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Research paper
Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis
  1. Chunrong Tao1,
  2. Steve Simpson Jr1,
  3. Ingrid van der Mei1,
  4. Leigh Blizzard1,
  5. Eva Havrdova2,
  6. Dana Horakova3,
  7. Vahid Shaygannejad4,
  8. Alessandra Lugaresi5,6,
  9. Guillermo Izquierdo7,
  10. Maria Trojano8,
  11. Pierre Duquette9,
  12. Marc Girard9,
  13. Franois Grand'Maison10,
  14. Pierre Grammond11,
  15. Raed Alroughani12,
  16. Murat Terzi13,
  17. Celia Oreja-Guevara14,
  18. Seyed Aidin Sajedi15,
  19. Gerardo Iuliano16,
  20. Patrizia Sola17,
  21. Jeannette Lechner-Scott18,
  22. Vincent Van Pesch19,
  23. Eugenio Pucci20,
  24. Roberto Bergamaschi21,
  25. Michael Barnett22,
  26. Cristina Ramo23,
  27. Bhim Singhal24,
  28. Daniele LA Spitaleri25,
  29. Mark Slee26,
  30. Freek Verheul27,
  31. Ricardo Fernández Bolaños28,
  32. Maria Pia Amato29,
  33. Edgardo Cristiano30,
  34. Franco Granella31,
  35. Suzanne Hodgkinson32,
  36. Marcela Fiol33,
  37. Orla Gray34,
  38. Pamela McCombe35,
  39. Maria Laura Saladino36,
  40. José Luis Sánchez Menoyo37,
  41. Neil Shuey38,
  42. Steve Vucic39,
  43. Cameron Shaw40,
  44. Norma Deri41,
  45. Walter Oleschko Arruda42,
  46. Helmut Butzkueven43,44,
  47. Tim Spelman43,
  48. Bruce V Taylor1
  49. on behalf of the MSBase Study Group
  1. 1Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  2. 2Department of Neurology, Faculty of Medicine, Center of Clinical Neuroscience, 1st General University Hospital and Charles University in Prague, Prague, Czech Republic
  3. 3Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague, General University Hospital, Prague, Czech Republic
  4. 4Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
  5. 5Department of Biomedical and NeuroMotor Sciences (DIBINEM), Alma Mater Studiorum—Università di Bologna, Bologna, Italy
  6. 6IRCCS Istituto delle Scienze Neurologiche—“UOSI Riabilitazione Sclerosi Multipla”, Bologna, Italy
  7. 7Hospital Universitario Virgen Macarena, Sevilla, Spain
  8. 8Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy
  9. 9CHUM—Hôpital Notre Dame, Montreal, Canada
  10. 10Neuro Rive-Sud, Hôpital Charles LeMoyne, Quebec, Quebec, Canada
  11. 11CISSS Chaudiere-Appalaches, Levis, Quebec, Canada
  12. 12Amiri Hospital, Kuwait City, Kuwait
  13. 13Department of Neurology, Mayis University, Samsun, Turkey
  14. 14University Hospital San Carlos, IdISSC, Madrid, Spain
  15. 15Department of Neurology, Golestan University of Medical Sciences, Gorgan, Iran
  16. 16Ospedali Riuniti di Salerno, Salerno, Italy
  17. 17Department of Neuroscience, Universitu of Modena e Reggio Emilia, Nuovo Ospedale Civile S. Agostino/Estense, Modena, Italy
  18. 18John Hunter Hospital, University of Newcastle, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
  19. 19Cliniques Universitaires Saint-Luc, Brussels, Belgium
  20. 20Neurology Unit, ASUR Marche—AV 3, Macerata, Italy
  21. 21C. Mondino National Neurological Institute, Pavia, Italy
  22. 22Brain and Mind Research Institute, Sydney, New South Wales, Australia
  23. 23Hospital Germans Trias I Pujol, Badalona, Spain
  24. 24Bombay Hospital Institute of Medical Sciences, Mumbai, India
  25. 25AORN San Giuseppe Moscati Avellino, Avellino, Italy
  26. 26Flinders University and Medical Centre, Adelaide, South Australia, Australia
  27. 27Groene Hart Ziekenhuis, Gouda, The Netherlands
  28. 28Hospital Universitario Virgen de Valme, Sevilla, Spain
  29. 29Department of Neurofarba, Section of Neurosciences, University of Florence, Florence, Italy
  30. 30Hospital Italiano, Buenos Aries, Argentina
  31. 31Department of Neuroscience, University of Parma, Parma, Italy
  32. 32Liverpool Hospital, Liverpool, New South Wales, Australia
  33. 33FLENI, Buenos Aries, Argentina
  34. 34Ulster Hospital, Dundonald, UK
  35. 35St Andrew's Place, Brisbane, Australia
  36. 36INEBA, Buenos Aries, Argentina
  37. 37Hospital de Galdakao-Usansolo, Galdakao, Spain
  38. 38St Vincent's Hospital, Melbourne, Victoria, Australia
  39. 39Westmead Hospital, Sydney, New South Wales, Australia
  40. 40Geelong Hospital, Geelong, Victoria, Australia
  41. 41Hospital Fernandez, Capital Federal, Argentina
  42. 42Hospital Ecoville, Curitiba, Brazil
  43. 43Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
  44. 44Department of Neurology, Eastern Health, Monash University, Box Hill, Victoria, Australia
  1. Correspondence to Professor Bruce Taylor, Menzies Institute for Medical Research, University of Tasmania, Private Bag 23, Hobart, TAS 7001, Australia; bruce.taylor{at}utas.edu.au

Abstract

Background Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process.

Methods The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression.

Results Compared with those living in lower latitudes (19.0–39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0–56.0°) (p=3.83×10−23). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10−17). We found that the AAO of female patients was ∼5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ∼9 years later than relapsing-onset patients (p=1.40×10−265).

Conclusions An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations.

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Footnotes

  • Contributors BVT designed and conceptualised the study. EH, DH, VS, AL, GI, MT, PD, MG, FG'M, PG, RA, MT, CO-G, SAS, GI, PS, JL-S, VVP, EP, RB, MB, CR, BS, DLAS, MS, FV, RFB, MPA, EC, FG, SH, MF, OG, PMC, MLS, JLSM, NS, SV, CS, ND, WOA and HB all participated in data collection. CT performed the statistical analysis and BVT, SSJ, IvdM, LB, TS interpreted the data. CT wrote the manuscript. All authors critically revised and approved the manuscript.

  • Funding The work was supported by MSBase foundation. The MSBase Foundation is a not-for-profit organisation that receives support from Merck Serono, Biogen Idec, Novartis Pharma, Bayer-Schering, Sanofi-Aventis and BioCSL.

  • Competing interests EH received speaker honoraria and consultant fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono. DH was supported by the Czech Ministry of Education project PRVOUK-P26/LF1/4 and by the Czech Science Foundation GA CR 16-03322S. She also received compensation for travel, speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme and Teva, as well as support for research activities from Biogen Idec. AL has served as a Bayer, Biogen, Merck Serono, Novartis and Genzyme Advisory Board Member. She received travel grants and honoraria from Bayer, Biogen, Merck Serono, Novartis, Sanofi, Teva and Fondazione Italiana Sclerosi Multipla and research grants for her Institution from Bayer, Biogen, Merck Serono, Novartis, Sanofi, Teva and Fondazione Italiana Sclerosi Multipla. GI received consulting fees from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi, and Teva. MT has served on scientific Advisory Boards for Biogen, Novartis, Almirall, Roche and Genzyme; has received speaker honoraria from Biogen-Idec, Sanofi Aventis, Merck-Serono, Teva, Genzyme, Almirall and Novartis; has received research grants for her Institution from Biogen-Idec, Merck-Serono and Novartis. PD has received honoraria for organising CME events and has obtained funding to attend meetings from Biogen Idec, EMD Serono, TEVA Neuroscience, Novartis, and Genzyme, has received funding for investigator-initiated trials with Biogen Idec, EMD Serono, Genzyme, and Novartis, and has received peer-review funding from CIHR and from the MS Society of Canada. MG has served on Scientific Advisory Board and speaker honoraria: Biogen, Genzyme, EMD Serono, Teva Canada Innovation and Novartis. FG'M received honoraria or research funding from Biogen Idec, Chugai, Opexa, Genzyme, Novartis and Actelion. PG has served on Advisory board: Biogen Idec, Merk-Serono, Genzyme, Novartis; Lectures, teaching events: Teva neuroscience, Merk-Serono, Genzyme, Biogen idec, Bayer; Research trial: Biogen Idec, Sanofi-Avantis, MSBase, EMD-Serono. RA received honororia as a speaker and for serving in scientific advisory boards from Bayer, Biologix, Biogen, Genzyme, Genpahrm, Novartis, Merck-Serono, and GSK. MT received travel grants from Merck Serono, Novartis, Bayer-Schering, Merck-Serono and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. CO-G received honoraria as speaker from Biogen-Idec, Bayer-Schering, Merck-Serono, Teva, Genzyme and Novartis. GI had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis, and Teva. PS has received research support for her Institution from Merck Serono, TEVA, Biogen Idec, Novartis, Genzyme Sanofi Aventis and has received a speaker honorarium from TEVA, Genzyme, Bayer Schering Pharma and Biogen Idec. JL-S has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Bayer Healthcare, Biogen Idec, CSL, Genzyme Sanofi, Merck, Novartis and TEVA. VVP has received travel grants from Biogen, Bayer Schering, Genzyme, Merck, Teva and Novartis Pharma. His institution receives honoraria for consultancy and lectures from Biogen, Bayer Schering, Genzyme, Merck, Roche, Teva and Novartis Pharma as well as research grants from Novartis Pharma and Bayer Schering. EP served on scientific advisory boards for Merck Serono, Genzyme and Biogen; he has received honoraria and travel grants from Sanofi, Novartis, Biogen, Merck Serono, Genzyme and Teva. Dr RB has served on scientific advisory boards for Biogen Idec and Almirall; has received honoraria for speaking from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva; has received funding for congress and travel/accommodation expenses for scientific meetings from Sanofi-Aventis, Genzyme, Biogen Idec, Bayer Schering, Teva, Merck Serono, Almirall, and Novartis; has received research grants from Merck Serono, Biogen Idec, Teva, Bayer Schering, Novartis, Sanofi-Aventis, Genzyme. MB has served on scientific advisory boards for Biogen-Idec, Novartis and Genzyme and has received conference travel support from Biogen-Idec and Novartis. He serves on steering committees for trials conducted by Novartis. His institution has received research support from Biogen-Idec, Merck-Serono and Novartis. CR received research funding and compensation for travel from Biogen-Idec and Novartis. BS received consultancy honoraria and compensation for travel from Biogen-Idec and Merck-Serono. DLAS received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen Idec, Sanofi Aventis, Teva and Merck-Serono. MS has participated in, but not received honoraria for, advisory board activity for Biogen Idec, MerckSerono, BayerSchering, Sanofi Aventis and Novartis. RFB received speaking honoraria from Biogen-Idec, Novartis, Merck Serono and Teva. MPA has served on scientific Advisory Boards for Biogen, Novartis, Almirall, Roche and Genzyme; has received speaker honoraria from Biogen-Idec, Sanofi Aventis, Merck-Serono, Teva, Genzyme, Almirall and Novartis; has received research grants from Biogen-Idec, Merck-Serono, Novartis and Teva. EC received honoraria as consultant on scientific advisory boards by Biogen-Idec, Bayer-Schering, Merck-Serono, Genzyme and Novartis; has participated in clinical trials/other research projects by Merck-Serono, Roche and Novartis. FG has served on scientific advisory boards for Biogen Idec, Novartis and Sanofi Aventis and has received funding for travel and speaker honoraria from Biogen Idec, Merck Serono and Almirall. SH has received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi and travel grants from Novartis, Biogen Idec and Bayer Schering. MF received honoraria and/or travel and accommodation by Merck Serono, Novartis, Biogen, Bayer, Genzyme, Teva. OG received honoraria as consultant on scientific advisory boards for Genzyme, Biogen Idec, Merck Serono and Novartis; has received travel grants from Biogen Idec, Merck Serono and Novartis; has participated in clinical trials by Biogen Idec and Merck Serono. PMC has received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi and travel grants from Novartis, Biogen Idec and Bayer Schering. JLS-M has accepted travel compensation from Novartis, Merch Serono and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck Serono, Almirall, Bayer and Teva and has participated in a clinical trial by Biogen. NS has received travel grants from Biogen, Novartis, and Bayer and has participated in clinical trials for Genzyme, Roche, Alexion, Medimmune, Biogen, and Novartis. CS received travel assistance from Biogen Idec and Novartis. ND received funding from Bayer, Merck Serono, Biogen Idec, Genzyme and Novartis and has participated in clinical trials/other research projects by Bayer, Merck-Serono, Biogen Idec, Genzyme, Sanofi Aventis and Novartis. HB has received consulting fees from Genzyme, Biogen, Novartis, Merck and Oxford PharmaGenesis; and grant/research support from Biogen, Novartis, Merck and Genzyme. TS received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen ; speaker honoraria from Novartis.

  • Patient consent Obtained.

  • Ethics approval The MSBase registry was approved by the Melbourne Health Human Research Ethics Committee, and local ethics committees in all participating centres gave regional approval for participation in the MSBase registry. Written informed consent was obtained from all participants who provided data to the registry.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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