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Animal exposure over the life-course and risk of multiple sclerosis: A case-control study within two cohorts of US women
Accepted Manuscript
Animal exposure over the life-course and risk of multiple sclerosis: a case-control study within two cohorts of US women Hilda J.I. de Jong , Helen Tremlett , Feng Zhu , Alberto Ascherio , Kassandra L. Munger PII: DOI: Reference:
S2211-0348(18)30508-X https://doi.org/10.1016/j.msard.2018.11.015 MSARD 1043
To appear in:
Multiple Sclerosis and Related Disorders
Please cite this article as: Hilda J.I. de Jong , Helen Tremlett , Feng Zhu , Alberto Ascherio , Kassandra L. Munger , Animal exposure over the life-course and risk of multiple sclerosis: a casecontrol study within two cohorts of US women, Multiple Sclerosis and Related Disorders (2018), doi: https://doi.org/10.1016/j.msard.2018.11.015
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ACCEPTED MANUSCRIPT Highlights
No association between overall animal exposure and MS risk was found.
In early adolescence, exposure to dogs was associated with an increased risk of MS. Further research in larger studies is needed to confirm these findings.
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ACCEPTED MANUSCRIPT Animal exposure over the life-course and risk of multiple sclerosis: a case-control study within two cohorts of US women Hilda J.I. de Jong, PhDa,b,c, Helen Tremlett, PhDa,b, Feng Zhu, MSca,b, Alberto
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Ascherio, MD, DrPHd,e,f, Kassandra L. Munger, ScDd
Author affiliations a
Centre for Brain Health and Faculty of Medicine (Neurology), University of British
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c
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Columbia, Vancouver, Canada
Vancouver Coastal Health Research Institute, Vancouver, Canada
School for Mental Health and Neuroscience, Maastricht University Medical Center,
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Maastricht, The Netherlands
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA,
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USA e
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MA, USA
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Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston,
Channing Division of Network Medicine, Department of Medicine, Brigham and
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Women’s Hospital and Harvard Medical School, Boston, MA, USA
Corresponding author Kassandra L. Munger Harvard School of Public Health 665 Huntington Ave, Building 2, 3rd Floor 2
ACCEPTED MANUSCRIPT Boston, MA 02115 Tel: 617-432-4220 Fax: 617-432-2435
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[email protected]
Word count
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Manuscript: 2,183
Running title
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Animal exposure and risk of multiple sclerosis
Keywords
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Multiple Sclerosis, animal, dog, risk factor, childhood, epidemiology, nested case-
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control study
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Declaration of interest
Hilda de Jong was funded by the Michael Smith Foundation for Health Research and
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the MS Society of Canada (Postdoctoral fellowships). Helen Tremlett reports grants from Martha Piper Research Fund, University of British Columbia, during the conduct of the study; grants from Canada Research Chair for Neuroepidemiology and Multiple Sclerosis, the National Multiple Sclerosis Society (NMSS), the Canadian Institutes of Health Research, the Multiple Sclerosis Scientific and Research Foundation, and the MS Society of Canada; speaker honoraria and/or travel expenses to attend conferences from the NMSS (2014, 2016), ECTRIMS 3
ACCEPTED MANUSCRIPT (2014, 2015, 2016, 2017), the American Academy of Neurology (2014, 2015, 2016), and ACTRIMS (2017), outside the submitted work. Alberto Ascherio reports grants from National Institutes of Health, NMSS, Department of Defense, Michael J Fox Foundation, Accelerated Cure Project, and Chronic Fatigue Initiative, and honoraria for scientific presentations from Bayer
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HealthCare, Almirall, and Serono.
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Feng Zhu and Kassandra Munger: none
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ACCEPTED MANUSCRIPT Abstract Background Whether animal exposure and specifically the timing of such exposure alters multiple sclerosis (MS) risk is unclear. We examined whether animal exposure was associated with MS risk, and whether risk differed by the participants age.
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Methods We conducted a case-control study within the Nurses’ Health Study ((NHS)/NHSII cohorts). Overall, 151 women with MS and 235 controls, matched by age and study cohort, completed an animal exposure history questionnaire. Animal exposure pre-MS
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onset was assessed as ‘any’ exposure, then by the participants age, and animal family. Conditional logistic regression was used to estimate relative MS risks, adjusted (adj.RR) for potential confounders.
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Results
‘Any’ animal exposure was reported by 136 (90.1%) MS cases compared to 200
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(85.1%) matched controls, with dog exposure being the most common [120 (79.5%) cases vs. 170 (72.3%) controls]. There was no association between ‘any’ animal
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exposure and MS risk (adj.RR:1.52;95%CI:0.76-3.04). However, both ‘any’ animal
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and specifically dog exposure at ages 10-14 years were associated with an increased MS risk (adj.RR:1.67;95%CI:1.05-2.66 and 1.76;95%CI:1.12-2.78, respectively).
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Conclusion
Animal exposure, and specifically dog exposure, in early adolescence was associated with an increased risk of MS. Further work is needed to confirm this finding.
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1 Introduction Multiple sclerosis (MS) is a chronic, inflammatory neurological disease affecting approximately 2.3 million individuals worldwide.[1] Several environmental exposures have been associated with an increased risk of MS, including infection with Epstein-Barr virus (EBV), low sunlight
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exposure or serum vitamin D levels and smoking.[2,3] Furthermore, it has been proposed that exposure to animals (kept as pets) may influence the risk of MS. For instance, exposure to animals who are prone to demyelinating diseases (e.g. German Shepherds) might be associated with an increased risk of MS.[4,5] Despite previous efforts, studies have shown conflicting
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results.[6-21] Several studies have shown that people living with MS were more often exposed to animals in the years before the onset compared to healthy controls or controls with other neurological diseases.[6-8,12,14,15,17,21] However, other studies have shown an inverse or no
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association between exposure to animals and the risk of developing MS.[9-11,13,16,18-20] In previous studies, it has been postulated that exposure to animals during infancy would be
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protective, whereas initial infection later in life (late childhood or adulthood) would result in a greater risk of developing MS.[2]
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To date, it is not clear whether there is an association between animal exposure and the risk of
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MS. Moreover, limited data on exposure to animals over specific ages and MS risk are available. We examined the association between exposure to animals and the risk of MS, with a focus on
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the timing of exposure, assessed across specific age groups.
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2 Materials and Methods 2.1 Study participants We conducted a case-control study within two large on going, prospective US cohorts, Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHS II), comprising a total of 238,371 female
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nurses. The NHS was established in 1976, and enrolled 121,700 nurses aged 30-55 years from 11 U.S. states who responded to a mailed questionnaire about disease history and lifestyle items. The NHS II was established in 1989, when 116,671 nurses aged 25-42 years from 14 states responded to a similar questionnaire. Every two years a follow-up questionnaire is mailed to the
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participants of both cohorts to update information on potential risk factors for chronic diseases and to assess major clinical events, including MS. People with MS were confirmed by either the treating or study neurologist who reviewed their medical records.[22] Within both cohorts, there
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and study cohort (NHS or NHSII).
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was a set of 183 incident MS cases and 438 controls without MS matched by age at cohort entry
2.2 Assessment of animal exposure
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In the years 2012-13, cases and controls were invited to participate in an additional study on ‘the
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effect of environmental and personal exposures on the risk of developing [either] MS [for MS cases]/or chronic diseases [for healthy controls]’ using a pre-piloted questionnaire [23] adapted
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for MS and to include animal exposures. Up to two reminders were sent to the participants. Questions about animals (kept as pets) were asked over specific ages (categorised into five-year age groups from 0-4 to 20-24 years, then every ten-years to <45 years), and by type (family) of animal (e.g. dog, cat) and dog breed, with free-text responses allowed. Initially ‘any’ animal exposure was examined prior to MS onset (i.e. the index date), then by animal family, grouped as
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dog, cat, rabbit, guinea pig, or bird, and by dog breed which was grouped as Cocker Spaniel, German Shepherd, Golden Retriever, or Labrador Retriever. Timing of exposure was considered by the study participants age, for ‘any’ animal exposure, and for the two most common family groups (dog and cat). For the years of animal exposure before MS onset, a case’s data were only
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included if MS onset had yet to be reached, e.g., the age group 15-19 only included those yet to develop MS, along with their matched controls.
2.3 Assessment of covariates
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Covariate information was obtained from the biennial questionnaires completed by all nurses in the cohorts and included ancestry (grouped as: Scandinavian; Southern European; all other Caucasians; other ethnic groups);[17] latitude of residence at age 15 (North, Middle, South);[24]
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body mass index (BMI) at age 18;[25] smoking status (ever vs. never);[26] supplemental intake
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2.4 Statistical analyses
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of vitamin D (nil, >nil<400, ≥400IU/day).[27]
From 621 women (183 incident MS cases and 438 matched controls) contacted, 90% (n=556)
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completed the ‘environmental’ questionnaire. Of the 167 MS cases, 16 cases had no matched control which resulted in 151 MS cases included in the analyses. Of the 151 MS cases, 84 had
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two matched controls and 67 had one. We assessed the association between exposure to ‘any’ animals or at specific age categories and MS risk, using conditional logistic regression, with findings reported as adjusted relative risks (RRs) and the corresponding 95% confidence intervals (CIs). We included cases with at least one age- and study cohort-matched control (‘Model 1’). In addition, models were adjusted for ancestry, smoking, supplemental vitamin D
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intake, tier of residence at age 15, and BMI at age 18 (‘Model 2’, see covariates above). Among women (120 cases and 170 controls) reporting having dogs as pets, we also examined whether exposure to specific dog breeds was associated with MS risk, using an unconditional logistic regression including the matching variables, in order to make best use of all the available data
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related to dog breeds.
One prior study (conducted in 1998) also examined the association between animal exposure (cat or dog) and MS risk using the NHS/NHSII cohorts.[17] Although our current study was designed to address broader issues related to animal exposure and over 60% of our cohort (69 cases and
those women unique to our current study.
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167 controls) had not been studied previously, we conducted a complementary analysis including
All the analyses were conducted using SAS V9.3 (SAS Institute Inc, Cary, N.C.). The study was
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approved by the Institutional Review Board of Brigham and Women’s Hospital. Return of the
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completed questionnaire was considered consent for participating in this sub-study.
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3 Results The mean MS onset age was 39.5 years (SD 8.9) and the majority developed MS by age 45 years (n=115; 76%). Characteristics are shown in Table 1.
Characteristics
Controls N=235 36.2 (4.5)
27 (17.9) 6 (4.0) 98 (64.9) 18 (11.9) 2 (1.3)
40 (17.0) 20 (8.5) 145 (61.7) 25 (10.6) 5 (2.1)
71 (47.0) 58 (38.4) 13 (8.6) 9 (6.0)
84 (35.7) 118 (50.2) 24 (10.2) 9 (3.8)
70 (46.4) 81 (53.6) 21.8 (3.2)
100 (42.6) 135 (57.4) 21.1 (2.8)
83 (55.0) 16 (10.6) 29 (19.2) 23 (15.2)
128 (54.5) 42 (17.9) 48 (20.4) 17 (7.2)
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Age at baseline* (years), mean SD) Age at MS onset (years), mean SD) Ancestry, N (%) South European ancestry Scandinavian ancestry All other Caucasians Other ethnic ancestries Missing Tier of residence at age 15, N (%) North Middle South Missing Ever smoked at baseline, N (%) Yes No Body mass index at age 18 (kg/m2), mean (SD) Supplemental vitamin D intake at baseline, N (%) Nil >nil<400IU/day ≥400IU/day Missing MS: multiple sclerosis; SD: standard deviation;
MS cases N=151 36.0 (4.5) 39.5 (8.9)
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Table 1. Characteristics of the MS patients (cases) and controls nested within the Nurses’ Health Studies
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Baseline: the date of entry into the NHS or NHSII
Among the women with MS, 136 (90.1%) reported exposure to an animal prior to MS onset as compared with 200 (85.1%) of their matched controls. No significant association was observed
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between animal exposure and MS risk (adjusted RR (model 2): 1.52 (95% CI, 0.76-3.04); p=0.24), Table 2. When specified by animal family, neither exposure to dogs, cats, guinea pigs
Table 2. Associations between animal exposure and risk of MS MS cases N (%) N=151
Controls N (%) N=235
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nor birds were associated with risk of MS (see Table 2).
RR (95% CI), p-value
RR (95% CI), p-value
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Model 1 Model 2 Exposure to animals before the index date Any pet Not exposed 15 (9.9) 35 (14.9) Reference reference Exposed 136 (90.1) 200 (85.1) 1.55 (0.81 – 2.96), 0.18 1.52 (0.76 – 3.04), 0.24 Dog Not exposed 31 (20.5) 65 (27.7) Reference reference Exposed 120 (79.5) 170 (72.3) 1.38 (0.85 – 2.24), 0.19 1.34 (0.80 – 2.25), 0.27 Cat Not exposed 65 (43.1) 111 (47.2) Reference reference Exposed 86 (56.9) 124 (52.8) 1.16 (0.77 – 1.77), 0.48 1.34 (0.84 – 2.15), 0.22 Rabbit Not exposed 129 (85.4) 194 (82.5) Reference reference Exposed 22 (14.6) 41 (17.5) 0.83 (0.48 – 1.43), 0.50 0.88 (0.49 – 1.61), 0.68 Guinea pig Not exposed 133 (88.1) 211 (89.8) Reference reference Exposed 18 (11.9) 24 (10.2) 1.14 (0.59 – 2.22), 0.69 1.26 (0.61 – 2.61), 0.54 Bird Not exposed 128 (84.8) 206 (87.7) Reference reference Exposed 23 (15.2) 29 (12.3) 1.33 (0.72 – 2.45), 0.37 1.54 (0.78 – 3.03), 0.22 Other pet† Not exposed 126 (83.4) 189 (80.4) Reference reference Exposed 25 (16.6) 46 (19.6) 0.82 (0.47 – 1.43), 0.49 0.95 (0.51 – 1.76), 0.87 Adjustments: Model 1: age and nurses’ health study cohort (NHS or NHSII), as used in the matching process Model 2: as for model 1, in addition: ancestry, ever smoked, supplemental vitamin D intake, tier of residence at age 15 and body mass index at age 18. † Example of other pets: rodents (excluding guinea pig), reptiles, spiders, ferrets.
When the timing of animal exposure was explored (Table 3), early adolescence (age 10-14 years) emerged as a potentially important time period, with exposure to ‘any’ animal, as well as 11
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specifically to dogs, being associated with a 67% and 76% increased risk of developing MS, respectively (fully adjusted RR (model 2): 1.67 (95% CI, 1.05-2.66); p=0.03 and 1.76 (95% CI, 1.12-2.78); p=0.01), see Table 3. While exposure to ‘any’ animal in those aged 35-44 years was associated with a decreased risk of MS, fewer individuals were still ‘at risk’ of developing MS
adjusted RR (model 2): 0.24 (95% CI, 0.06-0.89); p=0.03).
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by this age category, and consequently the 95% confidence intervals were relatively wide (fully
Using a multivariable unconditional logistic regression model adjusted for matching factors, exposure to Cocker Spaniels at any age was associated with an increased risk of MS: 2.56 (95%
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CI, 1.31-5.01); p=0.006. No associations were found between exposure to Cocker Spaniels or other specific dog breeds at age 10-14 years.
Table 3. Associations between animal exposure and risk of MS by age
Exposure to animals before the index date
0 to 4 years
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5 to 9 years
Any pet Not exposed Exposed Dog Not exposed Exposed Cat
RR (95% CI), p-value
RR (95% CI), p-value
Model 1
Model 2*
N=151
N=235
100 (66.2) 51 (33.8)
158 (67.2) 77 (32.8)
reference reference 1.07 (0.69 – 1.66), 0.77 1.25 (0.78 – 2.01), 0.35
114 (75.5) 37 (24.5)
176 (74.9) 59 (25.1)
reference reference 0.99 (0.61 – 1.61), 0.97 1.14 (0.68 – 1.93), 0.61
133 (88.1) 18 (11.9) N=151
208 (88.5) 27 (11.5) N=235
reference reference 1.00 (0.53 – 1.87), 1.00 1.37 (0.70 – 2.71), 0.36
71 (47.0) 80 (53.0)
108 (46.0) 127 (54.0)
reference reference 0.98 (0.65 – 1.47), 0.92 1.09 (0.70 – 1.71), 0.70
89 (58.9) 62 (41.1)
146 (62.1) 89 (37.9)
reference reference 1.13 (0.75 – 1.69), 0.56 1.11 (0.71 – 1.74), 0.63
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Any pet Not exposed Exposed Dog Not exposed Exposed Cat Not exposed Exposed
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Age group
Controls N, (%)
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MS Cases N, (%)
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Any pet Not exposed Exposed Dog Not exposed Exposed Cat Not exposed Exposed 20 to 24 years
107 (45.5) 128 (54.5)
reference reference 1.55 (1.01 – 2.37), 0.04 1.67 (1.05 – 2.66), 0.03
68 (45.0) 83 (55.0)
137 (58.3) 98 (41.7)
reference reference 1.66 (1.10 – 2.52), 0.02 1.76 (1.12 – 2.78), 0.01
110 (72.9) 41 (27.1) N=150
179 (76.2) 56 (23.8) N=233
reference reference 1.18 (0.75 – 1.86), 0.48 1.43 (0.85 – 2.39), 0.17
81 (54.0) 69 (46.0)
116 (49.8) 117 (50.2)
reference reference 0.81 (0.53 – 1.25), 0.35 0.83 (0.52 – 1.33), 0.43
91 (60.7) 59 (39.3)
147 (63.1) 86 (36.9)
reference reference 1.04 (0.68 – 1.58), 0.86 1.04 (0.65 – 1.64), 0.88
123 (82.0) 27 (18.0) N=143
181 (77.7) 52 (22.3) N=222
reference reference 0.78 (0.47 – 1.29), 0.33 0.99 (0.56 – 1.76), 0.97
82 (57.3) 61 (42.7)
127 (57.2) 95 (42.8)
reference reference 0.95 (0.62 – 1.47), 0.83 0.89 (0.55 – 1.43), 0.62
98 (68.5) 45 (31.5)
166 (74.8) 56 (25.2)
reference reference 1.35 (0.85 – 2.16), 0.20 1.25 (0.75 – 2.10), 0.39
117 (81.8) 26 (18.2) N=106
170 (76.6) 52 (23.4) N=165
reference reference 0.72 (0.43 – 1.21), 0.21 0.65 (0.36 – 1.15), 0.14
35 (33.0) 71 (67.0)
63 (38.2) 102 (61.8)
reference reference 1.31 (0.79 – 2.18), 0.29 1.26 (0.72 – 2.19), 0.43
59 (55.7) 47 (44.3)
94 (57.0) 71 (43.0)
reference reference 1.13 (0.66 – 1.92), 0.65 1.13 (0.63 – 2.04), 0.68
70 (66.0)
115 (69.7)
reference
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25 to 34 years
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Any pet Not exposed Exposed Dog Not exposed Exposed Cat Not exposed Exposed
54 (35.8) 97 (64.2)
Any pet Not exposed Exposed Dog Not exposed Exposed Cat Not exposed
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15 to 19 years
reference reference 0.97 (0.59 – 1.60), 0.90 1.24 (0.71 – 2.17), 0.45
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Any pet Not exposed Exposed Dog Not exposed Exposed Cat Not exposed Exposed
183 (77.9) 52 (22.1) N=235
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10 to 14 years
118 (78.2) 33 (21.8) N=151
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Not exposed Exposed
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Exposed
36 (34.0) N=41
35 to 44 years
50 (30.3) N=69
1.19 (0.70 – 2.03), 0.53 1.03 (0.57 – 1.88), 0.91
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Any pet Not exposed 16 (39.0) 13 (18.8) reference reference Exposed 25 (61.0) 56 (81.2) 0.41 (0.18 – 0.95), 0.04 0.24 (0.06 – 0.89), 0.03 Dog Not exposed 21 (51.2) 28 (41.0) reference reference Exposed 20 (48.8) 41 (59.4) 0.65 (0.31 – 1.38), 0.26 0.85 (0.31 – 2.34), 0.75 Cat Not exposed 24 (58.5) 42 (60.9) reference reference Exposed 17 (41.5) 27 (39.1) 1.08 (0.51 – 2.30), 0.85 0.84 (0.27 – 2.62), 0.76 Adjustments: Model 1: age and nurses’ health study cohort (NHS or NHSII), as used in the matching process Model 2: as for model 1, in addition: ancestry, ever smoked, supplemental vitamin D intake, tier of residence at age 15 and body mass index at age 18.
In the complementary analysis, focused on women who were not part of a prior study,[17] did not materially change the effect estimate, though it was no longer statistically significant (‘any’
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dog exposure and dog exposure at age 10-14: 1.16 (0.56-2.41); p=0.70 and 1.67 (0.90-3.12);
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p=0.11). No association was found for ‘any’ cat exposure, consistent with the previous
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results.[17]
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4 Discussion We found no association between overall animal exposure and the risk of developing MS. However, exposure to ‘any’ animal and specifically to dogs in early adolescence was associated
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with a nearly 1.7-fold increased risk of developing MS.
Results from previous case-control studies of animal exposure on MS risk have been mixed.[621] Some studies have concurred with ours, by reporting no association between ‘any’ animal exposure and MS risk,[9-11,13,18,19] or by showing that dog exposure is associated with an
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increased risk of MS.[6-8,12,15,17] However, only five of these studies were able to consider the timing of exposure.[9,11,17,19,21] First contact with a dog during adolescence and adulthood (age 15+ years) was associated with a 70% increased risk of MS in the USA NHS/NHS II
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cohorts.[17] While there was some overlap in participants between our study and this prior work,[17] over 60% of our participants were unique and excluding women contributing to both
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studies did not change the direction of findings. We also extended previous work through a more detailed and dynamic exploration of animal exposure and MS risk. We were able to consider the
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participants age when the animal exposure occurred (up to age 45 years) and also include a wider
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array of animals and specific dog breeds and the risk of MS.
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Other studies with exposure to animals across age categories found no associations with MS risk.[9,11,19,21] Two of the studies had modest sample sizes (fewer than 75 MS cases and 75 controls) which may have limited the ability to detect an effect.[9,11] The other two studies [19,21] used either different or broader age categories which may have obscured any associations
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in some instances (exposure at 10-14 in the current study vs. 6-16 years [19] or exposure before 6, 10, 15 or 20 years and during puberty (age 12-18 years)[21]).
Three other studies found a significant association with birds kept as pets and increased risk of
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MS;[12,14,16] however, relatively few of our participants (13.5%) reported bird ownership. Thus, our study may have been underpowered to detect a true association between bird exposure and the risk of MS.
One population-based study reported an increased risk of MS associated with cat exposure
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during puberty [21] whereas no such association was observed in our study. Further, two studies reported a lower risk of MS in relation to animal exposure and for cat exposure specifically, although none examined the timing of exposure at specific age groups.[16,20] While we also
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found ‘any’ animal exposure associated with a lower risk, this was for those aged 35-44 years only. This finding should be interpreted with caution as there was a small samples size in this
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delayed diagnosis of MS.
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group and may be due to reverse causation since this age category might include patients with a
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The underlying mechanism by which exposure to animals, and dogs in particular, may alter the risk of MS is unclear. The role of animals in altering levels of microorganisms and endotoxins
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individuals are exposed to, or in shaping the human microbiota (especially for dog owners),[2830] could be postulated to alter MS risk, but to date there has been no conclusive evidence. While some have suggested a link between Canine Distemper Virus (CDV) infections and MS,[4,5,26] this remains largely unconfirmed. Additionally, the common practice to vaccinate dogs against CVD combined with no apparent decrease in MS incidence has further diminished this
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concern.[27,28] Our lack of association with German Shepherds or other large breed dogs (Golden Retriever and Labrador Retriever), and MS risk, perhaps also provides some reassurances to owners of these animals in context of prior concerns raised over degenerative myelopathy,[4,5] a disease similar to MS. Although we found a potential relationship with the
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Cocker Spaniel and MS risk, no other studies have reported an association. As our risk estimate had wide confidence intervals, a chance finding is possible, and this result needs confirmation and should be interpreted cautiously.
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Our study has several strengths. Compared with the previous work,[6-16,18-20,21] we assessed MS risk related to animal exposure using two large, well-defined cohorts. This minimizes selection bias since cases and controls were sourced from the same broader population. We also
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had a high response rate to our questionnaire, and were able to assess animal exposure by participants’ age at exposure as well as by animal family and dog breed. This allowed us to
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examine exposure over childhood and adolescence, considered potentially etiologically relevant time periods in modulating future MS risk. However, exposure to animals was collected
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retrospectively, and we cannot rule out that recall bias may have influenced our self-reported
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data, although it seems unlikely that women with MS would differentially report their exposure to animals, and dogs in particular, during their adolescent years. Further, the questions about
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animal exposure were embedded with other unrelated environmental exposures as to minimize the participants’ awareness of the specific study objectives. This approach may help minimize reporting bias.[31] While we did adjust for latitude of residence at age 15, we were not able to adjust for rural versus urban classification of residence. While the nature of the association between type of residence and risk of MS is unclear, if type of pet ownership varies between
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rural versus urban settings, there may be some residual confounding. We had access to prospectively collected data on rich set of other potential confounders from the NHS and NHSII, and were able to adjust for many of the known risk factors for MS. 5 Conclusions
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In conclusion, we found no association between overall animal exposure and MS risk. However, in early adolescence, exposure to dogs was associated with an increased risk of MS. However, further research in larger studies is needed to confirm the age-dependence of this finding.
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Acknowledgements
We thank Leslie Unger and Allison Gordon for data cleaning and entry and Thomas Duggan for
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facilitating with data coding.
Funding
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This work was supported by the Martha Piper Research Fund, University of British Columbia, Canada and the US National Institutes of Health [grant numbers UM1 CA186107 and UM1
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CA176726]. The funder had no role in study design; in the collection, analysis and interpretation
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of data; in the writing of the report; and in the decision to submit the article for publication.
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2. Ascherio A and Munger KL. Environmental risk factors for multiple sclerosis. Part I: the
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4. Clemmons RM. Degenerative myelopathy. Vet Clin North Am Small Anim Pract
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5. Lincoln JA, Hankiewicz K, Cook SD. Could Epstein-Barr virus or canine distemper virus cause multiple sclerosis? Neurol Clin 2008;26:699-715,viii.
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6. Cook SD and Dowling PC. A possible association between house pets and multiple sclerosis. Lancet 1977;1:980-982.
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7. Jotkowitz S. Multiple sclerosis and exposure to house pets. JAMA 1977;238:854. 8. Cook SD, Natelson BH, Levin BE, et al. Further evidence of a possible association
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10. Norman JE Jr, Cook SD and Dowling PC. Household pets among veterans with multiple sclerosis and age-matched controls. Pilot survey. Arch Neurol 1983;40:213-214.
11. Anderson LJ, Kibler RF, Kaslow RA, et al. Multiple sclerosis unrelated to dog exposure. A case-referent study. Neurology 1984;34:1149-1154.
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12. Flodin U, Söderfeldt B, Noorlind-Brage H, et al. Multiple sclerosis, solvents, and pets. Arch Neurol 1988;45:620-623. 13. Operskalski EA, Visscher BR. Malmgren RM, et al. A case-control study of multiple sclerosis. Neurology 1989;39:825-829.
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14. Landtblom AM, Flodin U, Karlsson M, et al. Multiple sclerosis and exposure to solvents, ionizing radiation and animals. Scand J Work Environ Health 1993;19:399-404.
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17. Hernán MA, Zhang SM, Lipworth L, et al. Multiple sclerosis and age at infection of common viruses. Epidemiology 2001;12:301-306.
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22. Ascherio A, Zhang SM, Hernán MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Eng J Med 2001;344:327-332. 23. Han J, Colditz GA and Hunter DJ. Risk factors for skin cancers: a nested-case control study within the Nurses’ Health Study. Int J Epidemiol 2006;35:1514-1521.
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24. Hernán MA, Olek MJ and Ascherio A. Geographic variation of MS incidence in two prospective studies of US women. Neurology 1999;53:1711-1718.
25. Munger KL, Chitnis T and Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology 2009;73:1543-1550.
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27. Munger KL, Zhang SM, O’Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004;62:60-65.
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Animal exposure over the life-course and risk of multiple sclerosis: a case-control study within two cohorts of US women Hilda J.I. de Jong , Helen Tremlett , Feng Zhu , Alberto Ascherio , Kassandra L. Munger PII: DOI: Reference:
S2211-0348(18)30508-X https://doi.org/10.1016/j.msard.2018.11.015 MSARD 1043
To appear in:
Multiple Sclerosis and Related Disorders
Please cite this article as: Hilda J.I. de Jong , Helen Tremlett , Feng Zhu , Alberto Ascherio , Kassandra L. Munger , Animal exposure over the life-course and risk of multiple sclerosis: a casecontrol study within two cohorts of US women, Multiple Sclerosis and Related Disorders (2018), doi: https://doi.org/10.1016/j.msard.2018.11.015
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ACCEPTED MANUSCRIPT Highlights
No association between overall animal exposure and MS risk was found.
In early adolescence, exposure to dogs was associated with an increased risk of MS. Further research in larger studies is needed to confirm these findings.
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ACCEPTED MANUSCRIPT Animal exposure over the life-course and risk of multiple sclerosis: a case-control study within two cohorts of US women Hilda J.I. de Jong, PhDa,b,c, Helen Tremlett, PhDa,b, Feng Zhu, MSca,b, Alberto
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Ascherio, MD, DrPHd,e,f, Kassandra L. Munger, ScDd
Author affiliations a
Centre for Brain Health and Faculty of Medicine (Neurology), University of British
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c
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Columbia, Vancouver, Canada
Vancouver Coastal Health Research Institute, Vancouver, Canada
School for Mental Health and Neuroscience, Maastricht University Medical Center,
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Maastricht, The Netherlands
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA,
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USA e
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MA, USA
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Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston,
Channing Division of Network Medicine, Department of Medicine, Brigham and
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Women’s Hospital and Harvard Medical School, Boston, MA, USA
Corresponding author Kassandra L. Munger Harvard School of Public Health 665 Huntington Ave, Building 2, 3rd Floor 2
ACCEPTED MANUSCRIPT Boston, MA 02115 Tel: 617-432-4220 Fax: 617-432-2435
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[email protected]
Word count
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Manuscript: 2,183
Running title
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Animal exposure and risk of multiple sclerosis
Keywords
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Multiple Sclerosis, animal, dog, risk factor, childhood, epidemiology, nested case-
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control study
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Declaration of interest
Hilda de Jong was funded by the Michael Smith Foundation for Health Research and
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the MS Society of Canada (Postdoctoral fellowships). Helen Tremlett reports grants from Martha Piper Research Fund, University of British Columbia, during the conduct of the study; grants from Canada Research Chair for Neuroepidemiology and Multiple Sclerosis, the National Multiple Sclerosis Society (NMSS), the Canadian Institutes of Health Research, the Multiple Sclerosis Scientific and Research Foundation, and the MS Society of Canada; speaker honoraria and/or travel expenses to attend conferences from the NMSS (2014, 2016), ECTRIMS 3
ACCEPTED MANUSCRIPT (2014, 2015, 2016, 2017), the American Academy of Neurology (2014, 2015, 2016), and ACTRIMS (2017), outside the submitted work. Alberto Ascherio reports grants from National Institutes of Health, NMSS, Department of Defense, Michael J Fox Foundation, Accelerated Cure Project, and Chronic Fatigue Initiative, and honoraria for scientific presentations from Bayer
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HealthCare, Almirall, and Serono.
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Feng Zhu and Kassandra Munger: none
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ACCEPTED MANUSCRIPT Abstract Background Whether animal exposure and specifically the timing of such exposure alters multiple sclerosis (MS) risk is unclear. We examined whether animal exposure was associated with MS risk, and whether risk differed by the participants age.
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Methods We conducted a case-control study within the Nurses’ Health Study ((NHS)/NHSII cohorts). Overall, 151 women with MS and 235 controls, matched by age and study cohort, completed an animal exposure history questionnaire. Animal exposure pre-MS
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onset was assessed as ‘any’ exposure, then by the participants age, and animal family. Conditional logistic regression was used to estimate relative MS risks, adjusted (adj.RR) for potential confounders.
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Results
‘Any’ animal exposure was reported by 136 (90.1%) MS cases compared to 200
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(85.1%) matched controls, with dog exposure being the most common [120 (79.5%) cases vs. 170 (72.3%) controls]. There was no association between ‘any’ animal
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exposure and MS risk (adj.RR:1.52;95%CI:0.76-3.04). However, both ‘any’ animal
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and specifically dog exposure at ages 10-14 years were associated with an increased MS risk (adj.RR:1.67;95%CI:1.05-2.66 and 1.76;95%CI:1.12-2.78, respectively).
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Conclusion
Animal exposure, and specifically dog exposure, in early adolescence was associated with an increased risk of MS. Further work is needed to confirm this finding.
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1 Introduction Multiple sclerosis (MS) is a chronic, inflammatory neurological disease affecting approximately 2.3 million individuals worldwide.[1] Several environmental exposures have been associated with an increased risk of MS, including infection with Epstein-Barr virus (EBV), low sunlight
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exposure or serum vitamin D levels and smoking.[2,3] Furthermore, it has been proposed that exposure to animals (kept as pets) may influence the risk of MS. For instance, exposure to animals who are prone to demyelinating diseases (e.g. German Shepherds) might be associated with an increased risk of MS.[4,5] Despite previous efforts, studies have shown conflicting
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results.[6-21] Several studies have shown that people living with MS were more often exposed to animals in the years before the onset compared to healthy controls or controls with other neurological diseases.[6-8,12,14,15,17,21] However, other studies have shown an inverse or no
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association between exposure to animals and the risk of developing MS.[9-11,13,16,18-20] In previous studies, it has been postulated that exposure to animals during infancy would be
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protective, whereas initial infection later in life (late childhood or adulthood) would result in a greater risk of developing MS.[2]
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To date, it is not clear whether there is an association between animal exposure and the risk of
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MS. Moreover, limited data on exposure to animals over specific ages and MS risk are available. We examined the association between exposure to animals and the risk of MS, with a focus on
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the timing of exposure, assessed across specific age groups.
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2 Materials and Methods 2.1 Study participants We conducted a case-control study within two large on going, prospective US cohorts, Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHS II), comprising a total of 238,371 female
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nurses. The NHS was established in 1976, and enrolled 121,700 nurses aged 30-55 years from 11 U.S. states who responded to a mailed questionnaire about disease history and lifestyle items. The NHS II was established in 1989, when 116,671 nurses aged 25-42 years from 14 states responded to a similar questionnaire. Every two years a follow-up questionnaire is mailed to the
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participants of both cohorts to update information on potential risk factors for chronic diseases and to assess major clinical events, including MS. People with MS were confirmed by either the treating or study neurologist who reviewed their medical records.[22] Within both cohorts, there
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and study cohort (NHS or NHSII).
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was a set of 183 incident MS cases and 438 controls without MS matched by age at cohort entry
2.2 Assessment of animal exposure
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In the years 2012-13, cases and controls were invited to participate in an additional study on ‘the
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effect of environmental and personal exposures on the risk of developing [either] MS [for MS cases]/or chronic diseases [for healthy controls]’ using a pre-piloted questionnaire [23] adapted
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for MS and to include animal exposures. Up to two reminders were sent to the participants. Questions about animals (kept as pets) were asked over specific ages (categorised into five-year age groups from 0-4 to 20-24 years, then every ten-years to <45 years), and by type (family) of animal (e.g. dog, cat) and dog breed, with free-text responses allowed. Initially ‘any’ animal exposure was examined prior to MS onset (i.e. the index date), then by animal family, grouped as
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dog, cat, rabbit, guinea pig, or bird, and by dog breed which was grouped as Cocker Spaniel, German Shepherd, Golden Retriever, or Labrador Retriever. Timing of exposure was considered by the study participants age, for ‘any’ animal exposure, and for the two most common family groups (dog and cat). For the years of animal exposure before MS onset, a case’s data were only
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included if MS onset had yet to be reached, e.g., the age group 15-19 only included those yet to develop MS, along with their matched controls.
2.3 Assessment of covariates
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Covariate information was obtained from the biennial questionnaires completed by all nurses in the cohorts and included ancestry (grouped as: Scandinavian; Southern European; all other Caucasians; other ethnic groups);[17] latitude of residence at age 15 (North, Middle, South);[24]
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body mass index (BMI) at age 18;[25] smoking status (ever vs. never);[26] supplemental intake
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2.4 Statistical analyses
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of vitamin D (nil, >nil<400, ≥400IU/day).[27]
From 621 women (183 incident MS cases and 438 matched controls) contacted, 90% (n=556)
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completed the ‘environmental’ questionnaire. Of the 167 MS cases, 16 cases had no matched control which resulted in 151 MS cases included in the analyses. Of the 151 MS cases, 84 had
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two matched controls and 67 had one. We assessed the association between exposure to ‘any’ animals or at specific age categories and MS risk, using conditional logistic regression, with findings reported as adjusted relative risks (RRs) and the corresponding 95% confidence intervals (CIs). We included cases with at least one age- and study cohort-matched control (‘Model 1’). In addition, models were adjusted for ancestry, smoking, supplemental vitamin D
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intake, tier of residence at age 15, and BMI at age 18 (‘Model 2’, see covariates above). Among women (120 cases and 170 controls) reporting having dogs as pets, we also examined whether exposure to specific dog breeds was associated with MS risk, using an unconditional logistic regression including the matching variables, in order to make best use of all the available data
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related to dog breeds.
One prior study (conducted in 1998) also examined the association between animal exposure (cat or dog) and MS risk using the NHS/NHSII cohorts.[17] Although our current study was designed to address broader issues related to animal exposure and over 60% of our cohort (69 cases and
those women unique to our current study.
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167 controls) had not been studied previously, we conducted a complementary analysis including
All the analyses were conducted using SAS V9.3 (SAS Institute Inc, Cary, N.C.). The study was
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approved by the Institutional Review Board of Brigham and Women’s Hospital. Return of the
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completed questionnaire was considered consent for participating in this sub-study.
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3 Results The mean MS onset age was 39.5 years (SD 8.9) and the majority developed MS by age 45 years (n=115; 76%). Characteristics are shown in Table 1.
Characteristics
Controls N=235 36.2 (4.5)
27 (17.9) 6 (4.0) 98 (64.9) 18 (11.9) 2 (1.3)
40 (17.0) 20 (8.5) 145 (61.7) 25 (10.6) 5 (2.1)
71 (47.0) 58 (38.4) 13 (8.6) 9 (6.0)
84 (35.7) 118 (50.2) 24 (10.2) 9 (3.8)
70 (46.4) 81 (53.6) 21.8 (3.2)
100 (42.6) 135 (57.4) 21.1 (2.8)
83 (55.0) 16 (10.6) 29 (19.2) 23 (15.2)
128 (54.5) 42 (17.9) 48 (20.4) 17 (7.2)
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Age at baseline* (years), mean SD) Age at MS onset (years), mean SD) Ancestry, N (%) South European ancestry Scandinavian ancestry All other Caucasians Other ethnic ancestries Missing Tier of residence at age 15, N (%) North Middle South Missing Ever smoked at baseline, N (%) Yes No Body mass index at age 18 (kg/m2), mean (SD) Supplemental vitamin D intake at baseline, N (%) Nil >nil<400IU/day ≥400IU/day Missing MS: multiple sclerosis; SD: standard deviation;
MS cases N=151 36.0 (4.5) 39.5 (8.9)
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Table 1. Characteristics of the MS patients (cases) and controls nested within the Nurses’ Health Studies
*
Baseline: the date of entry into the NHS or NHSII
Among the women with MS, 136 (90.1%) reported exposure to an animal prior to MS onset as compared with 200 (85.1%) of their matched controls. No significant association was observed
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between animal exposure and MS risk (adjusted RR (model 2): 1.52 (95% CI, 0.76-3.04); p=0.24), Table 2. When specified by animal family, neither exposure to dogs, cats, guinea pigs
Table 2. Associations between animal exposure and risk of MS MS cases N (%) N=151
Controls N (%) N=235
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nor birds were associated with risk of MS (see Table 2).
RR (95% CI), p-value
RR (95% CI), p-value
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Model 1 Model 2 Exposure to animals before the index date Any pet Not exposed 15 (9.9) 35 (14.9) Reference reference Exposed 136 (90.1) 200 (85.1) 1.55 (0.81 – 2.96), 0.18 1.52 (0.76 – 3.04), 0.24 Dog Not exposed 31 (20.5) 65 (27.7) Reference reference Exposed 120 (79.5) 170 (72.3) 1.38 (0.85 – 2.24), 0.19 1.34 (0.80 – 2.25), 0.27 Cat Not exposed 65 (43.1) 111 (47.2) Reference reference Exposed 86 (56.9) 124 (52.8) 1.16 (0.77 – 1.77), 0.48 1.34 (0.84 – 2.15), 0.22 Rabbit Not exposed 129 (85.4) 194 (82.5) Reference reference Exposed 22 (14.6) 41 (17.5) 0.83 (0.48 – 1.43), 0.50 0.88 (0.49 – 1.61), 0.68 Guinea pig Not exposed 133 (88.1) 211 (89.8) Reference reference Exposed 18 (11.9) 24 (10.2) 1.14 (0.59 – 2.22), 0.69 1.26 (0.61 – 2.61), 0.54 Bird Not exposed 128 (84.8) 206 (87.7) Reference reference Exposed 23 (15.2) 29 (12.3) 1.33 (0.72 – 2.45), 0.37 1.54 (0.78 – 3.03), 0.22 Other pet† Not exposed 126 (83.4) 189 (80.4) Reference reference Exposed 25 (16.6) 46 (19.6) 0.82 (0.47 – 1.43), 0.49 0.95 (0.51 – 1.76), 0.87 Adjustments: Model 1: age and nurses’ health study cohort (NHS or NHSII), as used in the matching process Model 2: as for model 1, in addition: ancestry, ever smoked, supplemental vitamin D intake, tier of residence at age 15 and body mass index at age 18. † Example of other pets: rodents (excluding guinea pig), reptiles, spiders, ferrets.
When the timing of animal exposure was explored (Table 3), early adolescence (age 10-14 years) emerged as a potentially important time period, with exposure to ‘any’ animal, as well as 11
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specifically to dogs, being associated with a 67% and 76% increased risk of developing MS, respectively (fully adjusted RR (model 2): 1.67 (95% CI, 1.05-2.66); p=0.03 and 1.76 (95% CI, 1.12-2.78); p=0.01), see Table 3. While exposure to ‘any’ animal in those aged 35-44 years was associated with a decreased risk of MS, fewer individuals were still ‘at risk’ of developing MS
adjusted RR (model 2): 0.24 (95% CI, 0.06-0.89); p=0.03).
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by this age category, and consequently the 95% confidence intervals were relatively wide (fully
Using a multivariable unconditional logistic regression model adjusted for matching factors, exposure to Cocker Spaniels at any age was associated with an increased risk of MS: 2.56 (95%
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CI, 1.31-5.01); p=0.006. No associations were found between exposure to Cocker Spaniels or other specific dog breeds at age 10-14 years.
Table 3. Associations between animal exposure and risk of MS by age
Exposure to animals before the index date
0 to 4 years
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5 to 9 years
Any pet Not exposed Exposed Dog Not exposed Exposed Cat
RR (95% CI), p-value
RR (95% CI), p-value
Model 1
Model 2*
N=151
N=235
100 (66.2) 51 (33.8)
158 (67.2) 77 (32.8)
reference reference 1.07 (0.69 – 1.66), 0.77 1.25 (0.78 – 2.01), 0.35
114 (75.5) 37 (24.5)
176 (74.9) 59 (25.1)
reference reference 0.99 (0.61 – 1.61), 0.97 1.14 (0.68 – 1.93), 0.61
133 (88.1) 18 (11.9) N=151
208 (88.5) 27 (11.5) N=235
reference reference 1.00 (0.53 – 1.87), 1.00 1.37 (0.70 – 2.71), 0.36
71 (47.0) 80 (53.0)
108 (46.0) 127 (54.0)
reference reference 0.98 (0.65 – 1.47), 0.92 1.09 (0.70 – 1.71), 0.70
89 (58.9) 62 (41.1)
146 (62.1) 89 (37.9)
reference reference 1.13 (0.75 – 1.69), 0.56 1.11 (0.71 – 1.74), 0.63
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Any pet Not exposed Exposed Dog Not exposed Exposed Cat Not exposed Exposed
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Age group
Controls N, (%)
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MS Cases N, (%)
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Any pet Not exposed Exposed Dog Not exposed Exposed Cat Not exposed Exposed 20 to 24 years
107 (45.5) 128 (54.5)
reference reference 1.55 (1.01 – 2.37), 0.04 1.67 (1.05 – 2.66), 0.03
68 (45.0) 83 (55.0)
137 (58.3) 98 (41.7)
reference reference 1.66 (1.10 – 2.52), 0.02 1.76 (1.12 – 2.78), 0.01
110 (72.9) 41 (27.1) N=150
179 (76.2) 56 (23.8) N=233
reference reference 1.18 (0.75 – 1.86), 0.48 1.43 (0.85 – 2.39), 0.17
81 (54.0) 69 (46.0)
116 (49.8) 117 (50.2)
reference reference 0.81 (0.53 – 1.25), 0.35 0.83 (0.52 – 1.33), 0.43
91 (60.7) 59 (39.3)
147 (63.1) 86 (36.9)
reference reference 1.04 (0.68 – 1.58), 0.86 1.04 (0.65 – 1.64), 0.88
123 (82.0) 27 (18.0) N=143
181 (77.7) 52 (22.3) N=222
reference reference 0.78 (0.47 – 1.29), 0.33 0.99 (0.56 – 1.76), 0.97
82 (57.3) 61 (42.7)
127 (57.2) 95 (42.8)
reference reference 0.95 (0.62 – 1.47), 0.83 0.89 (0.55 – 1.43), 0.62
98 (68.5) 45 (31.5)
166 (74.8) 56 (25.2)
reference reference 1.35 (0.85 – 2.16), 0.20 1.25 (0.75 – 2.10), 0.39
117 (81.8) 26 (18.2) N=106
170 (76.6) 52 (23.4) N=165
reference reference 0.72 (0.43 – 1.21), 0.21 0.65 (0.36 – 1.15), 0.14
35 (33.0) 71 (67.0)
63 (38.2) 102 (61.8)
reference reference 1.31 (0.79 – 2.18), 0.29 1.26 (0.72 – 2.19), 0.43
59 (55.7) 47 (44.3)
94 (57.0) 71 (43.0)
reference reference 1.13 (0.66 – 1.92), 0.65 1.13 (0.63 – 2.04), 0.68
70 (66.0)
115 (69.7)
reference
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25 to 34 years
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Any pet Not exposed Exposed Dog Not exposed Exposed Cat Not exposed Exposed
54 (35.8) 97 (64.2)
Any pet Not exposed Exposed Dog Not exposed Exposed Cat Not exposed
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15 to 19 years
reference reference 0.97 (0.59 – 1.60), 0.90 1.24 (0.71 – 2.17), 0.45
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Any pet Not exposed Exposed Dog Not exposed Exposed Cat Not exposed Exposed
183 (77.9) 52 (22.1) N=235
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118 (78.2) 33 (21.8) N=151
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36 (34.0) N=41
35 to 44 years
50 (30.3) N=69
1.19 (0.70 – 2.03), 0.53 1.03 (0.57 – 1.88), 0.91
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Any pet Not exposed 16 (39.0) 13 (18.8) reference reference Exposed 25 (61.0) 56 (81.2) 0.41 (0.18 – 0.95), 0.04 0.24 (0.06 – 0.89), 0.03 Dog Not exposed 21 (51.2) 28 (41.0) reference reference Exposed 20 (48.8) 41 (59.4) 0.65 (0.31 – 1.38), 0.26 0.85 (0.31 – 2.34), 0.75 Cat Not exposed 24 (58.5) 42 (60.9) reference reference Exposed 17 (41.5) 27 (39.1) 1.08 (0.51 – 2.30), 0.85 0.84 (0.27 – 2.62), 0.76 Adjustments: Model 1: age and nurses’ health study cohort (NHS or NHSII), as used in the matching process Model 2: as for model 1, in addition: ancestry, ever smoked, supplemental vitamin D intake, tier of residence at age 15 and body mass index at age 18.
In the complementary analysis, focused on women who were not part of a prior study,[17] did not materially change the effect estimate, though it was no longer statistically significant (‘any’
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dog exposure and dog exposure at age 10-14: 1.16 (0.56-2.41); p=0.70 and 1.67 (0.90-3.12);
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p=0.11). No association was found for ‘any’ cat exposure, consistent with the previous
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4 Discussion We found no association between overall animal exposure and the risk of developing MS. However, exposure to ‘any’ animal and specifically to dogs in early adolescence was associated
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with a nearly 1.7-fold increased risk of developing MS.
Results from previous case-control studies of animal exposure on MS risk have been mixed.[621] Some studies have concurred with ours, by reporting no association between ‘any’ animal exposure and MS risk,[9-11,13,18,19] or by showing that dog exposure is associated with an
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increased risk of MS.[6-8,12,15,17] However, only five of these studies were able to consider the timing of exposure.[9,11,17,19,21] First contact with a dog during adolescence and adulthood (age 15+ years) was associated with a 70% increased risk of MS in the USA NHS/NHS II
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cohorts.[17] While there was some overlap in participants between our study and this prior work,[17] over 60% of our participants were unique and excluding women contributing to both
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studies did not change the direction of findings. We also extended previous work through a more detailed and dynamic exploration of animal exposure and MS risk. We were able to consider the
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participants age when the animal exposure occurred (up to age 45 years) and also include a wider
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array of animals and specific dog breeds and the risk of MS.
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Other studies with exposure to animals across age categories found no associations with MS risk.[9,11,19,21] Two of the studies had modest sample sizes (fewer than 75 MS cases and 75 controls) which may have limited the ability to detect an effect.[9,11] The other two studies [19,21] used either different or broader age categories which may have obscured any associations
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in some instances (exposure at 10-14 in the current study vs. 6-16 years [19] or exposure before 6, 10, 15 or 20 years and during puberty (age 12-18 years)[21]).
Three other studies found a significant association with birds kept as pets and increased risk of
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MS;[12,14,16] however, relatively few of our participants (13.5%) reported bird ownership. Thus, our study may have been underpowered to detect a true association between bird exposure and the risk of MS.
One population-based study reported an increased risk of MS associated with cat exposure
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during puberty [21] whereas no such association was observed in our study. Further, two studies reported a lower risk of MS in relation to animal exposure and for cat exposure specifically, although none examined the timing of exposure at specific age groups.[16,20] While we also
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found ‘any’ animal exposure associated with a lower risk, this was for those aged 35-44 years only. This finding should be interpreted with caution as there was a small samples size in this
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delayed diagnosis of MS.
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group and may be due to reverse causation since this age category might include patients with a
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The underlying mechanism by which exposure to animals, and dogs in particular, may alter the risk of MS is unclear. The role of animals in altering levels of microorganisms and endotoxins
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individuals are exposed to, or in shaping the human microbiota (especially for dog owners),[2830] could be postulated to alter MS risk, but to date there has been no conclusive evidence. While some have suggested a link between Canine Distemper Virus (CDV) infections and MS,[4,5,26] this remains largely unconfirmed. Additionally, the common practice to vaccinate dogs against CVD combined with no apparent decrease in MS incidence has further diminished this
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concern.[27,28] Our lack of association with German Shepherds or other large breed dogs (Golden Retriever and Labrador Retriever), and MS risk, perhaps also provides some reassurances to owners of these animals in context of prior concerns raised over degenerative myelopathy,[4,5] a disease similar to MS. Although we found a potential relationship with the
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Cocker Spaniel and MS risk, no other studies have reported an association. As our risk estimate had wide confidence intervals, a chance finding is possible, and this result needs confirmation and should be interpreted cautiously.
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Our study has several strengths. Compared with the previous work,[6-16,18-20,21] we assessed MS risk related to animal exposure using two large, well-defined cohorts. This minimizes selection bias since cases and controls were sourced from the same broader population. We also
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had a high response rate to our questionnaire, and were able to assess animal exposure by participants’ age at exposure as well as by animal family and dog breed. This allowed us to
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examine exposure over childhood and adolescence, considered potentially etiologically relevant time periods in modulating future MS risk. However, exposure to animals was collected
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retrospectively, and we cannot rule out that recall bias may have influenced our self-reported
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data, although it seems unlikely that women with MS would differentially report their exposure to animals, and dogs in particular, during their adolescent years. Further, the questions about
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animal exposure were embedded with other unrelated environmental exposures as to minimize the participants’ awareness of the specific study objectives. This approach may help minimize reporting bias.[31] While we did adjust for latitude of residence at age 15, we were not able to adjust for rural versus urban classification of residence. While the nature of the association between type of residence and risk of MS is unclear, if type of pet ownership varies between
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rural versus urban settings, there may be some residual confounding. We had access to prospectively collected data on rich set of other potential confounders from the NHS and NHSII, and were able to adjust for many of the known risk factors for MS. 5 Conclusions
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In conclusion, we found no association between overall animal exposure and MS risk. However, in early adolescence, exposure to dogs was associated with an increased risk of MS. However, further research in larger studies is needed to confirm the age-dependence of this finding.
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Acknowledgements
We thank Leslie Unger and Allison Gordon for data cleaning and entry and Thomas Duggan for
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facilitating with data coding.
Funding
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This work was supported by the Martha Piper Research Fund, University of British Columbia, Canada and the US National Institutes of Health [grant numbers UM1 CA186107 and UM1
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CA176726]. The funder had no role in study design; in the collection, analysis and interpretation
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of data; in the writing of the report; and in the decision to submit the article for publication.
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