Abstract
Objectives: To examine whether past and recent sun exposure and vitamin D status (serum 25-hydroxyvitamin D [25(OH)D] levels) are associated with risk of first demyelinating events (FDEs) and to evaluate the contribution of these factors to the latitudinal gradient in FDE incidence in Australia.
Methods: This was a multicenter incident case-control study. Cases (n = 216) were aged 18–59 years with a FDE and resident within one of 4 Australian centers (from latitudes 27°S to 43°S), from November 1, 2003, to December 31, 2006. Controls (n = 395) were matched to cases on age, sex, and study region, without CNS demyelination. Exposures measured included self-reported sun exposure by life stage, objective measures of skin phenotype and actinic damage, and vitamin D status.
Results: Higher levels of past, recent, and accumulated leisure-time sun exposure were each associated with reduced risk of FDE, e.g., accumulated leisure-time sun exposure (age 6 years to current), adjusted odds ratio (AOR) = 0.70 (95% confidence interval [CI] 0.53–0.94) for each ultraviolet (UV) dose increment of 1,000 kJ/m2 (range 508–6,397 kJ/m2). Higher actinic skin damage (AOR = 0.39 [95% CI 0.17–0.92], highest grade vs the lowest) and higher serum vitamin D status (AOR = 0.93 [95% CI 0.86–1.00] per 10 nmol/L increase in 25(OH)D) were independently associated with decreased FDE risk. Differences in leisure-time sun exposure, serum 25(OH)D level, and skin type additively accounted for a 32.4% increase in FDE incidence from the low to high latitude regions.
Conclusions: Sun exposure and vitamin D status may have independent roles in the risk of CNS demyelination. Both will need to be evaluated in clinical trials for multiple sclerosis prevention.
The etiology of multiple sclerosis (MS), a T-cell–mediated autoimmune disease of the CNS, is uncertain. Positive latitude gradients in the occurrence of MS1 and its common precursor, first demyelinating events (FDEs),2 along with findings from individual-level epidemiologic studies,3,–,5 indicate that low sun exposure may increase risk. However, most such studies have involved prevalent MS cases so that disease-related changes in either recall of past sun exposure or in sun exposure behavior cannot be excluded. Examining these factors in incident cases with first onset of demyelination should improve the accuracy of the findings.
Two prospective epidemiologic studies found that higher vitamin D intake6 or serum levels7 were associated with reduced MS risk. In studies of the animal model of MS, experimental allergic encephalomyelitis (EAE), high dose supplementation with the active form of vitamin D (1,25[OH]D),8 or ultraviolet (UV) exposure without significant increase in vitamin D status9 suppressed the development of EAE. Previous human studies have not measured past sun exposure before the onset of MS and thus have been unable to differentiate potentially separate or interlinked etiologic roles of sun exposure and vitamin D status, although this could have important implications for preventive interventions for MS.
We present the results of a large, epidemiologic study that has been able to address each of these issues in study design and conduct. We also examined the extent to which the latitudinal gradient in the incidence of FDEs across Australia2 can be attributed to recent and past sun exposure.
METHODS
The Ausimmune Study is a multicenter case-control study in 4 regions of Australia: Brisbane City (latitude 27° South), Newcastle City and surrounds (33° South), Geelong City and the Western Districts of Victoria (37° South), and the island of Tasmania (43° South).10 Participants were aged 18–59 years and resident within a study region between November 1, 2003, and December 31, 2006.
Participants.
Cases had an incident first clinical diagnosis of CNS demyelination (FCD) within the study period, including classic FDEs (defined as a single, first, episode of demyelination11), primary progressive MS (PPMS), and possible subsequent events, where the historical first event had not previously been clinically diagnosed. Cases were notified to the study by medical specialists and a study neurologist confirmed the date and symptomatology of the FDE and conducted a full neurologic examination. Case clinical information was reviewed annually by the study neurologist group to assess eligibility as FDE, FCD, or PPMS. We aimed to recruit all incident cases within each study region from November 1, 2003–December 31, 2006.
Controls were randomly selected from the Australian Electoral Roll (compulsory registration for citizens ≥18 years) and matched to cases on age (within 2 years), sex, and study region.10
Measurements.
Questionnaire data.
Sun exposure measurements included time in the sun during weekends and holidays (leisure time) in summer and winter for different periods of life (6–10 y, 11–15 y, 16–20 y, and last 3 y) and a calendar, noting, for each year of life, the location of residence, school/occupation, and leisure time in the sun in summer and winter from age 6 years. The validity and reliability of these measures has been previously reported.12,13 For example, the test-retest reliability (with an 11-week interval between tests) for recall of childhood/adolescent sun exposure (e.g., time in the sun in summer, aged 6–10 years, weighted kappa = 0.61 [95% confidence interval (CI) 0.34–0.88]) was similar to that for recall of recent adult sun exposure (time in the sun in summer, last 3 years, weighted kappa = 0.60 [95% CI 0.33–0.86]), and total lifetime sun exposure (assessed from the calendar data) was significantly correlated with the actinic damage score (r = 0.34, p < 0.01).
Other relevant data included self-reported propensity to tan or burn; freckles as a teenager; smoking history (total years smoking as a continuous variable); highest education level (3 categories, see table 1); usual physical activity (scored and categorized into 3 levels according to the International Physical Activity Questionnaire)14; a food frequency questionnaire; and use of vitamin D–containing supplements in the last year (assumed to contain 400 IU if supplement not named or dose supplied6).
Characteristics of Ausimmune Study cases (incident CNS demyelination) and controlsa
Examination data.
Research officers noted the natural skin and eye color (with reference to standardized color photographs) and ethnicity (Caucasian, Asian, African, Australian Aboriginal or Torres Strait Islander, Other), and undertook a nevi count on the left arm.13 Skin reflectance on the buttock (non-sun-exposed site) was measured using a hand-held spectrophotometer (Minolta CM-2500D) to estimate cutaneous melanin density.13 Silicone rubber impressions (casts) of the skin on the dorsum of both hands were made as previously described.13 Casts were photographed and graded on a scale from 1 to 6, representing minimal to severe, actinic skin damage.
Biological measures.
Most participants provided a blood sample (94%) for DNA analysis. Serum aliquots (1 mL) were stored at −80°C and analyzed at study completion for 25-hydroxyvitamin D concentration [25(OH)D], using liquid chromatography dual mass spectrometry. There was high interbatch agreement for duplicate samples (n = 39 pairs, intraclass correlation = 0.89). SNP genotyping for vitamin D binding protein alleles previously shown to be relevant to vitamin D status15 was done using the SNPline method by KBiosciences Hoddesdon Herts UK.
Data analysis.
Ambient UV over the life course.
Average daily ambient erythemally weighted UV for every month of life for each participant was estimated using the latitude and longitude of residence (assigned using GIS software) and data from the TOMS satellite.16 The leisure-time UV dose was calculated as follows: (ambient UV × proportion of day in the sun), summed over the relevant period, from 6 years of age.13
Vitamin D status.
For control-only analyses, the 25(OH)D level was deseasonalized by fitting region-specific sine and cosine curves17 to the individual data points. For case-control analyses, we used these curves to project control 25(OH)D levels to the blood collection date of the matched case, i.e., the case 25(OH)D level was unchanged, to allow for seasonal effects on disease onset.
Statistical analysis.
Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression18 with fractional polynomial models used to examine for departure from linearity. Adjusted ORs (AORs) include adjustment for physical activity, smoking, and past history of infectious mononucleosis, with additional adjustment where noted. Tests for trend of categorical variables were undertaken by replacing the binary predictors with a single predictor, taking category rank scores. Statistical significance was defined as p < 0.05. Participants with missing data on factors of interest were excluded from those specific analyses.
To examine whether any UV-related factors could “account” for the observed latitudinal variation in FDE incidence,2 we integrated the relative risk (approximated from the OR) of FDE per unit of the factor, over the regional distribution of that factor. By dividing the resulting value for Tasmania (highest incidence region) by that for Brisbane (lowest incidence region) we estimated the proportionate increase in incidence accounted for by the factor. All analyses were undertaken using Stata for Windows (version 9.2; StataCorp LP, College Station, TX).
Standard protocol approvals, registrations, and patient consents.
The Ausimmune Study was approved by 9 regional Human Research Ethics Committees. All participants gave written informed consent.
RESULTS
Of 330 cases notified to the Ausimmune Study, 19 (5.8%) were ruled ineligible and 29 (8.7%) refused to participate, leaving 282 participating eligible FCD cases (participation rate = 91%). Of these, 216 had a FCD consisting of a distinct FDE during the study period without a prior possible event (subsequently referred to as the FDE group); 18 had PPMS and the remainder had had an undiagnosed, possible historical event (n = 48). Of 1,118 controls initially selected, 937 were successfully contacted (84%), and 558 (including 548 initial controls13 and 10 additional controls with late return of data) participated in the study (60% of those contacted). A total of 395 controls (out of the total 558) were specifically matched to an eligible FDE case.
Participant characteristics are presented in table 1. FDE cases were similar in educational level, but fairer skinned than matched controls, by both self-report and spectrophotometric measurement of buttock melanin density (OR = 0.83; 95% CI 0.73–0.94). Accounting for this, FDE cases were also more likely to have a larger number of nevi on the left arm [p (trend) = 0.001].
Physical activity (see table 1) was not associated with FDE either before (AOR = 1.33; 95% CI 0.78–2.26) or after (AOR = 1.45; 95% CI 0.85–2.50) adjustment for 25(OH)D levels (highest category of physical activity compared to lowest). We retained this factor as a covariate in subsequent analyses to ensure that sun exposure or vitamin D effects were assessed independently of physical activity.
Sun exposure.
High coherence was observed across the markers of sun exposure. For example, among controls, higher recent time in the sun (hours) predicted vitamin D level (p < 0.001) and leisure-time UV dose (6 y to current age) predicted the actinic skin damage grade (p = 0.005).13
Higher self-reported time in the sun in the 3 years prior to interview, and increasing leisure-time UV dose (6y to current age), were associated with reduced FDE risk (table 2), and this finding was not altered by adjustment for use of sun protection. Consistent with these findings, a higher actinic skin damage grade (table 3) was associated with lower odds of being a FDE case. Sunburn history was not associated with FDE risk (e.g., past history of blistering sunburn, AOR = 1.36; 95% CI 0.91–2.01).
Reported time in the sun and leisure time UV dose and risk of a first demyelinating event in the Ausimmune Study
Higher actinic skin damage (silicone cast grade) is associated with reduced risk of a first demyelinating event in the Ausimmune Study
Vitamin D status.
FDE cases had lower 25(OH)D levels than matched controls (mean [SD] nmol/L: cases 75.1 [31.9]; controls 80.4 [31.4]) and FDE risk decreased with increasing 25(OH)D level (figure): AOR = 0.93 (95% CI 0.86–1.00) per 10 nmol/L increase and AOR = 0.69 (95% CI 0.48–0.98) per 50 nmol/L increase. Fractional polynomial modeling confirmed no departure from a linear association and no evidence of a threshold effect. These associations were unaltered by further adjustment for buttock melanin density, other phenotypic factors, e.g., eye color, or vitamin D binding protein alleles previously associated with 25(OH)D level.15 The findings did not vary significantly by sex, study region, or different FDE presentation subtypes (optic neuritis, spinal cord syndrome, brainstem/cerebellar symptoms, other). PPMS risk also decreased with higher 25(OH)D level (AOR = 0.62; 95% CI 0.36–1.07 per 10 nmol/L increase), but the estimate was imprecise due to the few cases (n = 16).
Adjusted for total years smoking, history of infectious mononucleosis, and physical activity. Trend (linear), p = 0.03; bars are 95% confidence intervals.
In models containing both sun exposure measures and serum 25(OH)D levels (per 10 nmol/L increase), both factors were independently associated with reduced FDE risk (table 4), including for UV over the lifetime and recent UV dose. Findings were similar for the larger FCD case-control sample, where a possible prior (undiagnosed) event is still unlikely to have influenced sun exposure behavior and vitamin D level, but the larger sample size affords greater precision.
Independent associations of higher sun exposure and 25(OH)D levels with reduced disease risk in both the FDE and the larger FCD case-control sample, where a possible prior (undiagnosed) event is unlikely to have influenced sun exposure behavior or 25(OH)D level
Vitamin D supplements.
The lower serum 25(OH)D levels among FDE cases occurred despite higher vitamin D supplement use. At interview, 34.3% of FDE cases and 26.6% of matched controls were taking a vitamin D–containing supplement (p = 0.05). Of these participants, 16.7% of cases compared to 7.8% of controls (p = 0.07) commenced the supplement within the 2 months following the case's first episode (compared to 2.8% of cases and 5.8% of controls, p = 0.34, commencing within the 2 months prior to the episode).
Additional analyses.
The median time lag from the first event to the study interview was 147.5 days (IQR 77.5–220), and, reassuringly, time lag did not influence 25(OH)D levels within the FDE group (p = 0.66). Furthermore, the association between 25(OH)D level and FDE risk also did not vary by the time lag (e.g., AOR = 0.93, 95% CI 0.86–1.01, and 0.93, 95% CI 0.79–1.09, for >90 days and ≤90 days per 10 nmol/L increase, respectively). Exclusion of 32 case-control pairs where the case commenced a vitamin D supplement after the first episode, but before the study interview (AOR = 0.93, 95% CI 0.86–1.00), or 51 participants with serum 25(OH)D levels <40 nmol/L (AOR = 0.94, 95% CI 0.86–1.02) did not significantly alter the association between serum 25(OH)D and FDE risk.
Contribution of sun exposure and vitamin D status to the latitude gradient in FDE incidence.
In the Ausimmune Study, age- and sex-standardized FDE incidence varied from 2.1 (95% CI 1.6–2.6) at 27°S to 8.7 (95% CI 6.6–10.7) at 43°S (per 100,000 per year during November 1, 2003, to December 31, 20062), a 4-fold increase. The sun-related indices individually or in a combined model [25(OH)D = 9.3%, leisure-time UV dose (6 y to current age) = 9.2%, buttock melanin density = 13.9%] accounted for only part (a 32.4% increase in incidence) of the observed latitudinal FDE incidence gradient across these Australian regions.
DISCUSSION
Higher recent or lifetime sun exposure and higher serum 25(OH)D levels were independently associated with a reduced risk of a first CNS demyelinating event. A high level of consistency was observed across a comprehensive set of subjective and objective markers of recent or lifetime sun exposure. These associations remained after adjustment for potential confounders and did not vary by study region, gender, or type of CNS demyelination. Regional differences in measured sun exposure markers accounted for part, but not all, of the latitudinal FDE incidence gradient in Australia.
Strengths of this study include the Australian setting, where a marked latitude gradient in MS prevalence has been previously described,1 and there is wide variation in ambient UV and in personal UV dose. The inclusion of people with a FDE, rather than established MS, minimized disease-related changes in behavior or recall. The similarity in risk estimates for FDE and FCD for factors that might be anticipated to be affected by a greater interval from disease onset to study enrollment provides reassurance that these associations are measured without major bias in those with FCD in this study. The case-control design allowed collection of detailed data on a comprehensive set of sun exposure measures as well as biological data. Such data are not generally available through cohort studies that typically collect a broad range of exposure data, with the level of detail constrained by the burden to participants.
The control participation rate was 60% (of those contacted). As is commonly reported in studies with less than full participation, control subjects were more highly educated than the general population (e.g., 39.7% vs 18.7% had completed university in the Brisbane study region19). However, control participants with higher education had less cumulative UV exposure,13 leading, if anything, to a likely underestimation of the true case-control differences. Furthermore, after adjusting for age, sex, and study region, there was no significant association between educational level and 25(OH)D level.
A lower past leisure time UV dose (6 y to current age), taking account of residential location, was a strong predictor of FDE, and internally consistent with the objective marker of cumulative sun exposure (actinic skin damage grade) and with previous work in Australia5 and elsewhere.3,4 Fair skin and a higher nevus count were also associated with increased FDE risk. Nevi are strongly genetically determined, and a fair skin phenotype, associated with a reduced function MC1R gene variant, has been implicated in higher MS risk.20 Alternatively, a higher nevus count may reflect insufficient ongoing sun exposure to induce nevus involution.21
We found a similar magnitude of effect (but with no evidence of a threshold) for higher 25(OH)D levels and decreased FDE risk as that reported in the US military cohort study for MS onset.7 As in that study, based on a largely male cohort, our findings do not support animal work suggesting that a vitamin D protective effect is confined to females.22
In this study, we were able to examine past sun exposure before the onset of MS and also to examine past sun exposure and vitamin D status at the same time. Here both recent sun exposure and current 25(OH)D levels contributed independently to the reduced FDE risk. This is consistent with recently reported findings in the EAE animal model of MS,9 but has not previously been demonstrated in humans. In the recent animal study, the UV source was a lamp emitting broad band UV (280–360 nm), covering both UVA and UVB wavelengths. In the Ausimmune Study, actinic skin damage (reflecting chronic, largely UVA-induced sun exposure) and 25(OH)D levels (reflecting recent UVB exposure) were both independently important to FDE risk. Nevertheless, it is unclear which factor is of primary importance. The findings in relation to vitamin D status were based on a single measurement of serum 25(OH)D, taken after FDE onset. This may not reflect long-term vitamin D status, while measurement error within self-reported sun exposure means that there may not be full adjustment of either effect for the other, in models including both factors. However, these findings do raise the possibility that both (recent) vitamin D status and (recent and/or long-term) sun exposure influence FDE onset.
UV and vitamin D independently stimulate T-regulatory cells and secretion of IL-10,23 reduce levels of the proinflammatory cytokine IL-17,24 and dampen T-helper (Th)-1 immune function, providing biologically plausible pathways to reduced MS risk. Genetic studies also provide support for a role of vitamin D in MS risk: the CYP27B1 (vitamin D 1,25 hydroxylase enzyme) gene has been implicated in MS risk,25 and a vitamin D response element occurs within the MS susceptibility gene, HLA-DRB1*1501.26 Here, we were only able to adjust for one of the 3 genes recently identified in a genome-wide association study as determining serum 25(OH)D levels, but the combined effect of these genetic variants was not large as only 1%–4% of the variation in serum 25(OH)D was attributed to their combined effect.27
Early life sun exposure alone was not associated with FDE risk here, but sun exposure prior to age 6 was not examined, although this may be important.28,29 However, we have previously shown that early-life sun exposure is strongly related to the silicone cast grade among these participants,13 and higher cast grade was independently associated with FDE risk. This is consistent with vitamin D/sun exposure exerting effects at multiple points in the life course, as recently proposed.28
In this study, part of the latitudinal FDE incidence gradient across 4 Australian regions was accounted for by differences in past sun exposure and vitamin D status. These factors are both potentially important in MS. Notably, the independent UV effect shown in the EAE animal model was transient and reversible, so that the frequency of UV exposure was important. If the findings presented here, and those of the EAE model, are true for MS, advocating vitamin D supplementation alone may be a less effective preventive intervention than has been suggested by previous epidemiologic studies.
AUTHOR CONTRIBUTIONS
Dr. Lucas had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Ponsonby, Dear, van der Mei, Pender, Taylor, Kilpatrick, Chapman, Williams, and McMichael contributed to the conception and design of the study. All authors contributed to data acquisition, critical revision of the manuscript for intellectual content, administrative and technical support in the study, and obtaining funding for the study. Drs. Lucas, Dear, and Ponsonby performed statistical analyses and initial drafting of the manuscript.
DISCLOSURE
Dr. Lucas receives research support from Multiple Sclerosis Research Australia, The Royal Australasian College of Physicians, and the National Health and Medical Research Council of Australia. Dr. Ponsonby receives research support from Multiple Sclerosis Research Australia and the National Health and Medical Research Council of Australia. Dr. Dear receives research support from Multiple Sclerosis Research Australia and the National Health and Medical Research Council of Australia. Dr. Valery receives research support from the National Health and Medical Research Council of Australia and the Australian Research Council. Dr. Pender serves on the editorial board of The Open Autoimmunity Journal; and receives research support from Multiple Sclerosis Research Australia and from the National Health and Medical Research Council of Australia. Dr. Taylor has received funding for travel and speaker honoraria from Bayer Schering Pharma and CSL Australia Pty Ltd.; served on the editorial advisory board of the International MS Journal; and receives/has received research support from the National Health and Medical Research Council of Australia, The Health Research Council of New Zealand, the National MS Society of USA, and the MS Society of Tasmania. Dr. Kilpatrick has served on scientific advisory boards for GlaxoSmithKline, Neurosciences Victoria, and the Victorian Neurotrauma Initiative; has received funding for travel from Bayer Schering Pharma and Merck Serono; served on the editorial board of Therapeutic Advances in Neurological Disorders; is listed as an inventor on patents re: HIV test kit method for detecting anti-HIV-I antibodies in saliva; A method of modulating cell survival and reagents useful for same; Methods for the treatment and prophylaxis of demyelinating disease; and Method of treatment in the field of inflammatory neurodegeneration; and receives research support from Bayer Schering Pharma, Biogen Idec, the Australian Research Council, the National Health and Medical Research Council of Australia, MS Research Australia, and the National Multiple Sclerosis Society. Dr. Dwyer receives research support from the National Health and Medical Research Council of Australia. Dr. Coulthard serves as an associate Editor of the Journal of Medical Imaging and Radiation Oncology. Dr. Chapman reports no disclosures. Dr. van der Mei receives research support from MS Research Australia and the National Health and Medical Research Council of Australia. Dr. Williams reports no disclosures. Dr. McMichael serves on editorial advisory boards for Environment Health Perspectives, Cancer Causes and Control, and EcoHealth; and receives research support from the National Health and Medical Research Council and the Poola Foundation.
ACKNOWLEDGMENT
The authors thank the physicians who referred case participants to the Ausimmune Study: Ioanne Anderson, FRANZCO, Coastal Eye Centre Queensland; Michael Bailey, FRANZCO, The Mount Gambier Eye Centre South Australia; Peter Batchelor, PhD, Barwon Health, Victoria; Jeffrey Blackie, FRACP, John Hunter Hospital, Newcastle, New South Wales; Richard Bourke, FRACGP, General Practice, Tasmania; Richard Boyle, FRACP, Princess Alexandra Hospital, Brisbane, Queensland; John Cameron, MD, Princess Alexandra Hospital, Brisbane, Queensland; Ross Carne, MD, Deakin University, Victoria; Chris Charnley, FRACP, Southwest Healthcare, Warrnambool, Victoria; Ben Clark, FRANZCO, Geelong Hospital, Victoria; Steven Collins, MD, St. Vincent's Hospital, Melbourne; Diana Conrad, FRANZCO, Wesley Medical Centre, Auchenflower, Queensland; Michael Coroneos, FRACS, Private Practice, Brisbane, Queensland; Nicholas Downie, FRANZCO, Launceston General Hospital, Tasmania; Michael Dreyer, MD, Royal Hobart Hospital, Tasmania; Mervyn Eadie, MD, Royal Brisbane and Women's Hospital, Queensland; David Floate, FRACP, John Hunter Hospital, Newcastle, New South Wales; Peter Gates, FRACP, Barwon Health, Geelong Hospital, Victoria; Kerryn Green, FRACP, University of Queensland, Queensland; Erwin Groeneveld, FRANZCO, Princess Alexandra Hospital, Brisbane, Queensland; Mark Guirguis, MBBS (Hons), Private Practice, Tasmania; John Harrison, FRANZCO, Royal Brisbane and Women's Hospital and Princess Alexandra Hospital, Brisbane, Queensland; Michael Haybittel, FRANZCO, North West Regional Hospital, Tasmania; Robert Henderson, FRACP, Royal Brisbane and Women's Hospital, Queensland; John Henshaw, MMed, University of Tasmania, Tasmania; Keith Ho, MBBS, Ballarat Medical Centre, Victoria; Eugene Hollenbach, MBBS, Private Practice, Newcastle, New South Wales; James Hurley, MD, University of Melbourne, Victoria; Dean Jones, FRACP, Royal Hobart Hospital, Tasmania; Michael Katekar, MBBS, John Hunter Hospital, Newcastle, New South Wales; Anthony Kemp, FRACP, Ballarat Health Services, Victoria; Mark King, FRACP, Geelong Private Hospital, Victoria; George Kiroff, FRACS, The Geelong Hospital, Victoria; Brett Knight, FRACP, Ballarat Health Services, Victoria; Thomas Kraemer, FRACP, The Geelong Hospital, Victoria; Cecile Lander, FRACP, Royal Brisbane and Women's Hospital, Queensland; Jeanette Lechner-Scott, FRACP, John Hunter Hospital, Newcastle, New South Wales; Patrick Lockie, FRACS, St. John of God Hospital, Geelong, Victoria; Andre Loiselle, FRACP, Hunter New England Health, Newcastle, New South Wales; Paul McCartney, FRANZCO, Royal Hobart Hospital, Tasmania; Pam McCombe, PhD, University of Queensland, Queensland; Mark McGree, FRANZCO, McCullough Medical Centre, Queensland; David McKnight, FRANZCO, Ballarat Base Hospital, Victoria; Dan McLaughlin, PhD, Royal Brisbane and Women's Hospital, Queensland; Ian Murrell, FRANZCO, The Eye Hospital, Launceston, Tasmania; Satish Nagarajah, MBBS, St. John of God Hospital, Geelong, Victoria; Robert Newton, MBBS, Bayside Medical Centre, Hobart, Tasmania; Rob Nightingale, FRACP, Calvary Hospital, Tasmania; Terence O'Brien, MD, University of Melbourne, Victoria; John O'Sullivan, MD, Royal Brisbane and Women's Hospital, Queensland; Gregory Outteridge, FRANZCO, Hunter Valley Private Hospital, Newcastle, New South Wales; Anthony Pane, FRANZCO, Queensland Eye Institute, Queensland; Mark Parsons, FRACP, Hunter Medical Research Institute, Newcastle, New South Wales; Melinda Pascoe, FRACP, Private Practice, Brisbane, Queensland; David Prentice, PhD FRACP, St. Vincent's Hospital, Melbourne, Victoria; Richard Ralph, FRACGP, Cascade Road Medical Centre, Hobart, Tasmania; Stephen Read, FRACP, Royal Brisbane and Women's Hospital, Queensland; Alison Reid, FRACP, Private Practice, Brisbane, Queensland; John Richmond, FRACP, Ballarat Health Services, Victoria; Ian Routley, FRANZCO, The Geelong Hospital, Victoria; Timothy Ruddell, FRANZCO, Private Practice, Newcastle, New South Wales; Noel Saines, FRACP, Wesley Medical Centre, Auchenflower, Queensland; Stan Siejka, MBBS (deceased), Launceston General Hospital, Tasmania; Peter Silburn, PhD, FRACP, University of Queensland, Queensland; Christopher Staples, FRACP, Mater Health Services, Brisbane, Queensland; Alice Ann Sullivan, FRACP, Royal Brisbane and Women's Hospital, Brisbane, Queensland; Paul Talman, FRACP, Barwon Health, Geelong Hospital, Victoria; Don Todman, FRACP, University of Queensland, Queensland; Nitin Verma, FRANZCO, Hobart Eye Surgeons, Tasmania; Brendan Vote, FRANZCO, University of Tasmania, Tasmania; Michael Waldie, FRANZCO, Queensland Eye Hospital, Queensland; Michael Weetch, FRACP, Private Practice, Bendigo, Victoria; Rodney Westmore, FRANZCO, Launceston General Hospital, Tasmania; Andrew Wong, FRACP, Princess Alexandra Hospital, Brisbane, Queensland. Notifying physicians received no payment for case notification to the study.
The authors also thank the paid research personnel, including the local research officers: Susan Agland, BN, Hunter New England Health, Newcastle, New South Wales; Barbara Alexander, BN, Queensland Institute for Medical Research, Queensland; Marcia Davis, MD, Queensland Institute for Medical Research, Queensland; Zoe Dunlop, BN, Barwon Health, Geelong Hospital, Victoria; Rosalie Scott, BN, Royal Brisbane and Women's Hospital, Queensland; Marie Steele, RN, Royal Brisbane and Women's Hospital, Queensland; Catherine Turner, MPH&TM, Menzies Research Institute, Tasmania; Brenda Wood, RN, Menzies Research Institute, Tasmania; and the Ausimmune Study project officers during the course of the study: Jane Gresham, MA (Int Law), National Centre for Epidemiology and Population Health, The Australian National University, Canberra; Australian Capital Territory; Camilla Jozwick, BSc(Hons), National Centre for Epidemiology and Population Health, The Australian National University, Canberra; Australian Capital Territory; Helen Rodgers, RN, National Centre for Epidemiology and Population Health, The Australian National University, Canberra; Australian Capital Territory.
The authors also thank Ivan Hanigan, BA(Hons), and Ann Maree Hughes, PhD, of the National Centre for Epidemiology and Population Health, The Australian National University, Canberra, for assistance with derivation of ambient UV data (I.H.) and data entry and cleaning (A.M.H.) and the Multiple Sclerosis Society of Australia for assistance with recruitment.
Footnotes
-
Study funding: Supported by the National Multiple Sclerosis Society of the United States of America, the National Health and Medical Research Council of Australia, the ANZ William Buckland Foundation, and Multiple Sclerosis Research Australia.
-
- AOR
- adjusted odds ratio
- CI
- confidence interval
- EAE
- experimental allergic encephalomyelitis
- FCD
- first clinical diagnosis of CNS demyelination
- FDE
- first demyelinating event
- MS
- multiple sclerosis
- OR
- odds ratio
- PPMS
- primary progressive multiple sclerosis
- UV
- ultraviolet
- Received August 2, 2010.
- Accepted October 7, 2010.
- Copyright © 2011 by AAN Enterprises, Inc.
REFERENCES
Letters: Rapid online correspondence
- Sun exposure and vitamin D are independent risk factors for CNS demyelination
- Reply from the authors
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
More Online
Hastening the Diagnosis of Amyotrophic Lateral Sclerosis
Dr. Brian Callaghan and Dr. Kellen Quigg