. (Dirkje), Braun-Fahrländer, C. (Charlotte), Horak, E. (Elisabeth), Ogorodova, L.M. (Ludmila M.), Puzyrev, V.P. (Valery P.), Bragina, E.Y. (Elena Yu), Hudson, T.J. (Thomas), Morin, C. (Charles), Duffy, D.L. (David), Marks, G.B. (Guy B.), Robertson, C., Montgomery, G.W. (Grant), Musk, A.W. (Arthur), Thompson, P.J. (Philip), Martin, N.G. (Nicholas), James, A.L. (Alan), Sleiman, P.M.A. (Patrick), Toskala, E. (Elina), Rodríguez, P.M., Fölster-Holst, R. (R.), Franke, A. (Andre), Lieb, W. (Wolfgang), Gieger, C. (Christian), Heinzmann, A. (Andrea), Rietschel, E. (Ernst), Keil, M. (Mark), Cichon, S. (Sven), Nöthen, M.M. (Markus M.), Pennell, C.E. (Craig), Sly, P.D., Schmidt, C.O. (Carsten Oliver), Matanovic, A. (Anja), Schneider, V. (Valentin), Heinig, M. (Matthias), Hübner, N. (Norbert), Holt, P.G. (Patrick), Lau, S. (Susanne), Kabesch, M. (Michael), Weidinger, S. (Stefan), Hakonarson, H. (Hakon), Ferreira, M.A. (Manuel), Laprise, C. (Catherine), Freidin, M.B. (M.), Genuneit, J. (Jon), Koppelman, G.H. (Gerard), Melén, E. (Erik), Dizier, M.-H., Arnold, A.M. (Alice), Henderson, A.J. (A. John), Lee, Y.-A. (Young-Ae), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Rüschendorf, F. (Franz), Bauerfeind, A. (Anja), Strachan, D.P. (David P.), Spycher, B.D. (Ben D.), Baurecht, H. (Hansjörg), Margaritte-Jeannin, P. (Patricia), Sääf, A. (Annika), Kerkhof, M. (Marjan), Ege, M. (Markus), Baltic, S. (Svetlana), Matheson, J., Li, J. (Jin), Michel, S. (Sven), Ang, W.Q. (Wei Q.), McArdle, W.L. (Wendy), Homuth, G. (Georg), Demenais, F. (Florence), Bouzigon, E. (Emmanuelle), Söderhäll, C. (Cilla), Pershagen, G. (Göran), Jongste, J.C. (Johan) de, Postma, D.S. (Dirkje), Braun-Fahrländer, C. (Charlotte), Horak, E. (Elisabeth), Ogorodova, L.M. (Ludmila M.), Puzyrev, V.P. (Valery P.), Bragina, E.Y. (Elena Yu), Hudson, T.J. (Thomas), Morin, C. (Charles), Duffy, D.L. (David), Marks, G.B. (Guy B.), Robertson, C., Montgomery, G.W. (Grant), Musk, A.W. (Arthur), Thompson, P.J. (Philip), Martin, N.G. (Nicholas), James, A.L. (Alan), Sleiman, P.M.A. (Patrick), Toskala, E. (Elina), Rodríguez, P.M., Fölster-Holst, R. (R.), Franke, A. (Andre), Lieb, W. (Wolfgang), Gieger, C. (Christian), Heinzmann, A. (Andrea), Rietschel, E. (Ernst), Keil, M. (Mark), Cichon, S. (Sven), Nöthen, M.M. (Markus M.), Pennell, C.E. (Craig), Sly, P.D., Schmidt, C.O. (Carsten Oliver), Matanovic, A. (Anja), Schneider, V. (Valentin), Heinig, M. (Matthias), Hübner, N. (Norbert), Holt, P.G. (Patrick), Lau, S. (Susanne), Kabesch, M. (Michael), Weidinger, S. (Stefan), Hakonarson, H. (Hakon), Ferreira, M.A. (Manuel), Laprise, C. (Catherine), Freidin, M.B. (M.), Genuneit, J. (Jon), Koppelman, G.H. (Gerard), Melén, E. (Erik), Dizier, M.-H., Arnold, A.M. (Alice), Henderson, A.J. (A. John), and Lee, Y.-A. (Young-Ae)
Abstract: Eczema often precedes the development of asthma in a disease course called the a 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified a
Published: 2015
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16. Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis

Author: Lim, C.B., Prêle, C.M., Baltic, S., Arthur, P.G., Creaney, J., Watkins, D.N., Thompson, P.J., Mutsaers, S.E., Lim, C.B., Prêle, C.M., Baltic, S., Arthur, P.G., Creaney, J., Watkins, D.N., Thompson, P.J., and Mutsaers, S.E.
Abstract: Gli transcription factors of the Hedgehog (Hh) pathway have been reported to be drivers of malignant mesothelioma (MMe) cell survival. The Gli inhibitor GANT61 induces apoptosis in various cancer cell models, and has been associated directly with Gli inhibition. However various chemotherapeutics can induce cell death through generation of reactive oxygen species (ROS) but whether ROS mediates GANT61-induced apoptosis is unknown. In this study human MMe cells were treated with GANT61 and the mechanisms regulating cell death investigated. Exposure of MMe cells to GANT61 led to G1 phase arrest and apoptosis, which involved ROS but not its purported targets, GLI1 or GLI2. GANT61 triggered ROS generation and quenching of ROS protected MMe cells from GANT61-induced apoptosis. Furthermore, we demonstrated that mitochondria are important in mediating GANT61 effects: (1) ROS production and apoptosis were blocked by mitochondrial inhibitor rotenone; (2) GANT61 promoted superoxide formation in mitochondria; and (3) mitochondrial DNA-deficient LO68 cells failed to induce superoxide, and were more resistant to apoptosis induced by GANT61 than wild-type cells. Our data demonstrate for the first time that GANT61 induces apoptosis by promoting mitochondrial superoxide generation independent of Gli inhibition, and highlights the therapeutic potential of mitochondrial ROS-mediated anticancer drugs in MMe.
Published: 2015

17. TP 227b Induction of mesothelioma cell apoptosis by GANT61, a small molecule inhibitor of GLI transcription factors: Evidence for redox-driven cytotoxicity

Author: Lim, C.B., Prêle, C.M., Arthur, P.G., Creaney, J., Watkins, D.N., Baltic, S., Thompson, P.J., Mutsaers, S.E., Lim, C.B., Prêle, C.M., Arthur, P.G., Creaney, J., Watkins, D.N., Baltic, S., Thompson, P.J., and Mutsaers, S.E.
Abstract: Background: Although it has been shown that Gli transcription factors are the major intracellular target of the small molecule inhibitor GANT61, the underlying mechanism by which GANT61 inhibits cancer cell growth remains unclear. In this study, we aimed to elucidate the mechanisms that underlie the induction of mesothelioma cell apoptosis by GANT61. Method: Human mesothelioma cells were treated with GANT61. Levels of apoptosis and reactive oxygen species (ROS) were quantified by flow cytometry. Results: Our study showed that GANT61 induces growth inhibition and apoptosis in mesothelioma cells through the induction of oxidative stress. Exposure of mesothelioma cells to GANT61 resulted in the rapid production of ROS. Quenching of ROS by the antioxidants N-acetylcysteine and L-glutathione blocked the induction of apoptosis and depolarization of mitochondrial membrane potential by GANT61, indicating that ROS overproduction is the primary driver for the pro-apoptotic activity of GANT61. Although GANT61 could inhibit Gli transcriptional activity, the inhibition of Gli was not sufficient to initiate apoptosis in mesothelioma cells. Further study revealed that the ROS species generated was superoxide from the mitochondria, and that mitochondrial electron transport chain inhibition by rotenone significantly suppressed the pro-apoptotic effect of GANT61. Conclusion: Our study provides evidence that GANT61 is a potent anti-mesothelioma therapeutic agent, which induces apoptosis in mesothelioma cells through the generation of mitochondrial superoxide.
Published: 2015

18. Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis

Author: Freitag, DF, Butterworth, AS, Willeit, P, Howson, JMM, Burgess, S, Kaptoge, S, Young, R, Ho, WK, Wood, AM, Sweeting, M, Spackman, S, Staley, JR, Ramond, A, Harshfield, E, Nielsen, SF, Grande, P, Lange, LA, Bown, MJ, Jones, GT, Scott, RA, Bevan, S, Porcu, E, Thorleifsson, G, Zeng, LY, Kessler, T, Nikpay, M, Do, R, Zhang, WH, Hopewell, JC, Kleber, M, Delgado, GE, Nelson, CP, Goel, A, Bis, JC, Dehghan, Abbas, Ligthart, Symen, Smith, AV, Qu, LM, van 't Hof, FNG, de Bakker, PIW, Baas, AF, van Rij, A, Tromp, G, Kuivaniemi, H, Ritchie, MD, Verma, SS, Crawford, DC, Malinowski, J, de Andrade, M, Kullo, IJ, Peissig, PL, McCarty, CA, Bottinger, EP, Gottesman, O, Crosslin, DR, Carrell, DS, Rasmussen-Torvik, LJ, Pacheco, JA, Huang, J, Timpson, NJ, Kettunen, J, Ala-Korpela, M, Mitchell, GF, Parsa, A, Wilkinson, IB, Gorski, M, Li, Yunlei, Franceschini, N, Keller, MF, Ganesh, SK, Langefeld, CD, Bruijn, L, Brown, MA, Evans, DM, Baltic, S, Ferreira, MA, Baurecht, H, Weidinger, S, Franke, A, Lubitz, SA, Muller-Nurasyid, M, Felix, Janine, Smith, NL, Sudman, M, Thompson, SD, Zeggini, E, Panoutsopoulou, K, Nalls, MA, Singleton, A, Polychronakos, C, Bradfield, JP, Hakonarson, H, Easton, DF, Thompson, D, Tomlinson, IP, Dunlop, M, Hemminki, K, Morgan, G, Eisen, T, Goldschmidt, H, Allan, JM, Henrion, M, Whiffin, N, Wang, YF, Chubb, D, Houlston, RS, Iles, MM, Bishop, DT, Law, MH, Hayward, NK, Luo, Y, Nejentsev, S, Barbalic, M, Crossman, D, Sanna, S, Soranzo, N, Markus, HS, Wareham, NJ, Rader, DJ, O Reilly, M, Assimes, T, Harris, TB, Hofman, Bert, Franco Duran, OH, Gudnason, V, Tracy, R, Psaty, BM, Farrall, M, Watkins, H, Hall, AS, Samani, NJ, Marz, W, Clarke, R, Collins, R, Kooner, JS, Chambers, JC, Kathiresan, S, McPherson, R, Erdmann, J, Kastrati, A, Schunkert, H, Stefansson, K, Thorsteinsdottir, U, Walston, JD, Tybjaerg-Hansen, A, Alam, DS, Majumder, AA, Di Angelantonio, E, Chowdhury, R, Nordestgaard, BG, Saleheen, D, Thompson, SG, Danesh, J, Freitag, DF, Butterworth, AS, Willeit, P, Howson, JMM, Burgess, S, Kaptoge, S, Young, R, Ho, WK, Wood, AM, Sweeting, M, Spackman, S, Staley, JR, Ramond, A, Harshfield, E, Nielsen, SF, Grande, P, Lange, LA, Bown, MJ, Jones, GT, Scott, RA, Bevan, S, Porcu, E, Thorleifsson, G, Zeng, LY, Kessler, T, Nikpay, M, Do, R, Zhang, WH, Hopewell, JC, Kleber, M, Delgado, GE, Nelson, CP, Goel, A, Bis, JC, Dehghan, Abbas, Ligthart, Symen, Smith, AV, Qu, LM, van 't Hof, FNG, de Bakker, PIW, Baas, AF, van Rij, A, Tromp, G, Kuivaniemi, H, Ritchie, MD, Verma, SS, Crawford, DC, Malinowski, J, de Andrade, M, Kullo, IJ, Peissig, PL, McCarty, CA, Bottinger, EP, Gottesman, O, Crosslin, DR, Carrell, DS, Rasmussen-Torvik, LJ, Pacheco, JA, Huang, J, Timpson, NJ, Kettunen, J, Ala-Korpela, M, Mitchell, GF, Parsa, A, Wilkinson, IB, Gorski, M, Li, Yunlei, Franceschini, N, Keller, MF, Ganesh, SK, Langefeld, CD, Bruijn, L, Brown, MA, Evans, DM, Baltic, S, Ferreira, MA, Baurecht, H, Weidinger, S, Franke, A, Lubitz, SA, Muller-Nurasyid, M, Felix, Janine, Smith, NL, Sudman, M, Thompson, SD, Zeggini, E, Panoutsopoulou, K, Nalls, MA, Singleton, A, Polychronakos, C, Bradfield, JP, Hakonarson, H, Easton, DF, Thompson, D, Tomlinson, IP, Dunlop, M, Hemminki, K, Morgan, G, Eisen, T, Goldschmidt, H, Allan, JM, Henrion, M, Whiffin, N, Wang, YF, Chubb, D, Houlston, RS, Iles, MM, Bishop, DT, Law, MH, Hayward, NK, Luo, Y, Nejentsev, S, Barbalic, M, Crossman, D, Sanna, S, Soranzo, N, Markus, HS, Wareham, NJ, Rader, DJ, O Reilly, M, Assimes, T, Harris, TB, Hofman, Bert, Franco Duran, OH, Gudnason, V, Tracy, R, Psaty, BM, Farrall, M, Watkins, H, Hall, AS, Samani, NJ, Marz, W, Clarke, R, Collins, R, Kooner, JS, Chambers, JC, Kathiresan, S, McPherson, R, Erdmann, J, Kastrati, A, Schunkert, H, Stefansson, K, Thorsteinsdottir, U, Walston, JD, Tybjaerg-Hansen, A, Alam, DS, Majumder, AA, Di Angelantonio, E, Chowdhury, R, Nordestgaard, BG, Saleheen, D, Thompson, SG, and Danesh, J
Abstract: Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who ca
Published: 2015

19. The Role of Receptor for Advanced Glycation End Products in Airway Inflammation in CF and CF related Diabetes

Author: Mulrennan, S., Baltic, S., Aggarwal, S., Wood, J., Miranda, Alina, Frost, F., Kaye, J., Thompson, P., Mulrennan, S., Baltic, S., Aggarwal, S., Wood, J., Miranda, Alina, Frost, F., Kaye, J., and Thompson, P.
Abstract: Cystic Fibrosis (CF) is often accompanied by diabetes leading to worsening lung function, the reason for which is unclear. The receptor for advanced-glycation-end-products (RAGE) regulates immune responses and inflammation and has been linked to diabetes and possibly CF. We performed a pilot study to determine if CF and CF-related diabetes (CFRD) are associated with enhanced RAGE expression. Full length (fl)RAGE, soluble (s)RAGE, endogenous soluble (es)RAGE, S100A12 (enRAGE) and advanced-glycation-end-products (AGE) expression was assessed in serum, white blood cells and sputum of patients with CF; diabetes; CFRD and healthy subjects. Sputum enRAGE/sRAGE ratios were high in CF but particularly in CFRD which negatively correlated with % predicted FEV1. Serum AGE and AGE/sRAGE ratios were high in diabetics but not in CF. A complex, multifaceted approach was used to assess the role of RAGE and its ligands which is fundamental to determining their impact on airway inflammation. There is a clear association between RAGE activity in the airways of CF and CFRD patients that is not evident in the vascular compartment and correlates with lung function, in contrast to diabetes. This strongly suggests a role for RAGE in contributing to the inflammatory overdrive seen in CF and to a greater extent in CFRD.
Published: 2015

20. AB0647 Effects of Cyclophosphamide Pulse Therapy on Parameters of Lung Function in Patients with Systemic Sclerosis

Author: Pavlov-Dolijanovic, S.R., primary, Vujasinovic Stupar, N., additional, Zekovic, A., additional, Radnic-Zivanovic, T., additional, and Baltic, S., additional
Published: 2014
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21. Targeting of hedgehog pathway via pharmacologic inhibition of GLI induces apoptosis in malignant mesothelioma cells

Author: Lim, C.B., Thompson, P.J., Baltic, S., Lee, Y.C.G., Watkins, D.N., Prêle, C.M., Mutsaers, S.E., Lim, C.B., Thompson, P.J., Baltic, S., Lee, Y.C.G., Watkins, D.N., Prêle, C.M., and Mutsaers, S.E.
Published: 2013

22. Mutational Analysis of Hedgehog Signaling Pathway Genes in Human Malignant Mesothelioma

Author: Lim, C.B., Prêle, C.M., Cheah, H.M., Cheng, Y.Y., Klebe, S., Reid, G., Watkins, D.N., Baltic, S., Thompson, P.J., Mutsaers, S.E., Lim, C.B., Prêle, C.M., Cheah, H.M., Cheng, Y.Y., Klebe, S., Reid, G., Watkins, D.N., Baltic, S., Thompson, P.J., and Mutsaers, S.E.
Abstract: Background The Hedgehog (HH) signaling pathway is critical for embryonic development and adult homeostasis. Recent studies have identified regulatory roles for this pathway in certain cancers with mutations in the HH pathway genes. The extent to which mutations of the HH pathway genes are involved in the pathogenesis of malignant mesothelioma (MMe) is unknown. Methodology/Principal Findings Real-time PCR analysis of HH pathway genes PTCH1, GLI1 and GLI2 were performed on 7 human MMe cell lines. Exon sequencing of 13 HH pathway genes was also performed in cell lines and human MMe tumors. In silico programs were used to predict the likelihood that an amino-acid substitution would have a functional effect. GLI1, GLI2 and PTCH1 were highly expressed in MMe cells, indicative of active HH signaling. PTCH1, SMO and SUFU mutations were found in 2 of 11 MMe cell lines examined. A non-synonymous missense SUFU mutation (p.T411M) was identified in LO68 cells. In silico characterization of the SUFU mutant suggested that the p.T411M mutation might alter protein function. However, we were unable to demonstrate any functional effect of this mutation on Gli activity. Deletion of exons of the PTCH1 gene was found in JU77 cells, resulting in loss of one of two extracellular loops implicated in HH ligand binding and the intracellular C-terminal domain. A 3-bp insertion (69_70insCTG) in SMO, predicting an additional leucine residue in the signal peptide segment of SMO protein was also identified in LO68 cells and a MMe tumour. Conclusions/Significance We identified the first novel mutations in PTCH1, SUFU and SMO associated with MMe. Although HH pathway mutations are relatively rare in MMe, these data suggest a possible role for dysfunctional HH pathway in the pathogenesis of a subgroup of MMe and help rationalize the exploration of HH pathway inhibitors for MMe therapy.
Published: 2013

23. Absence of mutations in Hedgehog pathways genes PTCH1 and SMO are rare in malignant mesothelioma cells

Author: Lim, C.B., Cheah, H.M., Baltic, S., Thompson, P.J., Prêle, C.M., Mutsaers, S.E., Lim, C.B., Cheah, H.M., Baltic, S., Thompson, P.J., Prêle, C.M., and Mutsaers, S.E.
Published: 2012

24. Identification of STOML2 as a putative novel asthma risk gene associated with IL6R.

Author: Revez, J. A., Matheson, M. C., Hui, J., Baltic, S., James, A., Upham, J. W., Dharmage, S., Thompson, P. J., Martin, N. G., Hopper, J. L., and Ferreira, M. A. R.
Subjects: PROTEIN genetics, GENETICS of asthma, INTERLEUKIN-6 genetics, GENETIC polymorphisms, GENE expression, DISEASE risk factors
Abstract: Background Functional variants in the interleukin-6 receptor gene ( IL6R) are associated with asthma risk. We hypothesized that genes co-expressed with IL6R might also be regulated by genetic polymorphisms that are associated with asthma risk. The aim of this study was to identify such genes. Methods To identify genes whose expression was correlated with that of IL6R, we analyzed gene expression levels generated for 373 human lymphoblastoid cell lines by the Geuvadis consortium and for 38 hematopoietic cell types by the Differentiation Map Portal ( DMAP) project. Genes correlated with IL6R were then screened for nearby single nucleotide polymorphisms ( SNPs) that were significantly associated with both variation in gene expression levels ( eSNPs) and asthma risk. Results We identified 90 genes with expression levels correlated with those of IL6R and that also had a nearby eSNP associated with disease risk in a published asthma GWAS ( N = 20 776). For 16 (18%) genes, the association between the eSNP and asthma risk replicated with the same direction of effect in a further independent published asthma GWAS ( N = 27 378). Among the top replicated associations ( FDR < 0.05) were eSNPs for four known ( IL18R1, IL18 RAP, BCL6, and STAT6) and one putative novel asthma risk gene, stomatin-like protein 2 ( STOML2). The expression of STOML2 was negatively correlated with IL6R, while eSNPs that increased the expression of STOML2 were associated with an increased asthma risk. Conclusion The expression of STOML2, a gene that plays a key role in mitochondrial function and T-cell activation, is associated with both IL-6 signaling and asthma risk. [ABSTRACT FROM AUTHOR]
Published: 2016
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25. Analysis of Mammography Trials Renews Debate on Mortality Reduction

Author: Baltic, S., primary
Published: 2001
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26. Conference Addresses Potential Flaws in Peer Review Process

Author: Baltic, S., primary
Published: 2001
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27. Genome-wide association study to identify genetic determinants of severe asthma

Author: Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, Hall, Ian P., Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, and Hall, Ian P.
Abstract: Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.
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28. Genome-wide association study to identify genetic determinants of severe asthma

Author: Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, Hall, Ian P., Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, and Hall, Ian P.
Abstract: Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.
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29. Genome-wide association study to identify genetic determinants of severe asthma

Author: Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, Hall, Ian P., Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, and Hall, Ian P.
Abstract: Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.
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30. Genome-wide association study to identify genetic determinants of severe asthma

Author: Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, Hall, Ian P., Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, and Hall, Ian P.
Abstract: Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.
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31. Genome-wide association study to identify genetic determinants of severe asthma

Author: Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, Hall, Ian P., Wan, Y.I., Shrine, N.R.G., Soler Artigas, M., Wain, L.V., Blakey, J.D., Moffatt, M.F., Bush, A., Chung, K. F., Cookson, W.O.C.M., Strachan, D.P., Heaney, L., Al-Momani, B.A.H., Mansur, A.H., Manney, S., Thomson, N.C., Chaudhuri, R., Brightling, C.E., Bafadhel, M., Singapuri, A., Niven, R., Simpson, A., Holloway, J.W., Howarth, P.H., Hui, J., Musk, A.W., James, A.L., Brown, M.A., Baltic, S., Ferreira, M.A.R., Thompson, P.J., Tobin, M.D., Sayers, Ian, and Hall, Ian P.
Abstract: Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.
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32. Creatine and sleep habits and disorders in the general population aged 16 years and over: NHANES 2007-2008.

Author: Baltic S, Grasaas E, and Ostojic SM
Abstract: Background: Preclinical studies have suggested that dietary creatine may affect sleep quality yet no studies have explored the potential association between creatine consumption and sleep patterns or disorders in the general population. Aim: This cross-sectional study aims to examine the association between creatine consumption and sleep habits and disorders among individuals aged 16 years and older, using data from the 2007-2008 National Health and Nutrition Examination Survey (NHANES). Methods: The analysis included 5988 individuals (50.5% females) with a mean age of 47.4 ± 19.5 years. Daily creatine intake was assessed through individual in-person 24-h food recall interviews, categorizing respondents into two groups: those with suboptimal creatine intake (<1.00 g per day) and those meeting recommended intake (dietary creatine ≥ 1.00 g per day). Sleep was evaluated during household interviews using questions on sleep habits and disorders from the NHANES Sleep Disorders component. Results: The average daily creatine intake among participants was 0.88 ± 0.85 g (95% CI, 0.86 to 0.90), while the mean nightly sleep duration was 6.8 ± 1.5 h (95% CI, 6.8 to 6.9). Additionally, 1331 respondents (22.2%) reported consulting a doctor or health professional for sleep-related issues. Participants with suboptimal creatine intake had a significantly higher prevalence of trouble sleeping compared to those consuming recommended amounts (23.7% vs 19.3%; P < 0.01), with an odds ratio of 1.30 (95% CI: 1.13 to 1.48) for experiencing sleep disturbances. However, the prevalence of more severe sleep disorders did not differ significantly between the two creatine sub-populations ( P > 0.05). Conclusion: Our findings suggest that participants meeting recommended creatine intake levels had a reduced risk of experiencing mild sleeping difficulties. These findings may serve as a basis for future interventional studies aimed at validating and confirming the potential benefits of dietary creatine in the field of sleep medicine., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SMO serves as a member of the Scientific Advisory Board on Creatine in Health and Medicine (AlzChem LLC). SMO co-owns patent “Supplements Based on Liquid Creatine” at the European Patent Office (WO2019150323 A1) and patent application “Composition Comprising Creatine for Use in Telomere Lengthening” at the U.S. Patent and Trademark Office (# 63/608,850). SMO has received research support related to creatine during the past 36 months from the Serbian Ministry of Education, Science, and Technological Development; Provincial Secretariat for Higher Education and Scientific Research; AlzChem GmbH; ThermoLife International; and Hueston Hennigan LLP. SMO does not own stocks and shares in any organization. SB and EG declare no known competing financial interests or personal relationships that could have appeared to influence the authorship of this paper.
Published: 2024
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33. Dietary creatine and carcinogenic biomarkers in adult population.

Author: Baltic S, Grasaas E, and Ostojic SM
Abstract: Background: Several reports suggest potential cytotoxic effects of creatine, possibly due to its role in facilitating the formation of food-borne chemical carcinogenic compounds. Aim: This cross-sectional study aims to investigate the relationship between creatine consumption and various carcinogenic biomarkers in blood and urine among individuals aged 18 years and older, utilizing data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES). Methods: Daily creatine intake was assessed using the Dietary Data databases, which were compiled from individual in-person 24-h food recall interviews. The concentrations of carcinogenic compounds (heterocyclic amines, acrylamide, and formaldehyde) were extracted from NHANES 2013-2014 Laboratory Data database. Results: The final analysis included 1763 adult respondents, of whom 907 (51.4%) were female. The mean daily creatine intake was 0.83 ± 0.77 grams (95% CI, from 0.80 to 0.87). Regression analysis revealed no significant relationship between daily creatine intake and most carcinogenic biomarkers, except for a significant correlation (Model 1) between creatine intake and acrylamide levels ( B = -3.999, ß = -0.088, p = 0.05). Model 2 (demographics) confirmed a significant relationship between daily creatine intake and circulating acrylamide ( B = -3.490, ß = -0.077, p = 0.02), as well as for blood levels of glycidamide ( B = -2.992, ß = -0.068, p = 0.05) and urinary 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (B = 0.190, ß = 0.088, p = 0.03). However, no correlation between creatine consumption and any carcinogenic biomarkers remained significant after adjusting for nutritional factors (Model 3) ( p > 0.05). Conclusion: In conclusion, the consumption of dietary creatine may be considered safe and not associated with increased levels of above carcinogens in the general population., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: State: - SMO serves as a member of the Scientific Advisory Board on Creatine in Health and Medicine (AlzChem LLC). SMO co-owns patent “Supplements Based on Liquid Creatine” at the European Patent Office (WO2019150323 A1) and patent application “Composition Comprising Creatine for Use in Telomere Lengthening” at the U.S. Patent and Trademark Office (# 63/608,850). SMO has received research support related to creatine during the past 36 months from the Serbian Ministry of Education, Science, and Technological Development; Provincial Secretariat for Higher Education and Scientific Research; AlzChem GmbH; ThermoLife International; and Hueston Hennigan LLP. SMO does not own stocks and shares in any organization. SB and EG declare no known competing financial interests or personal relationships that could have appeared to influence the authorship of this paper.
Published: 2024
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34. The Impact of Short-Term Supplementation With Guanidinoacetic Acid and Creatine Versus Creatine Alone on Body Composition Indices in Healthy Men and Women: Creatine-Guanidinoacetic Acid Affects Body Composition.

Author: Baltic S, Nedeljkovic D, Todorovic N, Ratgeber L, Betlehem J, Acs P, Stajer V, and Ostojic SM
Abstract: The main objective of this pilot study was to compare the effects of short-term supplementation with a mixture containing creatine and guanidinoacetic acid (GAA) versus creatine alone on body composition indices in men and women. Twenty-three apparently healthy young adults (mean age: 21.4 ± 0.6 years; 10 females) were randomly assigned to receive either a mixture (consisting of 2 g of creatine monohydrate and 2 g of GAA) or an equimolar amount of creatine monohydrate in a pretest-posttest control group experimental crossover design. After the intervention period, participants entered a 2-week washout phase to minimize any residual effects of the treatment. Body composition was assessed using a multifrequency bioelectrical impedance analysis at baseline (preadministration) and at the 7-day follow-up (postadministration). A significant interaction effect was found for extracellular mass ( p =0.009), with creatine-GAA outperforming creatine in augmenting extracellular mass across the whole sample. In the male subsample, creatine was superior to the mixture in increasing intracellular water ( p =0.049), whereas the mixture increased extracellular mass, contrasting with the reduction observed with creatine alone ( p =0.008). No significant differences between interventions were reported in the female subsample ( p > 0.05), indicating that adding GAA to creatine may produce unique, sex-specific effects on body composition. Further studies are needed to validate our findings across different demographic cohorts and various interventional regimens., Competing Interests: S.M.O. serves as a member of the Scientific Advisory Board on Creatine in Health and Medicine (AlzChem LLC). S.M.O. co-owns the patent “Supplements Based on Liquid Creatine” at the European Patent Office (WO2019150323 A1) and has a patent application for “Composition Comprising Creatine for Use in Telomere Lengthening” at the U.S. Patent and Trademark Office (#63/608,850). S.M.O. has received research support related to creatine over the past 36 months from the Serbian Ministry of Education, Science, and Technological Development; the Provincial Secretariat for Higher Education and Scientific Research; AlzChem GmbH; ThermoLife International; and Hueston Hennigan LLP. S.M.O. does not own stocks or shares in any organization. S.B., D.N., N.T., L.R., J.B., P.A., and V.S. declare no conflicts of interest that could have appeared to influence the authorship of this paper., (Copyright © 2024 Sonja Baltic et al.)
Published: 2024
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35. Dietary creatine is associated with lower serum neurofilament light chain levels.

Author: Ostojic SM, Grasaas E, Baltic S, and Cvejic J
Subjects: Humans, Middle Aged, Female, Adult, Male, Aged, Young Adult, Biomarkers blood, Diet, Creatine blood, Creatine administration & dosage, Neurofilament Proteins blood, Nutrition Surveys
Abstract: Low creatine availability may be linked to an elevated risk of neuronal damage, yet this association remains inadequately explored at the population level. Utilizing 2013-2014 National Health and Nutrition Examination Survey data, the current study found a negative correlation between dietary creatine intake and serum levels of neurofilament light chain (NfL; a biomarker for neuronal damage) in a cohort of 1912 individuals (52.2% females) aged 20-75 years. This inverse association persisted even after adjusting for other nutritional variables known to influence neuronal viability. The observed pattern, where increased dietary creatine intake was associated with reduced circulating NfL levels, suggests potential protective effects of creatine against neuronal injury., Competing Interests: SMO serves as a member of the Scientific Advisory Board on Creatine in Health and Medicine (AlzChem LLC). SMO co-owns patent “Supplements Based on Liquid Creatine” at the European Patent Office (WO2019150323 A1) and patent application “Composition Comprising Creatine for Use in Telomere Lengthening” at the U.S. Patent and Trademark Office (# 63/608,850). SMO has received research support related to creatine during the past 36 months from the Serbian Ministry of Education, Science, and Technological Development; Provincial Secretariat for Higher Education and Scientific Research; Alzchem GmbH; ThermoLife International; and Hueston Hennigan LLP. SMO does not own stocks and shares in any organization. EG, SB, and JC declare no known competing financial interests or personal relationships that could have appeared to influence the authorship of this paper.
Published: 2024
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36. The impact of six-week dihydrogen-pyrroloquinoline quinone supplementation on mitochondrial biomarkers, brain metabolism, and cognition in elderly individuals with mild cognitive impairment: a randomized controlled trial.

Author: Baltic S, Nedeljkovic D, Todorovic N, Ranisavljev M, Korovljev D, Cvejic J, Ostojic J, LeBaron TW, Timmcke J, Stajer V, and Ostojic SM
Subjects: Humans, Female, Aged, Male, Double-Blind Method, Cognitive Dysfunction, PQQ Cofactor pharmacology, Cognition drug effects, Biomarkers blood, Brain metabolism, Brain drug effects, Dietary Supplements, Brain-Derived Neurotrophic Factor metabolism, Brain-Derived Neurotrophic Factor blood, Mitochondria metabolism, Mitochondria drug effects
Abstract: Objectives: To assess the impact of medium-term supplementation with dihydrogen and pyrroloquinoline quinone (PQQ) on mitochondrial biomarkers, brain metabolism, and cognition in elderly individuals diagnosed with mild cognitive impairment., Design: A parallel-group, randomized, placebo-controlled, double-blind experimental design, maintaining a 1:1 allocation ratio between the experimental group (receiving the dihydrogen-producing minerals and PQQ) and the control group (receiving the placebo) throughout the trial., Setting and Participants: Thirty-four elderly individuals with mild cognitive impairment (mean age 71.9 ± 3.8 years; 28 females) voluntarily provided written consent to participate in this trial. Participants were assigned in a double-blind parallel-group design to receive either a dihydrogen-PQQ mixture (Alpha Hope®, CalerieLife, Irvine, CA) or placebo twice daily for a 6-week intervention period., Methods: The primary endpoint was the change in serum brain-derived neurotrophic factor (BDNF) from baseline to the 6-week follow-up; secondary outcomes included cognitive function indices, specific metabolites in brain tissue, brain oxygenation, and the prevalence and severity of side effects. Interaction effects (time vs. intervention) were evaluated using two-way ANOVA with repeated measures and Friedman's 2-way ANOVA by ranks, for normally distributed data with homogeneous variances and non-homogeneous variances, respectively., Results: Dihydrogen-PQQ resulted in a significant elevation in serum BDNF levels at the six-week follow-up (P = 0.01); conversely, no changes in BDNF levels were observed in the placebo group throughout the study duration (P = 0.27). A non-significant trend in the impact of interventions on BDNF levels was observed (treatment vs. time interaction, P = 0.14), suggesting a tendency for dihydrogen-PQQ to upregulate BDNF levels compared to the placebo. A significant interaction effect was observed for the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores in the orientation domain (P = 0.03), indicating the superiority of dihydrogen-PQQ over placebo in enhancing this cognitive aspect. Cerebral oxygenation saturation exhibited a significant increase following the administration of the dihydrogen-PQQ mixture, from 48.4 ± 7.2% at baseline to 52.8 ± 6.6% at 6-week post-administration (P = 0.005). In addition, brain N-acetyl aspartate levels significantly increased at seven out of thirteen locations post-intervention in participants receiving the mixture (P ≤ 0.05)., Conclusions: Despite the limited number of participants included in the study for interpreting clinical parameters, the dihydrogen-PQQ mixture blend shows promise as a potential dietary intervention for enhancing mental orientation and brain metabolism in individuals with age-related mild cognitive decline., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Published: 2024
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37. Plasma cell but not CD20-mediated B-cell depletion protects from bleomycin-induced lung fibrosis.

Author: Prêle CM, Miles T, Pearce DR, O'Donoghue RJ, Grainge C, Barrett L, Birnie K, Lucas AD, Baltic S, Ernst M, Rinaldi C, Laurent GJ, Knight DA, Fear M, Hoyne G, McAnulty RJ, and Mutsaers SE
Subjects: Humans, Mice, Animals, Bleomycin pharmacology, Plasma Cells, Lung metabolism, Idiopathic Pulmonary Fibrosis drug therapy, Lung Diseases, Interstitial chemically induced
Abstract: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease associated with chronic inflammation and tissue remodelling leading to fibrosis, reduced pulmonary function, respiratory failure and death. Bleomycin (Blm)-induced lung fibrosis in mice replicates several clinical features of human IPF, including prominent lymphoid aggregates of predominantly B-cells that accumulate in the lung adjacent to areas of active fibrosis. We have shown previously a requirement for B-cells in the development of Blm-induced lung fibrosis in mice. To determine the therapeutic potential of inhibiting B-cell function in pulmonary fibrosis, we examined the effects of anti-CD20 B-cell ablation therapy to selectively remove mature B-cells from the immune system and inhibit Blm-induced lung fibrosis. Anti-CD20 B-cell ablation did not reduce fibrosis in this model; however, immune phenotyping of peripheral blood and lung resident cells revealed that anti-CD20-treated mice retained a high frequency of CD19 + CD138 + plasma cells. Interestingly, high levels of CD138 + cells were also identified in the lung tissue of patients with IPF, consistent with the mouse model. Treatment of mice with bortezomib, which depletes plasma cells, reduced the level of Blm-induced lung fibrosis, implicating plasma cells as important effector cells in the development and progression of pulmonary fibrosis., Competing Interests: Conflict of interest: S.E. Mutsaers, C.M. Prêle, R.J. McAnulty, G.J. Laurent, G. Hoyne, D.A. Knight, R.J. O'Donoghue and M. Ernst received grants from National Health and Medical Research Council (NHMRC), project grants ID APP1067511. R.J. McAnulty, S.E. Mutsaers, C.M. Prêle and D.R. Pearce received grants from British Lung Foundation, project grant number PPRG15-10. T. Miles reports that Genentech provided the anti-CD20 antibody, and received UWA Research Training Program Scholarship and the Lung Foundation Australia Bill van Nierop PhD Scholarship. All other authors have nothing to disclose., (Copyright ©The authors 2022.)
Published: 2022
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38. Circulating RNA differences between patients with stable and progressive idiopathic pulmonary fibrosis.

Author: Clynick B, Jo HE, Corte TJ, Glaspole IN, Grainge C, Hopkins PMA, Reynolds PN, Chapman S, Walters EH, Zappala C, Keir GJ, Cooper WA, Mahar AM, Ellis S, Goh NS, Baltic S, Ryan M, Tan DBA, and Moodley YP
Subjects: Disease Progression, Humans, Cell-Free Nucleic Acids, Idiopathic Pulmonary Fibrosis genetics
Abstract: Competing Interests: Conflict of interest: B. Clynick has nothing to disclose. Conflict of interest: H.E. Jo has nothing to disclose. Conflict of interest: T.J. Corte has nothing to disclose. Conflict of interest: I.N. Glaspole has nothing to disclose. Conflict of interest: C. Grainge has nothing to disclose. Conflict of interest: P.M.A. Hopkins has nothing to disclose. Conflict of interest: P.N. Reynolds has nothing to disclose. Conflict of interest: S. Chapman has nothing to disclose. Conflict of interest: E.H. Walters has nothing to disclose. Conflict of interest: C. Zappala has nothing to disclose. Conflict of interest: G.J. Keir has nothing to disclose. Conflict of interest: W.A. Cooper has nothing to disclose. Conflict of interest: A.M. Mahar has nothing to disclose. Conflict of interest: S. Ellis has nothing to disclose. Conflict of interest: N.S. Goh has nothing to disclose. Conflict of interest: S. Baltic has nothing to disclose. Conflict of interest: M. Ryan has nothing to disclose. Conflict of interest: D.B.A. Tan has nothing to disclose. Conflict of interest: Y.P. Moodley has nothing to disclose.
Published: 2020
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39. Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.

Author: Moore C, Blumhagen RZ, Yang IV, Walts A, Powers J, Walker T, Bishop M, Russell P, Vestal B, Cardwell J, Markin CR, Mathai SK, Schwarz MI, Steele MP, Lee J, Brown KK, Loyd JE, Crapo JD, Silverman EK, Cho MH, James JA, Guthridge JM, Cogan JD, Kropski JA, Swigris JJ, Bair C, Kim DS, Ji W, Kim H, Song JW, Maier LA, Pacheco KA, Hirani N, Poon AS, Li F, Jenkins RG, Braybrooke R, Saini G, Maher TM, Molyneaux PL, Saunders P, Zhang Y, Gibson KF, Kass DJ, Rojas M, Sembrat J, Wolters PJ, Collard HR, Sundy JS, O'Riordan T, Strek ME, Noth I, Ma SF, Porteous MK, Kreider ME, Patel NB, Inoue Y, Hirose M, Arai T, Akagawa S, Eickelberg O, Fernandez IE, Behr J, Mogulkoc N, Corte TJ, Glaspole I, Tomassetti S, Ravaglia C, Poletti V, Crestani B, Borie R, Kannengiesser C, Parfrey H, Fiddler C, Rassl D, Molina-Molina M, Machahua C, Worboys AM, Gudmundsson G, Isaksson HJ, Lederer DJ, Podolanczuk AJ, Montesi SB, Bendstrup E, Danchel V, Selman M, Pardo A, Henry MT, Keane MP, Doran P, Vašáková M, Sterclova M, Ryerson CJ, Wilcox PG, Okamoto T, Furusawa H, Miyazaki Y, Laurent G, Baltic S, Prele C, Moodley Y, Shea BS, Ohta K, Suzukawa M, Narumoto O, Nathan SD, Venuto DC, Woldehanna ML, Kokturk N, de Andrade JA, Luckhardt T, Kulkarni T, Bonella F, Donnelly SC, McElroy A, Armstong ME, Aranda A, Carbone RG, Puppo F, Beckman KB, Nickerson DA, Fingerlin TE, and Schwartz DA
Subjects: ATP-Binding Cassette Transporters genetics, Case-Control Studies, DNA Helicases genetics, Exoribonucleases genetics, Female, GTPase-Activating Proteins genetics, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, Logistic Models, Male, Mucin-5B genetics, Promoter Regions, Genetic genetics, Pulmonary Surfactant-Associated Protein A genetics, Pulmonary Surfactant-Associated Protein C genetics, RNA genetics, Sequence Analysis, DNA, Telomerase genetics, Telomere-Binding Proteins genetics, Cellular Senescence genetics, Host-Pathogen Interactions genetics, Idiopathic Pulmonary Fibrosis genetics
Abstract: Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases ( n = 3,624) and control subjects ( n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1 ) individual common variants via logistic regression and 2 ) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele ( P = 9.60 × 10 -295 ). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.
Published: 2019
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40. Schnitzler syndrome: A rare cause of chronic recalcitrant urticaria successfully treated with Anakinra.

Author: Sharma S, Joske D, Watson D, Caccetta T, Baltic S, and Kumarasinghe SP
Subjects: Biopsy, Needle, Chronic Disease, Drug Administration Schedule, Female, Humans, Immunohistochemistry, Injections, Subcutaneous, Middle Aged, Prognosis, Rare Diseases, Schnitzler Syndrome diagnosis, Severity of Illness Index, Treatment Outcome, Urticaria pathology, Interleukin 1 Receptor Antagonist Protein therapeutic use, Schnitzler Syndrome complications, Urticaria drug therapy, Urticaria etiology
Published: 2018
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41. Airway Interleukin-33 and type 2 cytokines in adult patients with acute asthma.

Author: Poulsen NN, Bjerregaard A, Khoo SK, Laing IA, Le Souëf P, Backer V, Rapley L, Cohen SE, Barrett L, Thompson P, Baltic S, and Porsbjerg C
Subjects: Acute Disease, Adult, Cytokines genetics, Eosinophils immunology, Female, Follow-Up Studies, Gene Expression immunology, Humans, Interleukin-13 genetics, Interleukin-13 metabolism, Interleukin-33 genetics, Interleukin-33 metabolism, Interleukin-5 genetics, Interleukin-5 metabolism, Male, Middle Aged, Nasal Mucosa immunology, RNA, Messenger genetics, Severity of Illness Index, Sputum immunology, Young Adult, Asthma immunology, Cytokines metabolism, Inflammation Mediators metabolism
Abstract: Background: Several animal studies, and one inoculation study in adult asthmatics have shown that interleukin-33 (IL-33) is a major contributor to type-2 inflammation in acute asthma. However, the link between IL-33 and type-2 inflammation has not been shown in naturally occurring asthma exacerbations., Objectives: To determine if airway IL-33 is associated with type-2 inflammation measured by type-2 cytokines, FeNO and sputum eosinophils in patients presenting to the Emergency Department with an asthma exacerbations., Methods: Adult patients hospitalized due to acute asthma were enrolled. Upper airways were sampled with nasal swabs and lower airways with induced sputum. Cytokines were measured at protein level using a Luminex ® assay and mRNA expression level using droplet-digital-PCR. Airway sampling was repeated four weeks after exacerbation., Results: At the time of exacerbation, upper airway IL-33 correlated with upper airway IL-5 and IL-13 (R = 0.84, p < 0.01 and R = 0.76, p < 0.01, respectively) and with lower airway IL-13 (R = 0.49, p = 0.03). Similar associations were observed for mRNA expression. Lower airway IL-33 positively correlated with lower airway IL-13 (R = 0.84, p < 0.01). IL-13 and IL-33 were positively correlated with FeNO, and IL-5 with eosinophils. The association between IL-33 and type-2 cytokines were still present four weeks after exacerbation., Conclusion: This is the first study to demonstrate that airway IL-33 is associated with type-2 cytokines in naturally occurring asthma exacerbations in adults, providing in vivo evidence supporting that IL-33 may be driving type-2 inflammation in acute asthma. Thus supporting IL-33 as a potential future drug target due to its role, upstream in the immunological cascade., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
Published: 2018
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42. Polymorphisms in P2X4R and CAMKK2 may affect TNFα production: Implications for a role in HIV-associated sensory neuropathy.

Author: Gaff J, Halstrom S, Temple SEL, Baltic S, Kamerman P, and Price P
Subjects: Adult, Black People genetics, Blood Donors, Escherichia coli immunology, HIV Infections immunology, Haplotypes, Healthy Volunteers, Humans, Leukocytes, Mononuclear pathology, Peripheral Nervous System Diseases blood, Peripheral Nervous System Diseases etiology, Polymorphism, Single Nucleotide, Tumor Necrosis Factor-alpha immunology, White People genetics, Calcium-Calmodulin-Dependent Protein Kinase Kinase genetics, HIV Infections complications, Peripheral Nervous System Diseases genetics, Receptors, Purinergic P2X4 genetics, Tumor Necrosis Factor-alpha metabolism
Abstract: Polymorphisms in P2X4R and CAMKK2 associate with susceptibility to HIV-associated sensory neuropathy (HIV-SN) - a condition likely mediated by TNFα. As single nucleotide polymorphisms (SNPs) and haplotypes of CAMKK2, and a neighbouring gene P2X4R, mark susceptibility to HIV-SN in South Africans living with HIV, we examined the relationship between P2X4R and CAMKK2 genotypes and TNFα production. Peripheral blood mononuclear cells from 129 healthy donors were stimulated with killed Escherichia coli, and concentrations of soluble TNFα were assessed. Their DNA was genotyped for 22 SNPs in P2X4R and CAMKK2. Three SNPs within P2X4R and two SNPs within CAMKK2 influenced concentrations of TNFα, but these SNP did not associate with risk for HIV-SN. This incongruence may reflect differences in P2X4R haplotypes present in Africans and Europeans. However some CAMKK2 haplotypes were found in both populations, so CAMKK2 polymorphisms may impact upon HIV-SN via effects of the protein on pathways other than TNFα., (Copyright © 2018. Published by Elsevier Inc.)
Published: 2018
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43. A haplotype spanning P2X7R, P2X4R and CAMKK2 may mark susceptibility to pulmonary non-tuberculous mycobacterial disease.

Author: Halstrom S, Cherry CL, Black M, Thomson R, Goullee H, Baltic S, Allcock R, Temple SEL, and Price P
Subjects: Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Lung Diseases epidemiology, Lung Diseases microbiology, Male, Middle Aged, Mycobacterium Infections, Nontuberculous epidemiology, Mycobacterium Infections, Nontuberculous microbiology, Calcium-Calmodulin-Dependent Protein Kinase Kinase genetics, Lung Diseases genetics, Mycobacterium pathogenicity, Mycobacterium Infections, Nontuberculous genetics, Polymorphism, Single Nucleotide, Receptors, Purinergic P2X4 genetics, Receptors, Purinergic P2X7 genetics
Abstract: Despite widespread exposure to potentially pathogenic mycobacteria present in the soil and in domestic water supplies, it is not clear why only a small proportion of individuals contract pulmonary nontuberculous mycobacterial (NTM) infections. Here, we explore the impact of polymorphisms within three genes: P2X ligand gated ion channel 7 (P2X7R), P2X ligand gated ion channel 4 (P2X4R) and calcium/calmodulin-dependent protein kinase kinase 2 beta (CAMKK2) on susceptibility. Thirty single nucleotide polymorphisms (SNPs) were genotyped in NTM patients (n = 124) and healthy controls (n = 229). Weak associations were found between individual alleles in P2X7R and disease but were not significant in multivariate analyses adjusted to account for gender. Haplotypes spanning the three genes were derived using the fastPHASE algorithm. This yielded 27 haplotypes with frequencies >1% and accounting for 63.3% of the combined cohort. In univariate analyses, seven of these haplotypes displayed associations with NTM disease above our preliminary cut-off (p ≤ 0.20). When these were carried forward in a logistic regression model, gender and one haplotype (SH95) were independently associated with the disease (model p < 0.0001; R 2 = 0.05). Examination of individual alleles within these haplotypes implicated P2X7R and CAMKK2 in pathways affecting pulmonary NTM disease.
Published: 2017
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44. Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling.

Author: Ferreira MA, Jansen R, Willemsen G, Penninx B, Bain LM, Vicente CT, Revez JA, Matheson MC, Hui J, Tung JY, Baltic S, Le Souëf P, Montgomery GW, Martin NG, Robertson CF, James A, Thompson PJ, Boomsma DI, Hopper JL, Hinds DA, Werder RB, and Phipps S
Subjects: Animals, Genetic Variation genetics, Humans, Mice, Mice, Inbred C57BL, Mitochondrial Proton-Translocating ATPases genetics, Nucleotides biosynthesis, Quantitative Trait Loci genetics, Receptors, Purinergic P2 genetics, Receptors, Purinergic P2Y genetics, Asthma genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Nucleotides genetics, Software
Abstract: Background: Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed., Objective: We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes., Methods: We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both cis- and trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations., Results: We tested the association between asthma and 17,190 genes that were found to have cis- and/or trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, LIMS1, TINF2, and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: B4GALT3, USMG5, P2RY13, and P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs., Conclusion: We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
Published: 2017
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45. Susceptibility to non-tuberculous mycobacterial disease is influenced by rs1518111 in IL10.

Author: Halstrom S, Thomson R, Goullee H, Baltic S, Allcock R, Temple SE, and Price P
Subjects: Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Linkage Disequilibrium, Male, Middle Aged, Pneumonia microbiology, Polymorphism, Single Nucleotide, Interleukin-10 genetics, Mycobacterium Infections, Nontuberculous genetics, Nontuberculous Mycobacteria physiology, Pneumonia genetics, White People
Abstract: Although exposure to potentially pathogenic nontuberculous mycobacteria (NTM) via soil and domestic water supplies is common, pulmonary infection and disease are confined to a small proportion of older individuals. Previously, alleles of a polymorphism in IL10 (rs1800896) were associated with NTM disease and we demonstrated elevated production of IL-10 by blood leukocytes from patients with pulmonary NTM. Here seven additional polymorphisms in IL10 were investigated in a larger cohort of Caucasian controls and patients with pulmonary NTM disease. This demonstrated a significant association between pulmonary NTM disease and one polymorphism (rs1518111) in strong linkage disequilibrium with rs1800896., (Copyright © 2017 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)
Published: 2017
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46. Characteristics associated with clinical severity and inflammatory phenotype of naturally occurring virus-induced exacerbations of asthma in adults.

Author: Bjerregaard A, Laing IA, Poulsen N, Backer V, Sverrild A, Fally M, Khoo SK, Barrett L, Baltic S, Thompson PJ, Chidlow G, Sikazwe C, Smith DW, Bochkov YA, Le Souëf P, and Porsbjerg C
Subjects: Acute Disease, Adult, Asthma metabolism, Asthma physiopathology, Cytokines biosynthesis, Cytokines genetics, Eosinophilia virology, Female, Forced Expiratory Volume physiology, Gene Expression physiology, Humans, Inflammation metabolism, Inflammation physiopathology, Inflammation virology, Male, Middle Aged, Nitric Oxide metabolism, Phenotype, Prospective Studies, RNA, Messenger genetics, Respiratory Tract Infections metabolism, Respiratory Tract Infections physiopathology, Severity of Illness Index, Spirometry, Sputum cytology, Sputum metabolism, Virus Diseases metabolism, Virus Diseases physiopathology, Young Adult, Thymic Stromal Lymphopoietin, Asthma virology, Respiratory Tract Infections complications, Virus Diseases complications
Abstract: Background: In experimental studies viral infections have been shown to induce type 2 inflammation in asthmatics, but whether this is a feature of naturally occurring virus-induced asthma exacerbations is unknown. Thymic stromal lymphopoietin (TSLP) released from the airway epithelium in response to damage, has been suggested as a link between viral infection and type 2 inflammation, but the role of TSLP in asthma exacerbations is unknown., Objective: To assess whether type 2 inflammation, as measured by sputum eosinophils and fractional exhaled nitric oxide (FeNO), is a feature of naturally occurring virus-induced exacerbations of asthma and whether TSLP is associated with this type 2 inflammation., Methods: Patients presenting to hospital with acute asthma were examined during the exacerbation, and after 4 weeks recovery. The assessments included spirometry, FeNO and induced sputum for differential counts and TSLP mRNA levels. Nasal swabs were collected for viral detection., Results: Sputum eosinophils and FeNO were similar between virus-positive (n = 44) and negative patients (n = 44). In virus-positive patients, TSLP expression was lower at exacerbation than follow-up (p = 0.03). High TSLP at exacerbation was associated with lower sputum eosinophils (p = 0.01) and higher FEV1 (p = 0.03). In virus-positive patients, %-predicted FEV1 negatively correlated with both FeNO and sputum eosinophils (p = 0.02 and p = 0.05, respectively)., Conclusion: Our findings support that type 2 inflammation is present in patients during virus-induced asthma exacerbations, to the same degree as non-viral exacerbations, and correlate negatively with FEV1. However, in virus-positive patients, high TSLP expression during exacerbation was associated with low sputum eosinophils, suggesting that the effect of TSLP in vivo, in the setting of an asthma exacerbation, might be different than the type 2 inducing effects observed in experimental studies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
Published: 2017
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47. Histone Modifications and Asthma. The Interface of the Epigenetic and Genetic Landscapes.

Author: Kidd CD, Thompson PJ, Barrett L, and Baltic S
Subjects: Animals, Asthma immunology, Asthma metabolism, Asthma physiopathology, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Lung immunology, Lung physiopathology, Phenotype, Prognosis, Risk Factors, Asthma genetics, Chromatin Assembly and Disassembly, Epigenesis, Genetic, Histones metabolism
Abstract: Complex lung diseases, such as asthma, are influenced by both genetic predisposition and environmental stimuli. The epigenetic landscape of such diseases is attracting increasing interest and research. Epigenetics broadly covers the transient and the inheritable changes to gene expression that are not directly due to changes in nucleotide sequences. Epigenetic mechanisms could have significant impact on asthma-related allergic, immune, and regulatory pathways, as well as on the generation of biomarkers and the heritable transmission of asthma phenotypes. Recent technological advances have allowed mapping of the epigenome and analysis of genome-wide epigenetic contributors to disease. As a result, ground-breaking observations regarding histone post-translational modifications in a number of immunological diseases have emerged. In this review, we look beyond the biological information coded by DNA and review the epigenetic modifications made to histones, with evidence suggesting a role for their modification in asthma.
Published: 2016
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48. Meta-analysis identifies seven susceptibility loci involved in the atopic march.

Author: Marenholz I, Esparza-Gordillo J, Rüschendorf F, Bauerfeind A, Strachan DP, Spycher BD, Baurecht H, Margaritte-Jeannin P, Sääf A, Kerkhof M, Ege M, Baltic S, Matheson MC, Li J, Michel S, Ang WQ, McArdle W, Arnold A, Homuth G, Demenais F, Bouzigon E, Söderhäll C, Pershagen G, de Jongste JC, Postma DS, Braun-Fahrländer C, Horak E, Ogorodova LM, Puzyrev VP, Bragina EY, Hudson TJ, Morin C, Duffy DL, Marks GB, Robertson CF, Montgomery GW, Musk B, Thompson PJ, Martin NG, James A, Sleiman P, Toskala E, Rodriguez E, Fölster-Holst R, Franke A, Lieb W, Gieger C, Heinzmann A, Rietschel E, Keil T, Cichon S, Nöthen MM, Pennell CE, Sly PD, Schmidt CO, Matanovic A, Schneider V, Heinig M, Hübner N, Holt PG, Lau S, Kabesch M, Weidinger S, Hakonarson H, Ferreira MAR, Laprise C, Freidin MB, Genuneit J, Koppelman GH, Melén E, Dizier MH, Henderson AJ, and Lee YA
Subjects: Adaptor Proteins, Vesicular Transport genetics, Adolescent, Adult, Amino Acid Transport Systems, Neutral genetics, Calcium-Binding Proteins genetics, Carrier Proteins genetics, Child, Child, Preschool, DNA-Binding Proteins genetics, Disease Progression, Female, Filaggrin Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Ikaros Transcription Factor genetics, Interleukin-4 genetics, Kinesins genetics, Logistic Models, Male, Membrane Proteins genetics, Middle Aged, Neoplasm Proteins genetics, Nerve Tissue Proteins genetics, Nuclear Proteins genetics, Phenotype, Polymorphism, Single Nucleotide, Receptor, Fibroblast Growth Factor, Type 1 genetics, Repressor Proteins genetics, Transcription Factors genetics, Young Adult, Asthma genetics, Dermatitis, Atopic genetics
Abstract: Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.
Published: 2015
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49. The role of receptor for advanced glycation end products in airway inflammation in CF and CF related diabetes.

Author: Mulrennan S, Baltic S, Aggarwal S, Wood J, Miranda A, Frost F, Kaye J, and Thompson PJ
Subjects: Adult, Cystic Fibrosis blood, Cystic Fibrosis complications, Cystic Fibrosis pathology, Diabetes Mellitus blood, Diabetes Mellitus etiology, Diabetes Mellitus pathology, Female, Gene Expression Regulation, Glycation End Products, Advanced blood, Glycation End Products, Advanced genetics, Humans, Immunity, Innate genetics, Inflammation blood, Inflammation pathology, Male, Middle Aged, Receptor for Advanced Glycation End Products blood, Sputum metabolism, Cystic Fibrosis genetics, Diabetes Mellitus genetics, Inflammation genetics, Receptor for Advanced Glycation End Products biosynthesis
Abstract: Cystic Fibrosis (CF) is often accompanied by diabetes leading to worsening lung function, the reason for which is unclear. The receptor for advanced-glycation-end-products (RAGE) regulates immune responses and inflammation and has been linked to diabetes and possibly CF. We performed a pilot study to determine if CF and CF-related diabetes (CFRD) are associated with enhanced RAGE expression. Full length (fl)RAGE, soluble (s)RAGE, endogenous soluble (es)RAGE, S100A12 (enRAGE) and advanced-glycation-end-products (AGE) expression was assessed in serum, white blood cells and sputum of patients with CF; diabetes; CFRD and healthy subjects. Sputum enRAGE/sRAGE ratios were high in CF but particularly in CFRD which negatively correlated with % predicted FEV1. Serum AGE and AGE/sRAGE ratios were high in diabetics but not in CF. A complex, multifaceted approach was used to assess the role of RAGE and its ligands which is fundamental to determining their impact on airway inflammation. There is a clear association between RAGE activity in the airways of CF and CFRD patients that is not evident in the vascular compartment and correlates with lung function, in contrast to diabetes. This strongly suggests a role for RAGE in contributing to the inflammatory overdrive seen in CF and to a greater extent in CFRD.
Published: 2015
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50. Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis.

Author: Lim CB, Prêle CM, Baltic S, Arthur PG, Creaney J, Watkins DN, Thompson PJ, and Mutsaers SE
Subjects: Apoptosis drug effects, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, G1 Phase drug effects, HCT116 Cells, HT29 Cells, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Mesothelioma genetics, Mesothelioma pathology, Mesothelioma, Malignant, Mitochondria drug effects, Oxidative Stress drug effects, Oxidative Stress physiology, Transcription Factors metabolism, Zinc Finger Protein GLI1, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Mesothelioma drug therapy, Mesothelioma metabolism, Mitochondria metabolism, Pyridines pharmacology, Pyrimidines pharmacology, Reactive Oxygen Species metabolism
Abstract: Gli transcription factors of the Hedgehog (Hh) pathway have been reported to be drivers of malignant mesothelioma (MMe) cell survival. The Gli inhibitor GANT61 induces apoptosis in various cancer cell models, and has been associated directly with Gli inhibition. However various chemotherapeutics can induce cell death through generation of reactive oxygen species (ROS) but whether ROS mediates GANT61-induced apoptosis is unknown. In this study human MMe cells were treated with GANT61 and the mechanisms regulating cell death investigated. Exposure of MMe cells to GANT61 led to G1 phase arrest and apoptosis, which involved ROS but not its purported targets, GLI1 or GLI2. GANT61 triggered ROS generation and quenching of ROS protected MMe cells from GANT61-induced apoptosis. Furthermore, we demonstrated that mitochondria are important in mediating GANT61 effects: (1) ROS production and apoptosis were blocked by mitochondrial inhibitor rotenone; (2) GANT61 promoted superoxide formation in mitochondria; and (3) mitochondrial DNA-deficient LO68 cells failed to induce superoxide, and were more resistant to apoptosis induced by GANT61 than wild-type cells. Our data demonstrate for the first time that GANT61 induces apoptosis by promoting mitochondrial superoxide generation independent of Gli inhibition, and highlights the therapeutic potential of mitochondrial ROS-mediated anticancer drugs in MMe.
Published: 2015
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