Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis.
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.
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Chunrong
C
Tao
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Steve
http://orcid.org/0000-0001-6521-3056
S
Simpson
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Ingrid
I
van der Mei
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Leigh
L
Blizzard
Department of Neurology, Faculty of Medicine, Center of Clinical Neuroscience, 1st General University Hospital and Charles University in Prague, Prague, Czech Republic.
Eva
E
Havrdova
Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague, General University Hospital, Prague, Czech Republic.
Dana
D
Horakova
Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
Vahid
V
Shaygannejad
Department of Biomedical and NeuroMotor Sciences (DIBINEM), Alma Mater Studiorum-Università di Bologna, Bologna, Italy.|IRCCS Istituto delle Scienze Neurologiche-"UOSI Riabilitazione Sclerosi Multipla", Bologna, Italy.
Alessandra
A
Lugaresi
Hospital Universitario Virgen Macarena, Sevilla, Spain.
Guillermo
G
Izquierdo
Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.
Maria
M
Trojano
CHUM-Hôpital Notre Dame, Montreal, Canada.
Pierre
P
Duquette
CHUM-Hôpital Notre Dame, Montreal, Canada.
Marc
M
Girard
Neuro Rive-Sud, Hôpital Charles LeMoyne, Quebec, Quebec, Canada.
Franois
F
Grand'Maison
CISSS Chaudiere-Appalaches, Levis, Quebec, Canada.
Pierre
P
Grammond
Amiri Hospital, Kuwait City, Kuwait.
Raed
http://orcid.org/0000-0001-5436-5804
R
Alroughani
Department of Neurology, Mayis University, Samsun, Turkey.
Murat
M
Terzi
University Hospital San Carlos, IdISSC, Madrid, Spain.
Celia
C
Oreja-Guevara
Department of Neurology, Golestan University of Medical Sciences, Gorgan, Iran.
Seyed Aidin
SA
Sajedi
Ospedali Riuniti di Salerno, Salerno, Italy.
Gerardo
G
Iuliano
Department of Neuroscience, Universitu of Modena e Reggio Emilia, Nuovo Ospedale Civile S. Agostino/Estense, Modena, Italy.
Patrizia
P
Sola
John Hunter Hospital, University of Newcastle, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
Jeannette
J
Lechner-Scott
Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Vincent Van
VV
Pesch
Neurology Unit, ASUR Marche-AV 3, Macerata, Italy.
Eugenio
E
Pucci
C. Mondino National Neurological Institute, Pavia, Italy.
Roberto
R
Bergamaschi
Brain and Mind Research Institute, Sydney, New South Wales, Australia.
Michael
M
Barnett
Hospital Germans Trias I Pujol, Badalona, Spain.
Cristina
C
Ramo
Bombay Hospital Institute of Medical Sciences, Mumbai, India.
Bhim
B
Singhal
AORN San Giuseppe Moscati Avellino, Avellino, Italy.
Daniele
D
LA Spitaleri
Flinders University and Medical Centre, Adelaide, South Australia, Australia.
Mark
M
Slee
Groene Hart Ziekenhuis, Gouda, The Netherlands.
Freek
F
Verheul
Hospital Universitario Virgen de Valme, Sevilla, Spain.
Ricardo
R
Fernández Bolaños
Department of Neurofarba, Section of Neurosciences, University of Florence, Florence, Italy.
Maria Pia
MP
Amato
Hospital Italiano, Buenos Aries, Argentina.
Edgardo
E
Cristiano
Department of Neuroscience, University of Parma, Parma, Italy.
Franco
F
Granella
Liverpool Hospital, Liverpool, New South Wales, Australia.
Suzanne
S
Hodgkinson
FLENI, Buenos Aries, Argentina.
Marcela
M
Fiol
Ulster Hospital, Dundonald, UK.
Orla
O
Gray
St Andrew's Place, Brisbane, Australia.
Pamela
P
McCombe
INEBA, Buenos Aries, Argentina.
Maria Laura
ML
Saladino
Hospital de Galdakao-Usansolo, Galdakao, Spain.
José Luis
JL
Sánchez Menoyo
St Vincent's Hospital, Melbourne, Victoria, Australia.
Neil
N
Shuey
Westmead Hospital, Sydney, New South Wales, Australia.
Steve
S
Vucic
Geelong Hospital, Geelong, Victoria, Australia.
Cameron
C
Shaw
Hospital Fernandez, Capital Federal, Argentina.
Norma
N
Deri
Hospital Ecoville, Curitiba, Brazil.
Walter Oleschko
WO
Arruda
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.|Department of Neurology, Eastern Health, Monash University, Box Hill, Victoria, Australia.
Helmut
H
Butzkueven
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.
Tim
T
Spelman
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Bruce V
BV
Taylor
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001315:Australia; D015331:Cohort Studies; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005823:Genetics; D062306:Geography, Medical; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000453:epidemiology* / Q000209:etiology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology; D012307:Risk Factors; D014466:Ultraviolet Rays; D055815:Young Adult