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1. Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity

Author

Multiple Sclerosis Research Australia, Royal Melbourne Hospital, Multiple Sclerosis Society (UK), MSBase Foundation, Monash University, Jokubaitis, Vilija G., Campagna, Maria Pia, Ibrahim, Omar A., Stankovich, JIm, Kleinova, Pavlina, Matesanz, Fuencisla, Hui, Daniel, Eichau, Sara, Slee, Mark, Lechner-Scott, Jeannette, Lea, Rodney, Kilpatrick, Trevor J., Kalincik, Tomas, De Jager, Philip L., Beecham, Ashley, McCauley, Jacob L., Taylor, Bruce V., Vucic, Steve, Laverick, Louise, Vodehnalova, Karolina, García-Sánchez, María Isabel, Alcina, Antonio, van der Walt, Anneke, Kubala Havrdova, Eva, Izquierdo, Guillermo, Patsopoulos, Nikolaos, Horakova, Dana, Butzkueven, Helmut, Multiple Sclerosis Research Australia, Royal Melbourne Hospital, Multiple Sclerosis Society (UK), MSBase Foundation, Monash University, Jokubaitis, Vilija G., Campagna, Maria Pia, Ibrahim, Omar A., Stankovich, JIm, Kleinova, Pavlina, Matesanz, Fuencisla, Hui, Daniel, Eichau, Sara, Slee, Mark, Lechner-Scott, Jeannette, Lea, Rodney, Kilpatrick, Trevor J., Kalincik, Tomas, De Jager, Philip L., Beecham, Ashley, McCauley, Jacob L., Taylor, Bruce V., Vucic, Steve, Laverick, Louise, Vodehnalova, Karolina, García-Sánchez, María Isabel, Alcina, Antonio, van der Walt, Anneke, Kubala Havrdova, Eva, Izquierdo, Guillermo, Patsopoulos, Nikolaos, Horakova, Dana, and Butzkueven, Helmut

Abstract

Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (ß = ¿0.4882, P = 2.73 × 10¿7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62 000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79¿0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48¿0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; ßfemale = 0.8289, P = 3.52 × 10¿8), the other in males (rs698805; ßmale = ¿1.5395, P = 4.35 × 10¿8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrich

Published
2023

2. Erratum: A Neuroethics Framework for the Australian Brain Initiative (Neuron (2019) 101(3) (365–369), (S0896627319300054), (10.1016/j.neuron.2019.01.004))

Author

Carter, Adrian, Richards, Linda J., Apthorp, Deborah, Azghadi, Mostafa Rahimi, Badcock, David R., Balleine, Bernard, Bekkers, John M., Berk, Michael, Bourne, James A., Bradley, Andrew P., Breakspear, Michael, Brichta, Alan, Carter, Olivia, Castles, Anne, Chakli, Khaled, Cohen-Woods, Sarah, Conn, Simon J., Cornish, Jennifer, Cornish, Kim, de Zubicaray, Greg, Egan, Gary F., Enticott, Peter G., Fitzgibbon, Bernadette M., Forlini, Cynthia, Fornito, Alex, Griffiths, Lyn, Gullifer, Judith, Hall, Wayne, Halliday, Glenda, Hannan, Anthony J., Harrer, Stefan, Harvey, Alan, Hatherly, Chris, Hickie, Ian B., Kennett, Jeanette, Kiernan, Matthew, Kilpatrick, Trevor, Kiral-Kornek, Isabell, Korgaonkar, Mayuresh S., Lawrence, Andrew J., Leventer, Rick, Levy, Neil, Licinio, Julio, Lovell, Nigel, Mackellar, Geoff, Malcolm, Lynne, Mason, Alice, Mattingley, Jason B., Medland, Sarah E., Michie, Patricia T., Nithianantharajah, Jess, Parker, John, Payne, Jonathan M., Poole-Warren, Laura, Sah, Pankaj, Sarnyai, Zoltan, Schofield, Peter R., Shimoni, Olga, Shum, David H.K., Silk, Tim, Slee, Mark, Smith, Ashleigh E., Soulis, Tina, Sriram, Sharath, Stuart, Greg J., Tapson, Jonathan, Thompson, Matthew B., van Schaik, André, Vincent, Nicole A., Vissel, Bryce, Waters, Allison, other, and, Carter, Adrian, Richards, Linda J., Apthorp, Deborah, Azghadi, Mostafa Rahimi, Badcock, David R., Balleine, Bernard, Bekkers, John M., Berk, Michael, Bourne, James A., Bradley, Andrew P., Breakspear, Michael, Brichta, Alan, Carter, Olivia, Castles, Anne, Chakli, Khaled, Cohen-Woods, Sarah, Conn, Simon J., Cornish, Jennifer, Cornish, Kim, de Zubicaray, Greg, Egan, Gary F., Enticott, Peter G., Fitzgibbon, Bernadette M., Forlini, Cynthia, Fornito, Alex, Griffiths, Lyn, Gullifer, Judith, Hall, Wayne, Halliday, Glenda, Hannan, Anthony J., Harrer, Stefan, Harvey, Alan, Hatherly, Chris, Hickie, Ian B., Kennett, Jeanette, Kiernan, Matthew, Kilpatrick, Trevor, Kiral-Kornek, Isabell, Korgaonkar, Mayuresh S., Lawrence, Andrew J., Leventer, Rick, Levy, Neil, Licinio, Julio, Lovell, Nigel, Mackellar, Geoff, Malcolm, Lynne, Mason, Alice, Mattingley, Jason B., Medland, Sarah E., Michie, Patricia T., Nithianantharajah, Jess, Parker, John, Payne, Jonathan M., Poole-Warren, Laura, Sah, Pankaj, Sarnyai, Zoltan, Schofield, Peter R., Shimoni, Olga, Shum, David H.K., Silk, Tim, Slee, Mark, Smith, Ashleigh E., Soulis, Tina, Sriram, Sharath, Stuart, Greg J., Tapson, Jonathan, Thompson, Matthew B., van Schaik, André, Vincent, Nicole A., Vissel, Bryce, Waters, Allison, and other, and

Abstract

(Neuron 101, 365–369; February 6, 2019) In the original publication of this NeuroView, the member list for the Australian Brain Alliance was omitted. This has now been corrected online. Neuron apologizes for the error.

Published
2020

3. Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation

Author

Khalilidehkordi, Elham, Clarke, Laura, Arnett, Simon, Bukhari, Wajih, Jimenez Sanchez, Sofia, O'Gorman, Cullen, Sun, Jing, Prain, Kerri M., Woodhall, Mark, Silvestrini, Roger, Bundell, Christine S., Abernethy, David, Bhuta, Sandeep, Blum, Stefan, Boggild, Mike, Boundy, Karyn, Brew, Bruce J., Brown, Matthew, Brownlee, Wallace, Butzkueven, Helmut, Carroll, William M., Chen, Celia, Coulthard, Alan, Dale, Russell C., Das, Chandi, Fabis-Pedrini, Marzena J., Fulcher, David, Gillis, David, Hawke, Simon, Heard, Robert, Henderson, Andrew P.D., Heshmat, Saman, Hodgkinson, Suzanne, Kilpatrick, Trevor J., King, John, Kneebone, Chris, Kornberg, Andrew J., Lechner-Scott, Jeannette, Lin, Ming Wei, Lynch, Christopher, Macdonell, Richard A.L., Mason, Deborah F., McCombe, Pamela A., Pereira, Jennifer, Pollard, John D., Ramanathan, Sudarshini, Reddel, Stephen W., Shaw, Cameron, Spies, Judith, Stankovich, James, Sutton, Ian, Vucic, Steve, Walsh, Michael, Wong, Richard C., Yiu, Eppie M., Barnett, Michael H., Kermode, Allan G., Marriott, Mark P., Parratt, John, Slee, Mark, Taylor, Bruce V., Willoughby, Ernest, Brilot, Fabienne, Vincent, Angela, Waters, Patrick, Broadley, Simon A., Khalilidehkordi, Elham, Clarke, Laura, Arnett, Simon, Bukhari, Wajih, Jimenez Sanchez, Sofia, O'Gorman, Cullen, Sun, Jing, Prain, Kerri M., Woodhall, Mark, Silvestrini, Roger, Bundell, Christine S., Abernethy, David, Bhuta, Sandeep, Blum, Stefan, Boggild, Mike, Boundy, Karyn, Brew, Bruce J., Brown, Matthew, Brownlee, Wallace, Butzkueven, Helmut, Carroll, William M., Chen, Celia, Coulthard, Alan, Dale, Russell C., Das, Chandi, Fabis-Pedrini, Marzena J., Fulcher, David, Gillis, David, Hawke, Simon, Heard, Robert, Henderson, Andrew P.D., Heshmat, Saman, Hodgkinson, Suzanne, Kilpatrick, Trevor J., King, John, Kneebone, Chris, Kornberg, Andrew J., Lechner-Scott, Jeannette, Lin, Ming Wei, Lynch, Christopher, Macdonell, Richard A.L., Mason, Deborah F., McCombe, Pamela A., Pereira, Jennifer, Pollard, John D., Ramanathan, Sudarshini, Reddel, Stephen W., Shaw, Cameron, Spies, Judith, Stankovich, James, Sutton, Ian, Vucic, Steve, Walsh, Michael, Wong, Richard C., Yiu, Eppie M., Barnett, Michael H., Kermode, Allan G., Marriott, Mark P., Parratt, John, Slee, Mark, Taylor, Bruce V., Willoughby, Ernest, Brilot, Fabienne, Vincent, Angela, Waters, Patrick, and Broadley, Simon A.

Abstract

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis (p < 0.001) and area postrema relapses (P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS (p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January (P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.

Published
2020

4. Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis.

Author

Jia, Xiaoming, Jia, Xiaoming, Madireddy, Lohith, Caillier, Stacy, Santaniello, Adam, Esposito, Federica, Comi, Giancarlo, Stuve, Olaf, Zhou, Yuan, Taylor, Bruce, Kilpatrick, Trevor, Martinelli-Boneschi, Filippo, Cree, Bruce AC, Oksenberg, Jorge R, Hauser, Stephen L, Baranzini, Sergio E, Jia, Xiaoming, Jia, Xiaoming, Madireddy, Lohith, Caillier, Stacy, Santaniello, Adam, Esposito, Federica, Comi, Giancarlo, Stuve, Olaf, Zhou, Yuan, Taylor, Bruce, Kilpatrick, Trevor, Martinelli-Boneschi, Filippo, Cree, Bruce AC, Oksenberg, Jorge R, Hauser, Stephen L, and Baranzini, Sergio E

Abstract

ObjectivePrimary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS.MethodsWe examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip.ResultsWGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27-2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18-2.10; p = 0.002). Importantly, this enrichment was not detected in RMS.InterpretationThis study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51-63.

Published
2018

5. Association of inflammation and disability accrual in patients with progressive-onset multiple sclerosis

Author

Hughes, Jordana, Jokubaitis, Vilija, Lugaresi, Alessandra, Hupperts, Raymond, Izquierdo, Guillermo, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grand'maison, Francois, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Ramo-Tello, Cristina, Trojano, Maria, Slee, Mark, Shaygannejad, Vahid, Boz, Cavit, Lechner-Scott, Jeanette, Van Pesch, Vincent, Pucci, Eugenio, Solaro, Claudio, Verheul, Freek, Terzi, Murat, Granella, Franco, Spitaleri, Daniele, Alroughani, Raed, Jun, Jae-Kwan, Fambiatos, Adam, Van Der Walt, Anneke, Butzkueven, Helmut, Kalincik, Tomas, De Luca, Giovanna, Di Tommaso, Valeria, Travaglini, Daniela, Pietrolongo, Erika, Di Ioia, Maria, Farina, Deborah, Mancinelli, Luca, Vitetta, Francesca, Simone, Anna Maria, Haartsen, Jodi, Spelman, Tim, Marriott, Mark, Kilpatrick, Trevor, King, John, Buzzard, Katherine, Nguyen, Ai-Lan, Dwyer, Chris, Monif, Mastura, Brown, J William L, Kunchok, Amy, Diamanti, Matteo, Cartechini, Elisabetta, Curti, Erica, Tsantes, Elena, Zwanikken, Cees, Rio, Maria Edite, Hughes, Stella, Amato, Maria Pita, Van Wijmeersch, Bart, Sanchez-Menoyo, Jose Luis, Bolaños, Ricardo Fernandez, Sajedi, Seyed Aidin, Iuliano, Gerardo, Den Braber-Moerland, Leontien, Prevost, Julie, Sempere, Angel Perez, Sidhom, Youssef, Butler, Ernest, Vucic, Steve, Taylor, Bruce, Cabrera-Gomez, Jose Antonio, Oreja-Guevara, Celia, Bergamaschi, Roberto, Turkoglu, Recai, Olascoaga, Javier, Cristiano, Edgardo, Rojas, Juan Ingacio, Hodgkinson, Suzanne, Skibina, Olga, Al-Harbi, Talal, Altintas, Ayse, McCombe, Pamela, Sinnige, LGF, Ozakbas, Serken, Saladino, Maria Laura, Bacile, Elizabeth Alejandra, Vrech, Carlos, Shaw, Cameron, Hughes, Jordana, Jokubaitis, Vilija, Lugaresi, Alessandra, Hupperts, Raymond, Izquierdo, Guillermo, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grand'maison, Francois, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Ramo-Tello, Cristina, Trojano, Maria, Slee, Mark, Shaygannejad, Vahid, Boz, Cavit, Lechner-Scott, Jeanette, Van Pesch, Vincent, Pucci, Eugenio, Solaro, Claudio, Verheul, Freek, Terzi, Murat, Granella, Franco, Spitaleri, Daniele, Alroughani, Raed, Jun, Jae-Kwan, Fambiatos, Adam, Van Der Walt, Anneke, Butzkueven, Helmut, Kalincik, Tomas, De Luca, Giovanna, Di Tommaso, Valeria, Travaglini, Daniela, Pietrolongo, Erika, Di Ioia, Maria, Farina, Deborah, Mancinelli, Luca, Vitetta, Francesca, Simone, Anna Maria, Haartsen, Jodi, Spelman, Tim, Marriott, Mark, Kilpatrick, Trevor, King, John, Buzzard, Katherine, Nguyen, Ai-Lan, Dwyer, Chris, Monif, Mastura, Brown, J William L, Kunchok, Amy, Diamanti, Matteo, Cartechini, Elisabetta, Curti, Erica, Tsantes, Elena, Zwanikken, Cees, Rio, Maria Edite, Hughes, Stella, Amato, Maria Pita, Van Wijmeersch, Bart, Sanchez-Menoyo, Jose Luis, Bolaños, Ricardo Fernandez, Sajedi, Seyed Aidin, Iuliano, Gerardo, Den Braber-Moerland, Leontien, Prevost, Julie, Sempere, Angel Perez, Sidhom, Youssef, Butler, Ernest, Vucic, Steve, Taylor, Bruce, Cabrera-Gomez, Jose Antonio, Oreja-Guevara, Celia, Bergamaschi, Roberto, Turkoglu, Recai, Olascoaga, Javier, Cristiano, Edgardo, Rojas, Juan Ingacio, Hodgkinson, Suzanne, Skibina, Olga, Al-Harbi, Talal, Altintas, Ayse, McCombe, Pamela, Sinnige, LGF, Ozakbas, Serken, Saladino, Maria Laura, Bacile, Elizabeth Alejandra, Vrech, Carlos, and Shaw, Cameron

Published
2018

6. Sun exposure across the life course significantly modulates early multiple sclerosis clinical course

Author

Simpson, Steve, Van Der Mei, Ingrid, Lucas, Robyn M, Ponsonby, Anne-Louise, Broadley, Simon, Blizzard, Leigh, Dear, Keith, Dwyer, Terry, Taylor, Bruce V, Kilpatrick, Trevor, Williams, David, Lechner-Scott, Jeanette, Shaw, Cameron, Chapman, Caron, Coulthard, Alan, Pender, Michael P, Valery, Patricia, Taylor, Bruce, Simpson, Steve, Van Der Mei, Ingrid, Lucas, Robyn M, Ponsonby, Anne-Louise, Broadley, Simon, Blizzard, Leigh, Dear, Keith, Dwyer, Terry, Taylor, Bruce V, Kilpatrick, Trevor, Williams, David, Lechner-Scott, Jeanette, Shaw, Cameron, Chapman, Caron, Coulthard, Alan, Pender, Michael P, Valery, Patricia, and Taylor, Bruce

Abstract

Background: Low vitamin D and/or sun exposure have been associated with increased risk of multiple sclerosis (MS) onset. However, comparatively, few studies have prospectively examined associations between these factors and clinical course. Objectives: To evaluate the association of sun exposure parameters and vitamin D levels with conversion to MS and relapse risk in a prospectively monitored cohort of 145 participants followed after a first demyelinating event up to 5-year review (AusLong Study). Methods: Sun exposure prior to and after onset measured by annual questionnaire; ultraviolet radiation (UVR) "load" estimated by location of residence over the life course and ambient UVR levels. Serum 25-hydroxyvitamin D [25(OH)D] concentrations measured at baseline, 2/3-year, and 5-year review. MS conversion and relapse assessed by neurologist assessment and medical record review. Results: Over two-thirds (69%) of those followed to 5-year review (100/145) converted to MS, with a total of 252 relapses. Higher pre-MS onset sun exposure was associated with reduced risk of MS conversion, with internal consistency between measures and dose-response relationships. Analogous associations were also seen with risk of relapse, albeit less strong. No consistent associations were observed between postonset sun exposure and clinical course, however. Notably, those who increased their sun exposure during follow-up had significantly reduced hazards of MS conversion and relapse. Serum 25(OH)D levels and vitamin D supplementation were not associated with conversion to MS or relapse hazard. Conclusion: We found that preonset sun exposure was protective against subsequent conversion to MS and relapses. While consistent associations between postonset sun exposure or serum 25(OH)D level and clinical course were not evident, possibly masked by behavior change, those participants who markedly increased their sun exposur

Published
2018

7. Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status

Author

Binder, Michele D., Fox, Andrew D., Merlo, Daniel, Johnson, Laura J., Giuffrida, Lauren, Calvert, Sarah E., Akkermann, Rainer, Ma, Gerry Z.M., Perera, Ashwyn A., Gresle, Melissa M., Laverick, Louise, Foo, Grace, Fabis-Pedrini, Marzena J., Spelman, Timothy, Jordan, Margaret A., Baxter, Alan G., Foote, Simon, Butzkueven, Helmut, Kilpatrick, Trevor J., Field, Judith, Kermode, Allan G., Taylor, Bruce, Booth, David R., Mason, Deborah, Stewart, Graeme J., Charlesworth, Jac, Wiley, James, Lechner-Scott, Jeannette, Tajouri, Lotti, Griffiths, Lyn, Slee, Mark, Brown, Matthew A., Moscato, Pablo, Scott, Rodney J., Broadley, Simon, Vucic, Steve, MCarroll, William, other, and, Binder, Michele D., Fox, Andrew D., Merlo, Daniel, Johnson, Laura J., Giuffrida, Lauren, Calvert, Sarah E., Akkermann, Rainer, Ma, Gerry Z.M., Perera, Ashwyn A., Gresle, Melissa M., Laverick, Louise, Foo, Grace, Fabis-Pedrini, Marzena J., Spelman, Timothy, Jordan, Margaret A., Baxter, Alan G., Foote, Simon, Butzkueven, Helmut, Kilpatrick, Trevor J., Field, Judith, Kermode, Allan G., Taylor, Bruce, Booth, David R., Mason, Deborah, Stewart, Graeme J., Charlesworth, Jac, Wiley, James, Lechner-Scott, Jeannette, Tajouri, Lotti, Griffiths, Lyn, Slee, Mark, Brown, Matthew A., Moscato, Pablo, Scott, Rodney J., Broadley, Simon, Vucic, Steve, MCarroll, William, and other, and

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients.

Published
2016

8. A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Author

Gu, Ben J., Field, Judith, Dutertre, Sebastien, Ou, Amber, Kilpatrick, Trevor J., Lechner-Scott, Jeannette, Scott, Rodney, Lea, Rodney, Taylor, Bruce V., Stankovich, Jim, Butzkueven, Helmut, Gresle, Melissa, Laws, Simon M., Petrou, Steven, Hoffjan, Sabine, Akkad, Denis A., Graham, Colin A., Hawkins, Stanley, Glaser, Anna, Bedri, Sahl Khalid, Hillert, Jan, Matute, Carlos, Antiguedad, Alfredo, Baxter, Alan G., Kermode, Allan G., Booth, David R., Mason, Deborah F., Stewart, Graeme J., Charlesworth, Jac C., Tajouri, Lotti, Griffiths, Lyn R., Slee, Mark, Brown, Matthew A., Moscato, Pablo, Broadley, Simon A., Vucic, Steve, Carroll, William M., Barnett, Michael, Wiley, James S., Gu, Ben J., Field, Judith, Dutertre, Sebastien, Ou, Amber, Kilpatrick, Trevor J., Lechner-Scott, Jeannette, Scott, Rodney, Lea, Rodney, Taylor, Bruce V., Stankovich, Jim, Butzkueven, Helmut, Gresle, Melissa, Laws, Simon M., Petrou, Steven, Hoffjan, Sabine, Akkad, Denis A., Graham, Colin A., Hawkins, Stanley, Glaser, Anna, Bedri, Sahl Khalid, Hillert, Jan, Matute, Carlos, Antiguedad, Alfredo, Baxter, Alan G., Kermode, Allan G., Booth, David R., Mason, Deborah F., Stewart, Graeme J., Charlesworth, Jac C., Tajouri, Lotti, Griffiths, Lyn R., Slee, Mark, Brown, Matthew A., Moscato, Pablo, Broadley, Simon A., Vucic, Steve, Carroll, William M., Barnett, Michael, and Wiley, James S.

Abstract

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured byATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory 'pore' function.

Published
2015

9. A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Author

Gu, Ben, Field, Judith, Dutertre, Sebastien, Ou, Amber, Kilpatrick, Trevor, Lechner-Scott, Jeannette, Scott, Rodney, Lea, Rodney, Taylor, Bruce, Stankovich, Jim, other, and, Gu, Ben, Field, Judith, Dutertre, Sebastien, Ou, Amber, Kilpatrick, Trevor, Lechner-Scott, Jeannette, Scott, Rodney, Lea, Rodney, Taylor, Bruce, Stankovich, Jim, and other, and

Abstract

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case–control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of ‘pore’ function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln–270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory ‘pore’ function.

Published
2015

10. A new era in the treatment of multiple sclerosis

Author

Broadley, Simon A., Barnett, Michael H., Boggild, Mike, Brew, Bruce J., Butzkueven, Helmut, Heard, Robert, Hodgkinson, Suzanne, Kermode, Allan G., Lechner-Scott, Jeanette, Macdonell, Richard A., Marriott, Mark, Mason, Deborah F., Parratt, John, Reddel, Stephen W., Shaw, Cameron P., Slee, Mark, Spies, Judith M., Taylor, Bruce V., Carroll, William M., Kilpatrick, Trevor J., King, John, McCombe, Pamela A., Pollard, John D., Willoughby, Ernest, Broadley, Simon A., Barnett, Michael H., Boggild, Mike, Brew, Bruce J., Butzkueven, Helmut, Heard, Robert, Hodgkinson, Suzanne, Kermode, Allan G., Lechner-Scott, Jeanette, Macdonell, Richard A., Marriott, Mark, Mason, Deborah F., Parratt, John, Reddel, Stephen W., Shaw, Cameron P., Slee, Mark, Spies, Judith M., Taylor, Bruce V., Carroll, William M., Kilpatrick, Trevor J., King, John, McCombe, Pamela A., Pollard, John D., and Willoughby, Ernest

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.

Published
2015

11. The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function

Author

Field, Judith, Shahijanian, Fernando, Schibeci, Stephen, Johnson, Laura, Gresle, Melissa, Laverick, Louise, Parnell, Grant, Stewart, Graeme, McKay, Fiona, Kilpatrick, Trevor, Butzkueven, Helmut, Booth, David, Brown, Matthew, other, and, Field, Judith, Shahijanian, Fernando, Schibeci, Stephen, Johnson, Laura, Gresle, Melissa, Laverick, Louise, Parnell, Grant, Stewart, Graeme, McKay, Fiona, Kilpatrick, Trevor, Butzkueven, Helmut, Booth, David, Brown, Matthew, and other, and

Abstract

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS.

Published
2015

12. Analytical bias in the measurement of serum 25-hydroxyVitamin D concentrations impairs assessment of Vitamin D status in clinical and research settings

Author

Black, Lucinda, Anderson, Denise, Clarke, Michael, Ponsonby, Anne-Louise, Chapman, C, Coulthard, Alan, Dear, Keith, Dwyer, Terry, Kilpatrick, Trevor J, Lucas, Robyn, Black, Lucinda, Anderson, Denise, Clarke, Michael, Ponsonby, Anne-Louise, Chapman, C, Coulthard, Alan, Dear, Keith, Dwyer, Terry, Kilpatrick, Trevor J, and Lucas, Robyn

Abstract

Measured serum 25-hydroxyvitamin D concentrations vary depending on the type of assay used and the specific laboratory undertaking the analysis, impairing the accurate assessment of vitamin D status. We investigated differences in serum 25-hydroxyvitamin D concentrations measured at three laboratories (laboratories A and B using an assay based on liquid chroma-tography-tandem mass spectrometry and laboratory C using a DiaSorin Liaison assay), against a laboratory using an assay based on liquid chromatography-tandem mass spectrome-try that is certified to the standard reference method developed by the National Institute of Standards and Technology and Ghent University (referred to as the 'certified laboratory'). Separate aliquots from the same original serum sample for a subset of 50 participants from the Ausim-mune Study were analysed at the four laboratories. Bland-Altman plots were used to visually check agreement between each laboratory against the certified laboratory. Compared with the certified laboratory, serum 25-hydroxyvitamin D concentrations were on average 12.4 nmol/L higher at laboratory A (95% limits of agreement: -17.8,42.6); 12.8 nmol/L higher at laboratory B (95% limits of agreement: 0.8,24.8); and 10.6 nmol/L lower at laboratory C (95% limits of agreement: -484,27.1). The prevalence of vitamin D deficiency (defined here as 25-hydroxyvitamin D <50 nmol/L) was 24%, 16%, 12% and 41% at the certified laboratory, and laboratories A, B, and C, respectively. Our results demonstrate considerable differences in the measurement of 25-hydroxyvitamin D concentrations compared with a certified laboratory, even between laboratories using assays based on liquid chromatography-tandem mass spectrometry, which is often considered the gold-standard assay. To ensure accurate and reliable measurement of serum 25-hydroxyvitamin D concentrations, all laboratories should use an accuracy-based quality assurance system and, ideally, comply with international standardisation

Published
2015

13. Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation

Author

Jonas, Anna, Thiem, Stefan, Kuhlmann, Tanja, Wagener, Raimund, Aszodi, Attila, Nowell, Cameron, Hagemeier, Mann, Laverick, Louise, Perreau, Victoria, Jokubaitis, Vilija, Emery, Ben, Kilpatrick, Trevor, Butzkueven, Helmut, Gresle, Melissa, Jonas, Anna, Thiem, Stefan, Kuhlmann, Tanja, Wagener, Raimund, Aszodi, Attila, Nowell, Cameron, Hagemeier, Mann, Laverick, Louise, Perreau, Victoria, Jokubaitis, Vilija, Emery, Ben, Kilpatrick, Trevor, Butzkueven, Helmut, and Gresle, Melissa

Abstract

In patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE), inflammatory axonal injury is a major determinant of disability; however, the drivers of this injury are incompletely understood. Here, we used the EAE model and determined that the extracellular matrix protein matrilin-2 (MATN2) is an endogenous neuronal molecule that is regulated in association with inflammatory axonal injury. Compared with WT mice, mice harboring a deletion of Matn2 exhibited reduced disease severity and axon damage following induction of EAE. Evaluation of neuron-macrophage cocultures revealed that exogenous MATN2 specifically signals through TLR4 and directly induces expression of proinflammatory genes in macrophages, promoting axonal damage. Moreover, the MATN2-induced proinflammatory response was attenuated greatly in macrophages from Myd88 KO mice. Examination of brain sections from patients with MS revealed that MATN2 is expressed in lesions but not in normal-appearing white matter. Together, our results indicate that MATN2 is a deleterious endogenous neuroaxonal injury response signal that activates innate immune cells and could contribute to early axonal damage in CNS inflammatory diseases like MS.

Published
2014

14. Occupational Exposure and Risk of Central Nervous System Demyelination

Author

Valery, Patricia C., Lucas, Robyn M., Williams, David B., Pender, Michael P., Chapman, Caron, Coulthard, Alan, Dear, Keith, Dwyer, Terence, Kilpatrick, Trevor. J., McMichael, Anthony J., van, der Mei, Ingrid, Taylor, Bruce, Ponsonby, Anne-Louise, Valery, Patricia C., Lucas, Robyn M., Williams, David B., Pender, Michael P., Chapman, Caron, Coulthard, Alan, Dear, Keith, Dwyer, Terence, Kilpatrick, Trevor. J., McMichael, Anthony J., van, der Mei, Ingrid, Taylor, Bruce, and Ponsonby, Anne-Louise

Published
2013

15. Vitamin D status: Multifactorial contribution of environment, genes and other factors in healthy Australian adults across a latitude gradient

Author

Lucas, Robyn M., Ponsonby, Anne-Louise, Dear, Keith, Valery, Patricia C., Taylor, Bruce, van der Mei, Ingrid, McMichael, Anthony J., Pender, Michael P., Chapman, Caron, Coulthard, Alan, Kilpatrick, Trevor J., Stankovich, Jim, Williams, David B., Dwyer, Terence, Lucas, Robyn M., Ponsonby, Anne-Louise, Dear, Keith, Valery, Patricia C., Taylor, Bruce, van der Mei, Ingrid, McMichael, Anthony J., Pender, Michael P., Chapman, Caron, Coulthard, Alan, Kilpatrick, Trevor J., Stankovich, Jim, Williams, David B., and Dwyer, Terence

Published
2013

16. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, Ashley H., Patsopoulos, Nikolaos A., Xifara, Dionysia K., Davis, Mary F., Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas S., Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, DAlfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F., Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R., Hintzen, Rogier, F Barcellos, Lisa, Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Bach Sondergaard, Helle, Baker, Amie, Band, Gavin, Baranzini, Sergio E., Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Celine, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas M C., Blackburn, Hannah, Bomfim, Izaura L., Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J., Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G., Coman, Irene, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce A C., Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R., Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T., Donnelly, Peter, Dubois, Benedicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y., Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah E., Jagodic, Maja, Jelcic, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, Langford, Cordelia, Larsson, Malin, Lathrop, Mark, Lebrun-Frenay, Christine, Lechner-Scott, Jeannette, Lee, Michelle H., Leone, Maurizio A., Leppa, Virpi, Liberatore, Giuseppe, Lie, Benedicte A., Lill, Christina M., Linden, Magdalena, Link, Jenny, Luessi, Felix, Lycke, Jan, Macciardi, Fabio, Mannisto, Satu, Manrique, Clara P., Martin, Roland, Martinelli, Vittorio, Mason, Deborah, Mazibrada, Gordon, McCabe, Cristin, Mero, Inger-Lise, Mescheriakova, Julia, Moutsianas, Loukas, Myhr, Kjell-Morten, Nagels, Guy, Nicholas, Richard, Nilsson, Petra, Piehl, Fredrik, Pirinen, Matti, Price, Sian E., Quach, Hong, Reunanen, Mauri, Robberecht, Wim, Robertson, Neil P., Rodegher, Mariaemma, Rog, David, Salvetti, Marco, Schnetz-Boutaud, Nathalie C., Sellebjerg, Finn, Selter, Rebecca C., Schaefer, Catherine, Shaunak, Sandip, Shen, Ling, Shields, Simon, Siffrin, Volker, Slee, Mark, Soelberg Sorensen, Per, Sorosina, Melissa, Sospedra, Mireia, Spurkland, Anne, Strange, Amy, Sundqvist, Emilie, Thijs, Vincent, Thorpe, John, Ticca, Anna, Tienari, Pentti, van Duijn, Cornelia, Visser, Elizabeth M., Vucic, Steve, Westerlind, Helga, Wiley, James S., Wilkins, Alastair, Wilson, James F., Winkelmann, Juliane, Zajicek, John, Zindler, Eva, Haines, Jonathan L., Pericak-Vance, Margaret A., Ivinson, Adrian J., Stewart, Graeme, Hafler, David, Hauser, Stephen L., Compston, Alastair, McVean, Gil, De Jager, Philip, Sawcer, Stephen J., McCauley, Jacob L., Beecham, Ashley H., Patsopoulos, Nikolaos A., Xifara, Dionysia K., Davis, Mary F., Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas S., Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, DAlfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F., Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R., Hintzen, Rogier, F Barcellos, Lisa, Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Bach Sondergaard, Helle, Baker, Amie, Band, Gavin, Baranzini, Sergio E., Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Celine, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas M C., Blackburn, Hannah, Bomfim, Izaura L., Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J., Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G., Coman, Irene, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce A C., Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R., Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T., Donnelly, Peter, Dubois, Benedicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y., Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah E., Jagodic, Maja, Jelcic, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, Langford, Cordelia, Larsson, Malin, Lathrop, Mark, Lebrun-Frenay, Christine, Lechner-Scott, Jeannette, Lee, Michelle H., Leone, Maurizio A., Leppa, Virpi, Liberatore, Giuseppe, Lie, Benedicte A., Lill, Christina M., Linden, Magdalena, Link, Jenny, Luessi, Felix, Lycke, Jan, Macciardi, Fabio, Mannisto, Satu, Manrique, Clara P., Martin, Roland, Martinelli, Vittorio, Mason, Deborah, Mazibrada, Gordon, McCabe, Cristin, Mero, Inger-Lise, Mescheriakova, Julia, Moutsianas, Loukas, Myhr, Kjell-Morten, Nagels, Guy, Nicholas, Richard, Nilsson, Petra, Piehl, Fredrik, Pirinen, Matti, Price, Sian E., Quach, Hong, Reunanen, Mauri, Robberecht, Wim, Robertson, Neil P., Rodegher, Mariaemma, Rog, David, Salvetti, Marco, Schnetz-Boutaud, Nathalie C., Sellebjerg, Finn, Selter, Rebecca C., Schaefer, Catherine, Shaunak, Sandip, Shen, Ling, Shields, Simon, Siffrin, Volker, Slee, Mark, Soelberg Sorensen, Per, Sorosina, Melissa, Sospedra, Mireia, Spurkland, Anne, Strange, Amy, Sundqvist, Emilie, Thijs, Vincent, Thorpe, John, Ticca, Anna, Tienari, Pentti, van Duijn, Cornelia, Visser, Elizabeth M., Vucic, Steve, Westerlind, Helga, Wiley, James S., Wilkins, Alastair, Wilson, James F., Winkelmann, Juliane, Zajicek, John, Zindler, Eva, Haines, Jonathan L., Pericak-Vance, Margaret A., Ivinson, Adrian J., Stewart, Graeme, Hafler, David, Hauser, Stephen L., Compston, Alastair, McVean, Gil, De Jager, Philip, Sawcer, Stephen J., and McCauley, Jacob L.

Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P andlt; 1.0 x 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P andlt; 5.0 x 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals., Funding Agencies|US National Institutes of Health||Wellcome Trust||UK MS Society||UK Medical Research Council||US National MS Society||Cambridge National Institute for Health Research (NIHR) Biomedical Research Centre||DeNDRon||Swedish Brain Foundation||Swedish Research Council||Knut and Alice Wallenberg Foundation||Swedish Heart-Lung Foundation||Foundation for Strategic Research

Published
2013
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17. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis.

Author

UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Kalincik, Tomas, Vivek, Vino, Jokubaitis, Vilija, Lechner-Scott, Jeannette, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Grand'maison, Francois, Hupperts, Raymond, Oreja-Guevara, Celia, Bergamaschi, Roberto, Iuliano, Gerardo, Alroughani, Raed, Van Pesch, Vincent, Amato, Maria Pia, Slee, Mark, Verheul, Freek, Fernandez-Bolanos, Ricardo, Fiol, Marcela, Spitaleri, Daniele La, Cristiano, Edgardo, Gray, Orla, Cabrera-Gomez, Jose Antonio, Shaygannejad, Vahid, Herbert, Joseph, Vucic, Steve, Needham, Merilee, Petkovska-Boskova, Tatjana, Sirbu, Carmen-Adella, Duquette, Pierre, Girard, Marc, Grammond, Pierre, Boz, Cavit, Giuliani, Giorgio, Rio, Maria Edite, Barnett, Michael, Flechter, Shlomo, Moore, Fraser, Singhal, Bhim, Bacile, Elizabeth Alejandra, Saladino, Maria Laura, Shaw, Cameron, Skromne, Eli, Poehlau, Dieter, Vella, Norbert, Spelman, Timothy, Liew, Danny, Kilpatrick, Trevor J, Butzkueven, Helmut, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Kalincik, Tomas, Vivek, Vino, Jokubaitis, Vilija, Lechner-Scott, Jeannette, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Grand'maison, Francois, Hupperts, Raymond, Oreja-Guevara, Celia, Bergamaschi, Roberto, Iuliano, Gerardo, Alroughani, Raed, Van Pesch, Vincent, Amato, Maria Pia, Slee, Mark, Verheul, Freek, Fernandez-Bolanos, Ricardo, Fiol, Marcela, Spitaleri, Daniele La, Cristiano, Edgardo, Gray, Orla, Cabrera-Gomez, Jose Antonio, Shaygannejad, Vahid, Herbert, Joseph, Vucic, Steve, Needham, Merilee, Petkovska-Boskova, Tatjana, Sirbu, Carmen-Adella, Duquette, Pierre, Girard, Marc, Grammond, Pierre, Boz, Cavit, Giuliani, Giorgio, Rio, Maria Edite, Barnett, Michael, Flechter, Shlomo, Moore, Fraser, Singhal, Bhim, Bacile, Elizabeth Alejandra, Saladino, Maria Laura, Shaw, Cameron, Skromne, Eli, Poehlau, Dieter, Vella, Norbert, Spelman, Timothy, Liew, Danny, Kilpatrick, Trevor J, and Butzkueven, Helmut

Abstract

The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48 362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10(-12)). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10(-12)). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.

Published
2013

18. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis

Author

Kalincik, Tomas, Vivek, Vino, Jokubaitis, Vilija, Lechner-Scott, Jeannette, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Allessandra, Grand-Maison, Francois, Hupperts, Raymond, Oreja-Guevara, Celia, Bergamaschi, Roberto, Iuliano, Gerardo, Alroughani, Raed, Van, Pesch Vincent, Amato, Maria Pia, Slee, Mark, Verheul, Freek, Fernandez-Bolanos, Ricardo, Fiol, Marcela, La, Spitaleri Daniele, Cristiano, Edgardo, Gray, Orla, Cabrera-Gomez, Jose Antonio, Shaygannejad, Vahid, Herbert, Joseph, Vucic, Steve, Needham, Merilee, Petkovska-Boskova, Tatjana, Sirbu, Carmen-Adella, Duquette, Pierre, Girard, Marc, Grammond, Pierre, Boz, Cavit, Giuliani, Giorgio, Rio, Maria Edite, Barnett, Michael, Flechter, Shlomo, Moore, Fraser, Singhal, Bhim, Bacile, Elizabeth Alejandra, Saladino, Maria Laura, Shaw, Cameron, Skromne, Eli, Poehlau, Dieter, Vella, Norbert, Spelman, Timothy, Liew, Danny, Kilpatrick, Trevor J., Butkueven, Helmut, Kalincik, Tomas, Vivek, Vino, Jokubaitis, Vilija, Lechner-Scott, Jeannette, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Allessandra, Grand-Maison, Francois, Hupperts, Raymond, Oreja-Guevara, Celia, Bergamaschi, Roberto, Iuliano, Gerardo, Alroughani, Raed, Van, Pesch Vincent, Amato, Maria Pia, Slee, Mark, Verheul, Freek, Fernandez-Bolanos, Ricardo, Fiol, Marcela, La, Spitaleri Daniele, Cristiano, Edgardo, Gray, Orla, Cabrera-Gomez, Jose Antonio, Shaygannejad, Vahid, Herbert, Joseph, Vucic, Steve, Needham, Merilee, Petkovska-Boskova, Tatjana, Sirbu, Carmen-Adella, Duquette, Pierre, Girard, Marc, Grammond, Pierre, Boz, Cavit, Giuliani, Giorgio, Rio, Maria Edite, Barnett, Michael, Flechter, Shlomo, Moore, Fraser, Singhal, Bhim, Bacile, Elizabeth Alejandra, Saladino, Maria Laura, Shaw, Cameron, Skromne, Eli, Poehlau, Dieter, Vella, Norbert, Spelman, Timothy, Liew, Danny, Kilpatrick, Trevor J., and Butkueven, Helmut

Abstract

The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48 362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10−12). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10−12). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.

Published
2013

19. Occupational Exposure and Risk of Central Nervous System Demyelination

Author

Valery, Patricia C, Williams, David, Pender, M P, Chapman, C, Coulthard, Alan, Dear, Keith, Dwyer, Terry, Kilpatrick, Trevor J, McMichael, Anthony, Van Der Mei, Ingrid, Taylor, B V, Ponsonby, Anne-Louise, Lucas, Robyn, Valery, Patricia C, Williams, David, Pender, M P, Chapman, C, Coulthard, Alan, Dear, Keith, Dwyer, Terry, Kilpatrick, Trevor J, McMichael, Anthony, Van Der Mei, Ingrid, Taylor, B V, Ponsonby, Anne-Louise, and Lucas, Robyn

Abstract

Inconsistent evidence exists regarding the association between work-related factors and risk of multiple sclerosis (MS). We examined the association between occupational exposures and risk of a first clinical diagnosis of central nervous system demyelinat

Published
2013

20. The physical anthropology, lifestyle habits and blood pressure presenting with a first class clinical demyelinating event compared to controls: the Ausimmune study

Author

Ponsonby, Anne-Louise, Dear, Keith, Van Der Mei, Ingrid, Taylor, Bruce, Chapman, Caron, Coulthard, Alan, Dwyer, Terry, Kilpatrick, Trevor J, McMichael, Anthony, Pender, M P, Valery, Patricia C., Williams, David, Lucas, Robyn, Ponsonby, Anne-Louise, Dear, Keith, Van Der Mei, Ingrid, Taylor, Bruce, Chapman, Caron, Coulthard, Alan, Dwyer, Terry, Kilpatrick, Trevor J, McMichael, Anthony, Pender, M P, Valery, Patricia C., Williams, David, and Lucas, Robyn

Abstract

Introduction: Lifestyle factors prior to a first clinical demyelinating event (FCD), a disorder often preceding the development of clinically definite multiple sclerosis (MS), have not previously been examined in detail. Past tobacco smoking has been cons

Published
2013

21. Vitamin D status: multifactorial contribution of environment, genes and other factors in healthy Australian adults across a latitude gradient

Author

Ponsonby, Anne-Louise, Dear, Keith, Valery, Patricia C., Taylor, Bruce, Van Der Mei, Ingrid, McMichael, Anthony, Pender, M P, Chapman, Caron, Coulthard, Alan, Kilpatrick, Trevor J, Stankovich, James, Williams, David, Dwyer, Terry, Lucas, Robyn, Ponsonby, Anne-Louise, Dear, Keith, Valery, Patricia C., Taylor, Bruce, Van Der Mei, Ingrid, McMichael, Anthony, Pender, M P, Chapman, Caron, Coulthard, Alan, Kilpatrick, Trevor J, Stankovich, James, Williams, David, Dwyer, Terry, and Lucas, Robyn

Abstract

Vitamin D deficiency is common and implicated in risk of several human diseases. Evidence on the relative quantitative contribution of environmental, genetic and phenotypic factors to vitamin D status (assessed by the serum concentration of 25-hydroxyvita

Published
2013

22. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, Ashley H, Patsopoulos, Nikolaos A, Xifara, Dionysia K, Davis, Mary F, Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas S, Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, D'Alfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F, Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R, Hintzen, Rogier, Barcellos, Lisa F, Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Søndergaard, Helle Bach, Baker, Amie, Band, Gavin, Baranzini, Sergio E, Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Céline, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas, Blackburn, Hannah, Bomfim, Izaura L, Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J, Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G, Coman, Irène, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce A C, Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R, Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T, Donnelly, Peter, Dubois, Bénédicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y, Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah E, Jagodic, Maja, Jel?i?, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, Langford, Cordelia, Larsson, Malin, Lathrop, Mark, Lebrun-Frenay, Christine, Lechner-Scott, Jeannette, Lee, Michelle H, Leone, Maurizio A, Leppä, Virpi, Liberatore, Giuseppe, Lie, Benedicte A, Lill, Christina M, Lindén, Magdalena, Link, Jenny, Luessi, Felix, Lycke, Jan, Macciardi, Fabio, Männistö, Satu, Manrique, Clara P, Martin, Roland, Martinelli, Vittorio, Mason, Deborah, Mazibrada, Gordon, McCabe, Cristin, Mero, Inger-Lise, Mescheriakova, Julia, Moutsianas, Loukas, Myhr, Kjell-Morten, Nagels, Guy, Nicholas, Richard, Nilsson, Petra, Piehl, Fredrik, Pirinen, Matti, Price, Siân E, Quach, Hong, Reunanen, Mauri, Robberecht, Wim, Robertson, Neil P, Rodegher, Mariaemma, Rog, David, Salvetti, Marco, Schnetz-Boutaud, Nathalie C, Sellebjerg, Finn, Selter, Rebecca C, Schaefer, Catherine, Shaunak, Sandip, Shen, Ling, Shields, Simon, Siffrin, Volker, Slee, Mark, Sorensen, Per Soelberg, Sorosina, Melissa, Sospedra, Mireia, Spurkland, Anne, Strange, Amy, Sundqvist, Emilie, Thijs, Vincent, Thorpe, John, Ticca, Anna, Tienari, Pentti, van Duijn, Cornelia, Visser, Elizabeth M, Vucic, Steve, Westerlind, Helga, Wiley, James S, Wilkins, Alastair, Wilson, James, Winkelmann, Juliane, Zajicek, John, Zindler, Eva, Haines, Jonathan L, Pericak-Vance, Margaret A, Ivinson, Adrian J, Stewart, Graeme, Hafler, David, Hauser, Stephen L, Compston, Alastair, McVean, Gil, De Jager, Philip, Sawcer, Stephen J, McCauley, Jacob L, (IMSGC), International Multiple Sclerosis Genetics Consortium, Beecham, Ashley H, Patsopoulos, Nikolaos A, Xifara, Dionysia K, Davis, Mary F, Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas S, Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, D'Alfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne F, Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Oksenberg, Jorge R, Hintzen, Rogier, Barcellos, Lisa F, Agliardi, Cristina, Alfredsson, Lars, Alizadeh, Mehdi, Anderson, Carl, Andrews, Robert, Søndergaard, Helle Bach, Baker, Amie, Band, Gavin, Baranzini, Sergio E, Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Céline, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas, Blackburn, Hannah, Bomfim, Izaura L, Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy J, Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth G, Coman, Irène, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cree, Bruce A C, Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia R, Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander T, Donnelly, Peter, Dubois, Bénédicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene Y, Galimberti, Daniela, Gieger, Christian, Gourraud, Pierre-Antoine, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah E, Jagodic, Maja, Jel?i?, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, Langford, Cordelia, Larsson, Malin, Lathrop, Mark, Lebrun-Frenay, Christine, Lechner-Scott, Jeannette, Lee, Michelle H, Leone, Maurizio A, Leppä, Virpi, Liberatore, Giuseppe, Lie, Benedicte A, Lill, Christina M, Lindén, Magdalena, Link, Jenny, Luessi, Felix, Lycke, Jan, Macciardi, Fabio, Männistö, Satu, Manrique, Clara P, Martin, Roland, Martinelli, Vittorio, Mason, Deborah, Mazibrada, Gordon, McCabe, Cristin, Mero, Inger-Lise, Mescheriakova, Julia, Moutsianas, Loukas, Myhr, Kjell-Morten, Nagels, Guy, Nicholas, Richard, Nilsson, Petra, Piehl, Fredrik, Pirinen, Matti, Price, Siân E, Quach, Hong, Reunanen, Mauri, Robberecht, Wim, Robertson, Neil P, Rodegher, Mariaemma, Rog, David, Salvetti, Marco, Schnetz-Boutaud, Nathalie C, Sellebjerg, Finn, Selter, Rebecca C, Schaefer, Catherine, Shaunak, Sandip, Shen, Ling, Shields, Simon, Siffrin, Volker, Slee, Mark, Sorensen, Per Soelberg, Sorosina, Melissa, Sospedra, Mireia, Spurkland, Anne, Strange, Amy, Sundqvist, Emilie, Thijs, Vincent, Thorpe, John, Ticca, Anna, Tienari, Pentti, van Duijn, Cornelia, Visser, Elizabeth M, Vucic, Steve, Westerlind, Helga, Wiley, James S, Wilkins, Alastair, Wilson, James, Winkelmann, Juliane, Zajicek, John, Zindler, Eva, Haines, Jonathan L, Pericak-Vance, Margaret A, Ivinson, Adrian J, Stewart, Graeme, Hafler, David, Hauser, Stephen L, Compston, Alastair, McVean, Gil, De Jager, Philip, Sawcer, Stephen J, McCauley, Jacob L, and (IMSGC), International Multiple Sclerosis Genetics Consortium

Published
2013

23. Offspring number, pregnancy, and risk of a first clinical demyelinating event: the AusImmune Study

Author

Ponsonby, Anne-Louise, Lucas, Robyn M., van der Mei, Ingrid, Dear, Keith, Valery, Patricia C., Pender, Mchael P., Taylor, Bruce, Kilpatrick, Trevor. J., Coulthard, Alan, Chapman, Caron, Williams, David B., McMichael, Anthony. J., Dwyer, Terence, Ponsonby, Anne-Louise, Lucas, Robyn M., van der Mei, Ingrid, Dear, Keith, Valery, Patricia C., Pender, Mchael P., Taylor, Bruce, Kilpatrick, Trevor. J., Coulthard, Alan, Chapman, Caron, Williams, David B., McMichael, Anthony. J., and Dwyer, Terence

Published
2012

24. Interleukin-6 gene promoter-572 C allele may play a role in rate of disease progression in multiple sclerosis

Author

Yan, Jun, Liu, Jia, Lin, Clement Yihao, Scott, Rodney J., Lechner-Scott, Jeannette, Booth, David R., Stewart, Graeme J., Broadley, Simon, Mason, Deborah, Griffiths, Lyn, Moscato, Pablo, Slee, Mark, Taylor, Bruce, Wiley, James, Field, Judith, Butzkueven, Helmut, Kilpatrick, Trevor J., Csurhes, Peter A., Pender, Michael P., McCombe, Pamela A., Greer, Judith M., Yan, Jun, Liu, Jia, Lin, Clement Yihao, Scott, Rodney J., Lechner-Scott, Jeannette, Booth, David R., Stewart, Graeme J., Broadley, Simon, Mason, Deborah, Griffiths, Lyn, Moscato, Pablo, Slee, Mark, Taylor, Bruce, Wiley, James, Field, Judith, Butzkueven, Helmut, Kilpatrick, Trevor J., Csurhes, Peter A., Pender, Michael P., McCombe, Pamela A., and Greer, Judith M.

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system. Although the exact pathogenesis of MS is unknown, it is generally considered to be an autoimmune disease, with numerous genetic and environmental factors determining disease susceptibility and severity. One important mediator of immune responses and inflammation is interleukin-6 (IL-6). Previously, elevated levels of IL-6 in mononuclear cells in blood and in brain tissue from MS patients have been reported. Various polymorphisms in the promoter region of the IL6 gene have also been linked with IL-6 protein levels. In MS, several small studies have investigated whether two IL6 promoter polymorphisms (-597 G>A and -174 G>C) correlate with MS susceptibility, but with varying results. In the present study, we analyzed these polymorphisms, together with an additional polymorphism (-572 G>C) in 279 healthy controls and 509 patients with MS. We found no significant differences between MS patients and healthy controls for the different -597 or -174 IL6 promoter alleles or genotypes. There was a slight reduction in the percentage of individuals with MS who carried a C allele at position -572, although this was not significant after correction for multiple comparisons. Interestingly, however, the -572 C allele showed a significant correlation with the MS severity score, suggesting a possible role in disease progression.

Published
2012

25. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Sawcer, Stephen, Hellenthal, Garrett, Pirinen, Matti, Spencer, Chris C. A., Patsopoulos, Nikolaos A., Moutsianas, Loukas, Dilthey, Alexander, Su, Zhan, Freeman, Colin, Hunt, Sarah E., Edkins, Sarah, Gray, Emma, Booth, David R., Potter, Simon C., Goris, An, Band, Gavin, Oturai, Annette Bang, Strange, Amy, Saarela, Janna, Bellenguez, Celine, Fontaine, Bertrand, Gillman, Matthew, Hemmer, Bernhard, Gwilliam, Rhian, Zipp, Frauke, Jayakumar, Alagurevathi, Martin, Roland, Leslie, Stephen, Hawkins, Stanley, Giannoulatou, Eleni, D'alfonso, Sandra, Blackburn, Hannah, Boneschi, Filippo Martinelli, Liddle, Jennifer, Harbo, Hanne F., Perez, Marc L., Spurkland, Anne, Waller, Matthew J., Mycko, Marcin P., Ricketts, Michelle, Comabella, Manuel, Hammond, Naomi, Kockum, Ingrid, McCann, Owen T., Ban, Maria, Whittaker, Pamela, Kemppinen, Anu, Weston, Paul, Hawkins, Clive, Widaa, Sara, Zajicek, John, Dronov, Serge, Robertson, Neil, Bumpstead, Suzannah J., Barcellos, Lisa F., Ravindrarajah, Rathi, Abraham, Roby, Alfredsson, Lars, Ardlie, Kristin, Aubin, Cristin, Baker, Amie, Baker, Katharine, Baranzini, Sergio E., Bergamaschi, Laura, Bergamaschi, Roberto, Bernstein, Allan, Berthele, Achim, Boggild, Mike, Bradfield, Jonathan P., Brassat, David, Broadley, Simon A., Buck, Dorothea, Butzkueven, Helmut, Capra, Ruggero, Carroll, William M., Cavalla, Paola, Celius, Elisabeth G., Cepok, Sabine, Chiavacci, Rosetta, Clerget-Darpoux, Francoise, Clysters, Katleen, Comi, Giancarlo, Cossburn, Mark, Cournu-Rebeix, Isabelle, Cox, Mathew B., Cozen, Wendy, Cree, Bruce A. C., Cross, Anne H., Cusi, Daniele, Daly, Mark J., Davis, Emma, de Bakker, Paul I. W., Debouverie, Marc, D'hooghe, Marie Beatrice, Dixon, Katherine, Dobosi, Rita, Dubois, Benedicte, Ellinghaus, David, Elovaara, Irina, Esposito, Federica, Fontenille, Claire, Foote, Simon, Franke, Andre, Galimberti, Daniela, Ghezzi, Angelo, Glessner, Joseph, Gomez, Refujia, Gout, Olivier, Graham, Colin, Grant, Struan F. A., Guerini, Franca Rosa, Hakonarson, Hakon, Hall, Per, Hamsten, Anders, Hartung, Hans-Peter, Heard, Rob N., Heath, Simon, Hobart, Jeremy, Hoshi, Muna, Infante-Duarte, Carmen, Ingram, Gillian, Ingram, Wendy, Islam, Talat, Jagodic, Maja, Kabesch, Michael, Kermode, Allan G., Kilpatrick, Trevor J., Kim, Cecilia, Klopp, Norman, Koivisto, Keijo, Larsson, Malin, Lathrop, Mark, Lechner-Scott, Jeannette S., Leone, Maurizio A., Leppa, Virpi, Liljedahl, Ulrika, Bomfim, Izaura Lima, Lincoln, Robin R., Link, Jenny, Liu, Jianjun, Lorentzen, Aslaug R., Lupoli, Sara, Macciardi, Fabio, Mack, Thomas, Marriott, Mark, Martinelli, Vittorio, Mason, Deborah, McCauley, Jacob L., Mentch, Frank, Mero, Inger-Lise, Mihalova, Tania, Montalban, Xavier, Mottershead, John, Myhr, Kjell-Morten, Naldi, Paola, Ollier, William, Page, Alison, Palotie, Aarno, Pelletier, Jean, Piccio, Laura, Pickersgill, Trevor, Piehl, Fredrik, Pobywajlo, Susan, Quach, Hong L., Ramsay, Patricia P., Reunanen, Mauri, Reynolds, Richard, Rioux, Johnd., Rodegher, Mariaemma, Roesner, Sabine, Rubio, Justin P., Rueckert, Ina-Maria, Salvetti, Marco, Salvi, Erika, Santaniello, Adam, Schaefer, Catherine A., Schreiber, Stefan, Schulze, Christian, Scott, Rodney J., Sellebjerg, Finn, Selmaj, Krzysztof W., Sexton, David, Shen, Ling, Simms-Acuna, Brigid, Skidmore, Sheila, Sleiman, Patrick M. A., Smestad, Cathrine, Sorensen, Per Soelberg, Sondergaard, Helle Bach, Stankovich, Jim, Strange, Richard C., Sulonen, Anna-Maija, Sundqvist, Emilie, Syvänen, Ann-Christine, Taddeo, Francesca, Taylor, Bruce, Blackwell, Jenefer M., Tienari, Pentti, Bramon, Elvira, Tourbah, Ayman, Brown, Matthew A., Tronczynska, Ewa, Casas, Juan P., Tubridy, Niall, Corvin, Aiden, Vickery, Jane, Jankowski, Janusz, Villoslada, Pablo, Markus, Hugh S., Wang, Kai, Mathew, Christopher G., Wason, James, Palmer, Colin N. A., Wichmann, H-Erich, Plomin, Robert, Willoughby, Ernest, Rautanen, Anna, Winkelmann, Juliane, Wittig, Michael, Trembath, Richard C., Yaouanq, Jacqueline, Viswanathan, Ananth C., Zhang, Haitao, Wood, Nicholas W., Zuvich, Rebecca, Deloukas, Panos, Langford, Cordelia, Duncanson, Audrey, Oksenberg, Jorge R., Pericak-Vance, Margaret A., Haines, Jonathan L., Olsson, Tomas, Hillert, Jan, Ivinson, Adrian J., De Jager, Philip L., Peltonen, Leena, Stewart, Graeme J., Hafler, David A., Hauser, Stephen L., McVean, Gil, Donnelly, Peter, Compston, Alastair, Sawcer, Stephen, Hellenthal, Garrett, Pirinen, Matti, Spencer, Chris C. A., Patsopoulos, Nikolaos A., Moutsianas, Loukas, Dilthey, Alexander, Su, Zhan, Freeman, Colin, Hunt, Sarah E., Edkins, Sarah, Gray, Emma, Booth, David R., Potter, Simon C., Goris, An, Band, Gavin, Oturai, Annette Bang, Strange, Amy, Saarela, Janna, Bellenguez, Celine, Fontaine, Bertrand, Gillman, Matthew, Hemmer, Bernhard, Gwilliam, Rhian, Zipp, Frauke, Jayakumar, Alagurevathi, Martin, Roland, Leslie, Stephen, Hawkins, Stanley, Giannoulatou, Eleni, D'alfonso, Sandra, Blackburn, Hannah, Boneschi, Filippo Martinelli, Liddle, Jennifer, Harbo, Hanne F., Perez, Marc L., Spurkland, Anne, Waller, Matthew J., Mycko, Marcin P., Ricketts, Michelle, Comabella, Manuel, Hammond, Naomi, Kockum, Ingrid, McCann, Owen T., Ban, Maria, Whittaker, Pamela, Kemppinen, Anu, Weston, Paul, Hawkins, Clive, Widaa, Sara, Zajicek, John, Dronov, Serge, Robertson, Neil, Bumpstead, Suzannah J., Barcellos, Lisa F., Ravindrarajah, Rathi, Abraham, Roby, Alfredsson, Lars, Ardlie, Kristin, Aubin, Cristin, Baker, Amie, Baker, Katharine, Baranzini, Sergio E., Bergamaschi, Laura, Bergamaschi, Roberto, Bernstein, Allan, Berthele, Achim, Boggild, Mike, Bradfield, Jonathan P., Brassat, David, Broadley, Simon A., Buck, Dorothea, Butzkueven, Helmut, Capra, Ruggero, Carroll, William M., Cavalla, Paola, Celius, Elisabeth G., Cepok, Sabine, Chiavacci, Rosetta, Clerget-Darpoux, Francoise, Clysters, Katleen, Comi, Giancarlo, Cossburn, Mark, Cournu-Rebeix, Isabelle, Cox, Mathew B., Cozen, Wendy, Cree, Bruce A. C., Cross, Anne H., Cusi, Daniele, Daly, Mark J., Davis, Emma, de Bakker, Paul I. W., Debouverie, Marc, D'hooghe, Marie Beatrice, Dixon, Katherine, Dobosi, Rita, Dubois, Benedicte, Ellinghaus, David, Elovaara, Irina, Esposito, Federica, Fontenille, Claire, Foote, Simon, Franke, Andre, Galimberti, Daniela, Ghezzi, Angelo, Glessner, Joseph, Gomez, Refujia, Gout, Olivier, Graham, Colin, Grant, Struan F. A., Guerini, Franca Rosa, Hakonarson, Hakon, Hall, Per, Hamsten, Anders, Hartung, Hans-Peter, Heard, Rob N., Heath, Simon, Hobart, Jeremy, Hoshi, Muna, Infante-Duarte, Carmen, Ingram, Gillian, Ingram, Wendy, Islam, Talat, Jagodic, Maja, Kabesch, Michael, Kermode, Allan G., Kilpatrick, Trevor J., Kim, Cecilia, Klopp, Norman, Koivisto, Keijo, Larsson, Malin, Lathrop, Mark, Lechner-Scott, Jeannette S., Leone, Maurizio A., Leppa, Virpi, Liljedahl, Ulrika, Bomfim, Izaura Lima, Lincoln, Robin R., Link, Jenny, Liu, Jianjun, Lorentzen, Aslaug R., Lupoli, Sara, Macciardi, Fabio, Mack, Thomas, Marriott, Mark, Martinelli, Vittorio, Mason, Deborah, McCauley, Jacob L., Mentch, Frank, Mero, Inger-Lise, Mihalova, Tania, Montalban, Xavier, Mottershead, John, Myhr, Kjell-Morten, Naldi, Paola, Ollier, William, Page, Alison, Palotie, Aarno, Pelletier, Jean, Piccio, Laura, Pickersgill, Trevor, Piehl, Fredrik, Pobywajlo, Susan, Quach, Hong L., Ramsay, Patricia P., Reunanen, Mauri, Reynolds, Richard, Rioux, Johnd., Rodegher, Mariaemma, Roesner, Sabine, Rubio, Justin P., Rueckert, Ina-Maria, Salvetti, Marco, Salvi, Erika, Santaniello, Adam, Schaefer, Catherine A., Schreiber, Stefan, Schulze, Christian, Scott, Rodney J., Sellebjerg, Finn, Selmaj, Krzysztof W., Sexton, David, Shen, Ling, Simms-Acuna, Brigid, Skidmore, Sheila, Sleiman, Patrick M. A., Smestad, Cathrine, Sorensen, Per Soelberg, Sondergaard, Helle Bach, Stankovich, Jim, Strange, Richard C., Sulonen, Anna-Maija, Sundqvist, Emilie, Syvänen, Ann-Christine, Taddeo, Francesca, Taylor, Bruce, Blackwell, Jenefer M., Tienari, Pentti, Bramon, Elvira, Tourbah, Ayman, Brown, Matthew A., Tronczynska, Ewa, Casas, Juan P., Tubridy, Niall, Corvin, Aiden, Vickery, Jane, Jankowski, Janusz, Villoslada, Pablo, Markus, Hugh S., Wang, Kai, Mathew, Christopher G., Wason, James, Palmer, Colin N. A., Wichmann, H-Erich, Plomin, Robert, Willoughby, Ernest, Rautanen, Anna, Winkelmann, Juliane, Wittig, Michael, Trembath, Richard C., Yaouanq, Jacqueline, Viswanathan, Ananth C., Zhang, Haitao, Wood, Nicholas W., Zuvich, Rebecca, Deloukas, Panos, Langford, Cordelia, Duncanson, Audrey, Oksenberg, Jorge R., Pericak-Vance, Margaret A., Haines, Jonathan L., Olsson, Tomas, Hillert, Jan, Ivinson, Adrian J., De Jager, Philip L., Peltonen, Leena, Stewart, Graeme J., Hafler, David A., Hauser, Stephen L., McVean, Gil, Donnelly, Peter, and Compston, Alastair

Abstract

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Published
2011
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26. Polymorphisms in the receptor tyrosine kinase MERTK gene are associated with multiple sclerosis susceptibility

Author

Ma, Gerry, Stankovich, Jim, Kilpatrick, Trevor, Binder, Michele, Field, Judith, Griffiths, Lyn, Brown, Matthew, other, and, Ma, Gerry, Stankovich, Jim, Kilpatrick, Trevor, Binder, Michele, Field, Judith, Griffiths, Lyn, Brown, Matthew, and other, and

Abstract

Multiple sclerosis (MS) is a debilitating, chronic demyelinating disease of the central nervous system affecting over 2 million people worldwide. The TAM family of receptor tyrosine kinases (TYRO3, AXL and MERTK) have been implicated as important players during demyelination in both animal models of MS and in the human disease. We therefore conducted an association study to identify single nucleotide polymorphisms (SNPs) within genes encoding the TAM receptors and their ligands associated with MS. Analysis of genotype data from a genome-wide association study which consisted of 1618 MS cases and 3413 healthy controls conducted by the Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene) revealed several SNPs within the MERTK gene (Chromosome 2q14.1, Accession Number NG_011607.1) that showed suggestive association with MS. We therefore interrogated 28 SNPs in MERTK in an independent replication cohort of 1140 MS cases and 1140 healthy controls. We found 12 SNPs that replicated, with 7 SNPs showing p-values of less than 10-5 when the discovery and replication cohorts were combined. All 12 replicated SNPs were in strong linkage disequilibrium with each other. In combination, these data suggest the MERTK gene is a novel risk gene for MS susceptibility. © 2011 Ma et al.

Published
2011

27. The role of latitude, ultraviolet radiation exposure and vitamin D in childhood asthma and hayfever: an Australian multicenter study

Author

Hughes, Ann Maree, Ponsonby, Anne-Louise, Chapman, Caron, Coulthard, Alan, Dear, Keith, Dwyer, Terry, Kilpatrick, Trevor J, McMichael, Anthony, Pender, M P, Taylor, Bruce V, Valery, Patricia C, Van Der Mei, Ingrid, Williams, David, Lucas, Robyn, Hughes, Ann Maree, Ponsonby, Anne-Louise, Chapman, Caron, Coulthard, Alan, Dear, Keith, Dwyer, Terry, Kilpatrick, Trevor J, McMichael, Anthony, Pender, M P, Taylor, Bruce V, Valery, Patricia C, Van Der Mei, Ingrid, Williams, David, and Lucas, Robyn

Abstract

Observations of increasing allergy prevalence with decreasing distance from the Equator and positive associations with ambient ultraviolet radiation have contributed to a growing interest in the possible role of vitamin D in the etiology of allergy. The aims of this study were to describe any latitudinal variation in the prevalence of childhood allergy in Australia and to evaluate, in parallel, the individual associations between ultraviolet radiation (UVR)- and vitamin D-related measures and hayfever asthma and both conditions. Participants were population-based controls who took part in a multicenter case-control study, aged 18-61yr and resident in one of four study regions ranging in latitude from 27°S to 43°S. Data were derived from a self-administered questionnaire, interview and examination by a research officer and biologic sampling. Latitude and longitude coordinates were geocoded from participants' residential locations and climatic data were linked to postcodes of current residence. Stored serum was analyzed for 25-hydroxyvitamin D concentrations and silicone rubber casts of the skin were used as an objective measure of cumulative actinic damage. There was an inverse latitude gradient for asthma (a 9% decrease per increasing degree of latitude); however, this pattern did not persist after adjusting for average daily temperature. There was no association between any of the UVR- or vitamin D-related measures and childhood asthma, but greater time in the sun in winter between the ages 6-15yr was associated with an increase in the odds of having hayfever [adjusted odds ratios (OR) 1.29; 95% CI 1.01-1.63]. Oral supplementation with cod liver oil in childhood increased the odds of a history of having both asthma and hayfever (2.87; 1.00-8.32). Further investigation of the possible role of early vitamin D supplementation in the development of allergy is warranted. Our results also suggest that solar exposure during childhood may be important in allergic sensitiza

Published
2011

28. State-level differences in the oral health of Australian preschool and early primary school-age children

Author

Lucas, Nina, Neumann, A, Kilpatrick, Trevor, Nicholson, Jan, Lucas, Nina, Neumann, A, Kilpatrick, Trevor, and Nicholson, Jan

Abstract

Background: This study compares oral health outcomes and behaviours for young Australian children by residential state or territory to determine whether state differences arise from individual exposures to risk factors. Methods: Cross-sectional data for 4606 2-3 year olds and 4464 6-7 year olds were obtained from the Longitudinal Study of Australian Children. Outcome measures were parent-reports of children's caries experience, frequency of toothbrushing and dental services use. Results: For 2-3 year olds, children from the Australian Capital Territory were less likely to have parent-reported caries than children from other states, and more likely to brush their teeth twice daily and to have used dental services. For 6-7 year olds, optimal outcomes were observed in New South Wales for lowest caries experience, Western Australia for highest toothbrushing, and South Australia for highest dental services use. Adjustments for socio-demographic predictors did not eliminate state differences in oral health. Conclusions: Large state differences in the oral health of young children persisted after adjustment for individual sociodemographic determinants, suggesting these arise from variations in the systems to promote and care for children's oral health. Several states would benefit from a stronger emphasis on oral health promotion in young children, and disparities from a young age suggest the need for better engagement of early childhood professionals in oral health promotion.

Published
2011

29. Current and past Epstein-Barr virus infection in risk of initial CNS demyelination

Author

Ponsonby, Anne-Louise, Dear, Keith, Valery, Patricia C, Pender, M P, Burrows, J M, Burrows, Scott, Chapman, Caron, Coulthard, Alan, Dwyer, Dominic E, Dwyer, Terry, Kilpatrick, Trevor J, Lay, Meav-Lang, McMichael, Anthony, Taylor, B V, Van Der Mei, Ingrid, Williams, David, Lucas, Robyn, Ponsonby, Anne-Louise, Dear, Keith, Valery, Patricia C, Pender, M P, Burrows, J M, Burrows, Scott, Chapman, Caron, Coulthard, Alan, Dwyer, Dominic E, Dwyer, Terry, Kilpatrick, Trevor J, Lay, Meav-Lang, McMichael, Anthony, Taylor, B V, Van Der Mei, Ingrid, Williams, David, and Lucas, Robyn

Abstract

Objectives: To assess risk of a first clinical diagnosis of CNS demyelination (FCD) in relation to measures of Epstein-Barr virus (EBV) infection within the context of other known risk factors. Methods: This was a multicenter incident case-control study.

Published
2011

30. Multiple sclerosis susceptibility-associated SNPs do not influence disease severity measures in a cohort of Australian MS patients

Author

Jensen, Cathy, Stankovich, Jim, van der Walt, Anneke, Bahlo, Melanie, Taylor, Bruce, Van der Mei, Ingrid, Foote, Simon, Kilpatrick, Trevor, Johnson, Laura, Wilkins, Ella, Field, Judith, Danoy, Patrick, Brown, Matthew, Rubio, Justin, Butzkueven, Helmut, Griffiths, Lyn, other, and, Jensen, Cathy, Stankovich, Jim, van der Walt, Anneke, Bahlo, Melanie, Taylor, Bruce, Van der Mei, Ingrid, Foote, Simon, Kilpatrick, Trevor, Johnson, Laura, Wilkins, Ella, Field, Judith, Danoy, Patrick, Brown, Matthew, Rubio, Justin, Butzkueven, Helmut, Griffiths, Lyn, and other, and

Abstract

Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13–14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also modulate MS disease severity, as demonstrated previously for the MS risk allele HLA-DR15. We investigated this hypothesis in a cohort of 1006 well characterised MS patients from South-Eastern Australia. We tested the MS-associated SNPs for association with five measures of disease severity incorporating disability, age of onset, cognition and brain atrophy. We observed trends towards association between the RPL5 risk SNP and time between first demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. No associations were significant after correction for multiple testing. We found no evidence for the hypothesis that these new MS disease risk-associated SNPs influence disease severity.

Published
2010

31. A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis

Author

Field, Judith, Browning, Sharon, Johnson, Laura, Danoy, Patrick, Varney, Michael, Tait, Brian, Gandhi, Kaushal, Charlesworth, Jac, Heard, Robert, Stewart, Graeme, Kilpatrick, Trevor, Foote, Simon, Bahlo, Melanie, Butzkueven, Helmut, Wiley, James, Booth, David, Taylor, Bruce, Brown, Matthew, Rubio, Justin, Stankovich, Jim, Griffiths, Lyn, other, and, Field, Judith, Browning, Sharon, Johnson, Laura, Danoy, Patrick, Varney, Michael, Tait, Brian, Gandhi, Kaushal, Charlesworth, Jac, Heard, Robert, Stewart, Graeme, Kilpatrick, Trevor, Foote, Simon, Bahlo, Melanie, Butzkueven, Helmut, Wiley, James, Booth, David, Taylor, Bruce, Brown, Matthew, Rubio, Justin, Stankovich, Jim, Griffiths, Lyn, and other, and

Abstract

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each ). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls () and were highly significant in the combined dataset (). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set , replication set , combined ). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

Published
2010

32. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20

Author

Bahlo, Melanie, Booth, David, Broadley, Simon, Brown, Matthew, Foote, Simon, Griffiths, Lyn, Kilpatrick, Trevor, Lechner-Scott, Jeannette, Moscato, Pablo, Perreau, Victoria, other, and, Bahlo, Melanie, Booth, David, Broadley, Simon, Brown, Matthew, Foote, Simon, Griffiths, Lyn, Kilpatrick, Trevor, Lechner-Scott, Jeannette, Moscato, Pablo, Perreau, Victoria, and other, and

Abstract

To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

Published
2009

33. BDNF Exerts Contrasting Effects on Peripheral Myelination of NGF-Dependent and BDNF-Dependent DRG Neurons

Author

Xiao, Junhua, Wong, Agnes W, Willingham, Melanie M, Kaasinen, Selma, Hendry, Ian, Howitt, Jason, Putz, Ulrich, Barrett, Graham L, Kilpatrick, Trevor J, Murray, Simon S, Xiao, Junhua, Wong, Agnes W, Willingham, Melanie M, Kaasinen, Selma, Hendry, Ian, Howitt, Jason, Putz, Ulrich, Barrett, Graham L, Kilpatrick, Trevor J, and Murray, Simon S

Abstract

Although brain-derived neurotrophic factor (BDNF) has been shown to promote peripheral myelination during development and remy-elination after injury, the precise mechanisms mediating this effect remain unknown. Here, we determine that BDNF promotes myelination of nerve growth factor-dependent neurons, an effect dependent on neuronal expression of the p75 neurotrophin receptor, whereas BDNF inhibits myelination of BDNF-dependent neurons via the full-length TrkB receptor. Thus, BDNF exerts contrasting effects on Schwann cell myelination, depending on the complement of BDNF receptors that are expressed by different subpopulations of dorsal root ganglion neurons. These results demonstrate that BDNF exerts contrasting modulatory roles in peripheral nervous system myelination, and that its mechanism of action is acutely regulated and specifically targeted to neurons.

Published
2009

34. Associations between Silicone Skin Cast Score, Cumulative Sun Exposure, and Other Factors in the Ausimmune Study: A Multicenter Australian Study

Author

Ponsonby, Anne-Louise, Dear, Keith, Taylor, Bruce, Dwyer, Terry, McMichael, Anthony, Valery, Patricia C, Van Der Mei, Ingrid, Williams, David, Pender, Michael, Chapman, Caron, Coulthard, Alan, Kilpatrick, Trevor J, Lucas, Robyn, Ponsonby, Anne-Louise, Dear, Keith, Taylor, Bruce, Dwyer, Terry, McMichael, Anthony, Valery, Patricia C, Van Der Mei, Ingrid, Williams, David, Pender, Michael, Chapman, Caron, Coulthard, Alan, Kilpatrick, Trevor J, and Lucas, Robyn

Abstract

Past sun exposure is linked to a wide range of disease outcomes but is difficult to measure accurately. Silicone skin casts measure skin damage, but some studies show that age rather than sun exposure is the most important determinant of cast score. We examined skin damage scores from silicone casts of the back of the hand in a large adult sample (n = 534) with a broad range of past cumulative UV radiation (UVR) doses. Participants were ages 18 to 61 years and resided in one of four locations down the eastern Australian seaboard, spanning 27-43°S. Data were collected by questionnaire and during a nurse-led interview and examination. Silicone casts were graded from 1 to 6, where higher score represents greater damage. Higher skin damage score was associated with lighter skin pigmentation [adjusted odds ratio (AOR), 4.51; 95% confidence interval (95% CI), 2.33-8.75], fairer natural hair color, particularly red hair (AOR, 11.31; 95% CI, 4.08-31.36), and blue/gray eyes (AOR, 1.72; 95% CI, 1.14-2.59). Higher cumulative UVR dose, particularly before age 18 years, was associated with higher skin damage score (AOR, 2.06; 95% CI, 1.15-2.67 per 1,000 KJ/m2), as was number of sunburns, even after adjustment for cumulative UVR dose (AOR, 2.86; 95% CI, 1.50-5.43 for >10 sunburns ever compared with no sunburns ever). Silicone casts of the dorsum of the hand provide a measure of cumulative UVR dose and number of sunburns over the lifetime, which persists after adjustment for chronological age. They can be used as an objective measure of cumulative past sun exposure in epidemiologic studies, but other determinants of skin damage, such as skin pigmentation, should be concurrently evaluated.

Published
2009

35. Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia

Author

van der Mei, Ingrid A F, Ponsonby, Anne-Louise, Dwyer, Terry, Blizzard, Leigh, Taylor, Bruce V, Kilpatrick, Trevor, Butzkueven, Helmut, McMichael, Anthony, van der Mei, Ingrid A F, Ponsonby, Anne-Louise, Dwyer, Terry, Blizzard, Leigh, Taylor, Bruce V, Kilpatrick, Trevor, Butzkueven, Helmut, and McMichael, Anthony

Abstract

Background: Adequate 25(OH)D levels are required to prevent adverse effects on bone health. Population-based data on factors associated with 25(OH)D levels of people with MS have been lacking. Objectives: To examine the prevalence and determinants of vitamin D insufficiency in a population-based sample of MS cases and controls, and to compare 25(OH)D status between MS cases and controls, taking into account case disability. Methods: We conducted a population based case-control study in Tasmania, Australia (latitude 41-43°S) on 136 prevalent cases with MS confirmed by magnetic resonance imaging and 272 community controls, matched on sex and year of birth. Measurements included serum 25(OH)D, sun exposure, skin type, dietary vitamin D intake and disability including EDSS. Results: A high prevalence of vitamin D insufficiency was found in MS cases and controls. Among MS cases, increasing disability was strongly associated with lower levels of 25(OH)D and with reduced sun exposure. Cases with higher disability (EDSS > 3) were more likely to have vitamin D insufficiency than controls (OR = 3.07 (1.37, 6.90) for 25(OH)D ≤ 40 nmol/l), but cases with low disability were not (OR = 0.87 (0.41, 1.86)). Conclusion: The strong associations between disability, sun exposure and vitamin D status indicate that reduced exposure to the sun, related to higher disability, may contribute to the high prevalence of vitamin D insufficiency found in this population-based MS case sample. Active detection of vitamin D insufficiency among people with MS and intervention to restore vitamin D status to adequate levels should be considered as part of the clinical management of MS.

Published
2007

36. Observational analytic studies in multiple sclerosis: controlling bias through study design and conduct. The Australian Multicentre Study of Environment and Immune Function

Author

Ponsonby, Anne-Louise, McMichael, Anthony, Van Der Mei, Ingrid, Chapman, Caron, Coulthard, Alan, Dear, Keith, Dwyer, Terry, Kilpatrick, Trevor, Pender, Michael, Taylor, Bruce V, Valery, Patricia C, Williams, David, Lucas, Robyn, Ponsonby, Anne-Louise, McMichael, Anthony, Van Der Mei, Ingrid, Chapman, Caron, Coulthard, Alan, Dear, Keith, Dwyer, Terry, Kilpatrick, Trevor, Pender, Michael, Taylor, Bruce V, Valery, Patricia C, Williams, David, and Lucas, Robyn

Abstract

Rising multiple sclerosis incidence over the last 50 years and geographic patterns of occurrence suggest an environmental role in the causation of this multifactorial disease. Design options for epidemiological studies of environmental causes of multiple

Published
2007

37. Exposure to infant siblings during early life and risk of multiple sclerosis

Author

Ponsonby, Anne-Louise, van der Mei, Ingrid A F, Dwyer, Terence, Blizzard, Leigh, Taylor, Bruce, Kemp, Andrew, Simmons, Rex, Kilpatrick, Trevor, Ponsonby, Anne-Louise, van der Mei, Ingrid A F, Dwyer, Terence, Blizzard, Leigh, Taylor, Bruce, Kemp, Andrew, Simmons, Rex, and Kilpatrick, Trevor

Abstract

Context: The "hygiene hypothesis" has implicated sibship as a marker of infection load during early life and suggests that exposure or reexposure to infections can influence the developing immune system. Viral infection has also been implicated in the pathogenesis of multiple sclerosis (MS). Objectives: To evaluate whether exposure to infant siblings in early life is associated with the risk of MS, and to explore the possible mechanism for any apparent protective effect, including altered Epstein-Barr virus (EBV) infection patterns. Design, Setting, and Patients: Population-based case-control study in Tasmania, Australia, from 1999 to 2001 based on 136 cases of magnetic resonance imaging-confirmed MS and 272 community controls, matched on sex and year of birth. Main Outcome Measure: Risk of MS by duration of contact with younger siblings aged less than 2 years in the first 6 years of life. Results: Increasing duration of contact with a younger sibling aged less than 2 years in the first 6 years of life was associated with reduced MS risk (adjusted odds ratios [AORs]: <1 infant-year, 1.00 [reference]; 1 to <3 infant-years, 0.57 [95% confidence interval {CI}, 0.33-0.98]; 3 to <5 infant-years, 0.40 [95% CI, 0.19-0.92]; ≥5 infant-years, 0.12 [95% CI, 0.02-0.88]; test for trend, P=.002). A history of exposure to infant siblings was associated with a reduced IgG response to EBV among controls. Controls with at least 1 infant-year contact had a reduced risk of infectious mononucleosis and a reduced risk of very high composite EBV IgG titers (AOR, 0.33; 95% CI, 0.11-0.98) compared with other controls. The inverse association between higher infant contact and MS was independent of EBV IgG titer. Conclusion: Higher infant sibling exposure in the first 6 years of life was associated with a reduced risk of MS, possibly by altering childhood infection patterns and related immune responses.

Published
2005

38. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study

Author

van der Mei, Ingrid A F, Ponsonby, Anne-Louise, Dwyer, Terence, Blizzard, Leigh, Simmons, Rex, Taylor, Bruce, Butzkueven, Helmut, Kilpatrick, Trevor, van der Mei, Ingrid A F, Ponsonby, Anne-Louise, Dwyer, Terence, Blizzard, Leigh, Simmons, Rex, Taylor, Bruce, Butzkueven, Helmut, and Kilpatrick, Trevor

Abstract

Objective: To examine whether past high sun exposure is associated with a reduced risk of multiple sclerosis. Design: Population based case-control study. Setting: Tasmania, latitudes 41-3°S. Participants: 136 cases with multiple sclerosis and 272 contro

Published
2003

39. A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Author

Gu, Ben J., Field, Judith, Dutertre, Sebastien, Ou, Amber, Kilpatrick, Trevor J., Lechner-Scott, Jeannette, Scott, Rodney, Lea, Rodney, Taylor, Bruce V., Stankovich, Jim, Butzkueven, Helmut, Gresle, Melissa, Laws, Simon M., Petrou, Steven, Hoffjan, Sabine, Akkad, Denis A., Graham, Colin A., Hawkins, Stanley, Glaser, Anna, Bedri, Sahl Khalid, Hillert, Jan, Matute, Carlos, Antiguedad, Alfredo, Baxter, Alan G., Kermode, Allan G., Booth, David R., Mason, Deborah F., Stewart, Graeme J., Charlesworth, Jac C., Tajouri, Lotti, Griffiths, Lyn R., Slee, Mark, Brown, Matthew A., Moscato, Pablo, Broadley, Simon A., Vucic, Steve, Carroll, William M., Barnett, Michael, Wiley, James S., Gu, Ben J., Field, Judith, Dutertre, Sebastien, Ou, Amber, Kilpatrick, Trevor J., Lechner-Scott, Jeannette, Scott, Rodney, Lea, Rodney, Taylor, Bruce V., Stankovich, Jim, Butzkueven, Helmut, Gresle, Melissa, Laws, Simon M., Petrou, Steven, Hoffjan, Sabine, Akkad, Denis A., Graham, Colin A., Hawkins, Stanley, Glaser, Anna, Bedri, Sahl Khalid, Hillert, Jan, Matute, Carlos, Antiguedad, Alfredo, Baxter, Alan G., Kermode, Allan G., Booth, David R., Mason, Deborah F., Stewart, Graeme J., Charlesworth, Jac C., Tajouri, Lotti, Griffiths, Lyn R., Slee, Mark, Brown, Matthew A., Moscato, Pablo, Broadley, Simon A., Vucic, Steve, Carroll, William M., Barnett, Michael, and Wiley, James S.

Abstract

Gu, B.J., Field, J., Dutertre, S., Ou, A., Kilpatrick, T.J., Lechner-Scott, J., ...& Barnett, M.H. (2015). A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis in Human Molecular Genetics, 24(19), 5644-5654. Available here.

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