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1. Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Author

Clavero, E., Sanchez-Maldonado, J.M., Macauda, A., Horst, R. ter, Sampaio-Marques, B., Jurczyszyn, A., Clay-Gilmour, A., Stein, A., Hildebrandt, M.A., Weinhold, N., Buda, G., García-Sanz, R., Tomczak, W., Vogel, U., Jerez, A., Zawirska, D., Wątek, M., Hofmann, J.N., Landi, S., Spinelli, J.J., Butrym, A., Kumar, A., Martínez-López, J., Galimberti, S., Sarasquete, M.E., Subocz, E., Iskierka-Jażdżewska, E., Giles, G.G., Rybicka-Ramos, M., Kruszewski, M., Abildgaard, N., Verdejo, F.G., Sánchez Rovira, P., Silva Filho, M.I. da, Kadar, K., Razny, M., Cozen, W., Pelosini, M., Jurado, M., Bhatti, P., Dudzinski, M., Druzd-Sitek, A., Orciuolo, E., Li, Y., Norman, A.D., Zaucha, J.M., Reis, R.M., Markiewicz, M., Rodríguez Sevilla, J.J., Andersen, V., Jamroziak, K., Hemminki, K., Berndt, S.I., Rajkumar, V., Mazur, G., Kumar, S.K., Ludovico, P., Nagler, A., Chanock, S.J., Dumontet, C., Machiela, M.J., Varkonyi, J., Camp, N.J., Ziv, E., Vangsted, A.J., Brown, E.E., Campa, D., Vachon, C.M., Netea, M.G., Canzian, F., Försti, A., Sainz, J., Clavero, E., Sanchez-Maldonado, J.M., Macauda, A., Horst, R. ter, Sampaio-Marques, B., Jurczyszyn, A., Clay-Gilmour, A., Stein, A., Hildebrandt, M.A., Weinhold, N., Buda, G., García-Sanz, R., Tomczak, W., Vogel, U., Jerez, A., Zawirska, D., Wątek, M., Hofmann, J.N., Landi, S., Spinelli, J.J., Butrym, A., Kumar, A., Martínez-López, J., Galimberti, S., Sarasquete, M.E., Subocz, E., Iskierka-Jażdżewska, E., Giles, G.G., Rybicka-Ramos, M., Kruszewski, M., Abildgaard, N., Verdejo, F.G., Sánchez Rovira, P., Silva Filho, M.I. da, Kadar, K., Razny, M., Cozen, W., Pelosini, M., Jurado, M., Bhatti, P., Dudzinski, M., Druzd-Sitek, A., Orciuolo, E., Li, Y., Norman, A.D., Zaucha, J.M., Reis, R.M., Markiewicz, M., Rodríguez Sevilla, J.J., Andersen, V., Jamroziak, K., Hemminki, K., Berndt, S.I., Rajkumar, V., Mazur, G., Kumar, S.K., Ludovico, P., Nagler, A., Chanock, S.J., Dumontet, C., Machiela, M.J., Varkonyi, J., Camp, N.J., Ziv, E., Vangsted, A.J., Brown, E.E., Campa, D., Vachon, C.M., Netea, M.G., Canzian, F., Försti, A., and Sainz, J.

Abstract

Item does not contain fulltext, Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10(-9)) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10(-4)-5.79 × 10(-14)). Mechanistically, we found that the ULK4(rs6599175) SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10(-4)), whereas the IKBKE(rs17433804) SNP correlated with the number of transitional CD24(+)CD38(+) B cells (p = 4.8 × 10(-4)) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10(-4)). We also found that the CD46(rs1142469) SNP correlated with numbers of CD19(+) B cells, CD19(+)CD3(-) B cells, CD5(+)IgD(-) cells, IgM(-) cells, IgD(-)IgM(-) cells, and CD4(-)CD8(-) PBMCs (p = 4.9 × 10(-4)-8.6 × 10(-4)) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2A(rs2811710) SNP correlated with levels of CD4(+)EMCD45RO(+)CD27(-) cells (p = 9.3 × 10(-4)). These results s

Published
2023

2. Identification of novel genetic loci for risk of multiple myeloma by functional annotation.

Author

Macauda, A., Briem, K., Clay-Gilmour, A., Cozen, W., Försti, A., Giaccherini, M., Corradi, C., Sainz, J., Niazi, Y., Horst, R. ter, Li, Y., Netea, M.G., Vogel, U., Hemminki, K., Slager, S.L., Varkonyi, J., Andersen, V., Iskierka-Jazdzewska, E., Mártinez-Lopez, J., Zaucha, J., Camp, N.J., Rajkumar, S.V., Druzd-Sitek, A., Bhatti, P., Chanock, S.J., Kumar, S.K., Subocz, E., Mazur, G., Landi, S., Machiela, M.J., Jerez, A., Norman, A.D., Hildebrandt, M.A., Kadar, K., Berndt, S.I., Ziv, E., Buda, G., Nagler, A., Dumontet, C., Raźny, M., Watek, M., Butrym, A., Grzasko, N., Dudzinski, M., Rybicka-Ramos, M., Matera, E.L., García-Sanz, R., Goldschmidt, H., Jamroziak, K., Jurczyszyn, A., Clavero, E., Giles, G.G., Pelosini, M., Zawirska, D., Kruszewski, M., Marques, H., Haastrup, E., Sánchez-Maldonado, J.M., Bertsch, U., Rymko, M., Raab, M.S., Brown, E.E., Hofmann, J.N., Vachon, C., Campa, D., Canzian, F., Macauda, A., Briem, K., Clay-Gilmour, A., Cozen, W., Försti, A., Giaccherini, M., Corradi, C., Sainz, J., Niazi, Y., Horst, R. ter, Li, Y., Netea, M.G., Vogel, U., Hemminki, K., Slager, S.L., Varkonyi, J., Andersen, V., Iskierka-Jazdzewska, E., Mártinez-Lopez, J., Zaucha, J., Camp, N.J., Rajkumar, S.V., Druzd-Sitek, A., Bhatti, P., Chanock, S.J., Kumar, S.K., Subocz, E., Mazur, G., Landi, S., Machiela, M.J., Jerez, A., Norman, A.D., Hildebrandt, M.A., Kadar, K., Berndt, S.I., Ziv, E., Buda, G., Nagler, A., Dumontet, C., Raźny, M., Watek, M., Butrym, A., Grzasko, N., Dudzinski, M., Rybicka-Ramos, M., Matera, E.L., García-Sanz, R., Goldschmidt, H., Jamroziak, K., Jurczyszyn, A., Clavero, E., Giles, G.G., Pelosini, M., Zawirska, D., Kruszewski, M., Marques, H., Haastrup, E., Sánchez-Maldonado, J.M., Bertsch, U., Rymko, M., Raab, M.S., Brown, E.E., Hofmann, J.N., Vachon, C., Campa, D., and Canzian, F.

Abstract

Contains fulltext : 299996.pdf (Publisher’s version ) (Open Access), 01 november 2023

Published
2023

3. Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Author

Vachon C.M., Canzian F., Campa D., Watek M., Jurczyszyn A., Brown E.E., Berndt S., Butrym A., Norman A.D., Gemignani F., Slager S.L., Macauda A., Piredda C., Clay-Gilmour A.I., Sainz J., Buda G., Markiewicz M., Barington T., Ziv E., Hildebrandt M.A.T., Belachew A.A., Varkonyi J., Prejzner W., Druzd-Sitek A., Spinelli J., Andersen N.F., Hofmann J.N., Dudzinski M., Martinez-Lopez J., Iskierka-Jazdzewska E., Milne R.L., Mazur G., Giles G.G., Ebbesen L.H., Rymko M., Jamroziak K., Subocz E., Reis R.M., Garcia-Sanz R., Suska A., Haastrup E.K., Zawirska D., Grzasko N., Vangsted A.J., Dumontet C., Kruszewski M., Dutka M., Camp N.J., Waller R.G., Tomczak W., Pelosini M., Razny M., Marques H., Abildgaard N., Vachon C.M., Canzian F., Campa D., Watek M., Jurczyszyn A., Brown E.E., Berndt S., Butrym A., Norman A.D., Gemignani F., Slager S.L., Macauda A., Piredda C., Clay-Gilmour A.I., Sainz J., Buda G., Markiewicz M., Barington T., Ziv E., Hildebrandt M.A.T., Belachew A.A., Varkonyi J., Prejzner W., Druzd-Sitek A., Spinelli J., Andersen N.F., Hofmann J.N., Dudzinski M., Martinez-Lopez J., Iskierka-Jazdzewska E., Milne R.L., Mazur G., Giles G.G., Ebbesen L.H., Rymko M., Jamroziak K., Subocz E., Reis R.M., Garcia-Sanz R., Suska A., Haastrup E.K., Zawirska D., Grzasko N., Vangsted A.J., Dumontet C., Kruszewski M., Dutka M., Camp N.J., Waller R.G., Tomczak W., Pelosini M., Razny M., Marques H., and Abildgaard N.

Abstract

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P <.05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P =.007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.Copyright © 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.

Published
2021

4. Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Author

Vachon C.M., Canzian F., Campa D., Watek M., Jurczyszyn A., Brown E.E., Berndt S., Butrym A., Norman A.D., Gemignani F., Slager S.L., Macauda A., Piredda C., Clay-Gilmour A.I., Sainz J., Buda G., Markiewicz M., Barington T., Ziv E., Hildebrandt M.A.T., Belachew A.A., Varkonyi J., Prejzner W., Druzd-Sitek A., Spinelli J., Andersen N.F., Hofmann J.N., Dudzinski M., Martinez-Lopez J., Iskierka-Jazdzewska E., Milne R.L., Mazur G., Giles G.G., Ebbesen L.H., Rymko M., Jamroziak K., Subocz E., Reis R.M., Garcia-Sanz R., Suska A., Haastrup E.K., Zawirska D., Grzasko N., Vangsted A.J., Dumontet C., Kruszewski M., Dutka M., Camp N.J., Waller R.G., Tomczak W., Pelosini M., Razny M., Marques H., Abildgaard N., Vachon C.M., Canzian F., Campa D., Watek M., Jurczyszyn A., Brown E.E., Berndt S., Butrym A., Norman A.D., Gemignani F., Slager S.L., Macauda A., Piredda C., Clay-Gilmour A.I., Sainz J., Buda G., Markiewicz M., Barington T., Ziv E., Hildebrandt M.A.T., Belachew A.A., Varkonyi J., Prejzner W., Druzd-Sitek A., Spinelli J., Andersen N.F., Hofmann J.N., Dudzinski M., Martinez-Lopez J., Iskierka-Jazdzewska E., Milne R.L., Mazur G., Giles G.G., Ebbesen L.H., Rymko M., Jamroziak K., Subocz E., Reis R.M., Garcia-Sanz R., Suska A., Haastrup E.K., Zawirska D., Grzasko N., Vangsted A.J., Dumontet C., Kruszewski M., Dutka M., Camp N.J., Waller R.G., Tomczak W., Pelosini M., Razny M., Marques H., and Abildgaard N.

Abstract

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P <.05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P =.007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.Copyright © 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.

Published
2021

5. Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients

Author

Macauda, A, Piredda, C, Clay-Gilmour, A, Sainz, J, Buda, G, Markiewicz, M, Barington, T, Ziv, E, Hildebrandt, MAT, Belachew, AA, Varkonyi, J, Prejzner, W, Druzd-Sitek, A, Spinelli, J, Andersen, NF, Hofmann, JN, Dudzinski, M, Martinez-Lopez, J, Iskierka-Jazdzewska, E, Milne, RL, Mazur, G, Giles, GG, Ebbesen, LH, Rymko, M, Jamroziak, K, Subocz, E, Reis, RM, Garcia-Sanz, R, Suska, A, Haastrup, EK, Zawirska, D, Grzasko, N, Vangsted, AJ, Dumontet, C, Kruszewski, M, Dutka, M, Camp, NJ, Waller, RG, Tomczak, W, Pelosini, M, Razny, M, Marques, H, Abildgaard, N, Watek, M, Jurczyszyn, A, Brown, EE, Berndt, S, Butrym, A, Vachon, CM, Norman, AD, Slager, SL, Gemignani, F, Canzian, F, Campa, D, Macauda, A, Piredda, C, Clay-Gilmour, A, Sainz, J, Buda, G, Markiewicz, M, Barington, T, Ziv, E, Hildebrandt, MAT, Belachew, AA, Varkonyi, J, Prejzner, W, Druzd-Sitek, A, Spinelli, J, Andersen, NF, Hofmann, JN, Dudzinski, M, Martinez-Lopez, J, Iskierka-Jazdzewska, E, Milne, RL, Mazur, G, Giles, GG, Ebbesen, LH, Rymko, M, Jamroziak, K, Subocz, E, Reis, RM, Garcia-Sanz, R, Suska, A, Haastrup, EK, Zawirska, D, Grzasko, N, Vangsted, AJ, Dumontet, C, Kruszewski, M, Dutka, M, Camp, NJ, Waller, RG, Tomczak, W, Pelosini, M, Razny, M, Marques, H, Abildgaard, N, Watek, M, Jurczyszyn, A, Brown, EE, Berndt, S, Butrym, A, Vachon, CM, Norman, AD, Slager, SL, Gemignani, F, Canzian, F, and Campa, D

Abstract

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.

Published
2021

6. Marine Mammal Welfare Workshops Hosted in the Netherlands and the USA in 2012

Author

Brando, S., Bowles, A., Boye, M., Dudzinski, M., van Elk, N., Lucke, Klaus, McBrain, J., Singer, R., Wahlberg, M., Brando, S., Bowles, A., Boye, M., Dudzinski, M., van Elk, N., Lucke, Klaus, McBrain, J., Singer, R., and Wahlberg, M.

Abstract

In 2012, two marine mammal welfare and well-being workshops were held: one from 19-21 March 2012 at the Harderwijk Dolfinarium in the Netherlands, and the other from 9-11 November 2012 at Hubbs-SeaWorld Research Institute in San Diego, California. Well over 150 international participants attended, from Europe as well as North America. Herein, we present a summary of the presentations. The aim of the workshops was to discuss topics relevant to marine mammal welfare and well-being from a holistic perspective, including training, enrichment, nutrition, habitat choice, social behavior, anatomy and physiology, acoustics, and cognition. Presenters were asked to apply knowledge and information gained from research on wild and captive animals in order to strengthen, improve, and build on existing marine mammal care programs. Many of these topics require more research for us to make evidence-based decisions on animal needs and preferences—what promotes the reduction of negative welfare and/or what increases positive welfare and well-being.

Published
2016

7. Joint use of habitat by red kangaroos and shorthorn cattle in arid central Australia

Author

School of Natural Resources, University of Michigan, Ann Arbor, Michigan, USA 48104, Division of Mathematics and Statistics, CSIRO, PO Box 1965, Canberra City, Australia 2601, Division of Land Resources Management, CSIRO, Alice Springs, Australia 5750, Dudzinski, M. L., Lowe, W. A., Müller, W. J., Low, Bobbi S., School of Natural Resources, University of Michigan, Ann Arbor, Michigan, USA 48104, Division of Mathematics and Statistics, CSIRO, PO Box 1965, Canberra City, Australia 2601, Division of Land Resources Management, CSIRO, Alice Springs, Australia 5750, Dudzinski, M. L., Lowe, W. A., Müller, W. J., and Low, Bobbi S.

Abstract

The distribution of cattle and red kangaroos among the major communities of a 170 km 2 paddock in central Australia was determined from 108 and 82 air surveys respectively over a four and a half year period. Fifty-nine surveys of each species were used in this report. Changes in use of the communities by the two species were analysed in relation to forage conditions using linear regression techniques. The two species showed trends in time of use of the open and wooded communities. Kangaroos used the mulga-perennial community (groved Acacia woodland with a shrub and perennial grass understorey) during good forage conditions and moved to the drought refuge open communities when forage conditions deteriorated. Cattle, on the other hand, used the open communities during good forage conditions and tended to move to the mulga communities and the hills when drought began. Mulga-annual (ungroved Acacia woodland with short grass and forb understorey) was the only major community which showed no clear linear relationship between kangaroo use and forage conditions. This might be a buffer area from which kangaroos come and go as other areas become more attractive as feeding areas. Cattle, however, show some preference for mulga annual during medium forage conditions. There appears to be little spatial interaction by the two species except during drought when kangaroos concentrate on the open communities and some cattle continue to feed in these communities. Community selection seems to be determined mainly by forage conditions, as there is no evidence that one species attracts or repels the other in spatial terms. In the conditions observed, the two species successfully coexisted with some control of numbers of cattle by man.

Published
2010

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