Level of education and multiple sclerosis risk over a 50-year period: Registry-based sibling study

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1 646863MSJ / Multiple Sclerosis JournlK Bjørnevik, T Riise reserch-rticle2016 MULTIPLE SCLEROSIS JOURNAL MSJ Originl Reserch Pper Level of eduction nd multiple sclerosis risk over 50-yer period: Registry-bsed sibling study Kjetil Bjørnevik, Trond Riise, Espen Benjminsen, Elisbeth G Celius, Ole P Dhl, Mrgitt T Kmpmn, Kristin I Løken-Amsrud, Rune Midgrd, Kjell-Morten Myhr, Øivind Torkildsen, Anit Vtne nd Nin Grytten Abstrct Bckground: The conflicting results from studies on socioeconomic sttus (SES) nd multiple sclerosis (MS) risk might be due to chnge in the distribution of environmentl exposures over time or to methodologicl limittions in previous reserch. Objective: To exmine the ssocition between SES nd MS risk during 50 yers. Methods: We included ptients registered in Norwegin MS registries nd prevlence studies born between 1930 nd 1979, nd identified their siblings nd prents using the Norwegin Popultion Registry. Informtion on eduction ws retrieved from the Ntionl Eduction Registry, ctegorized into four levels (primry, secondry, undergrdute nd grdute) nd compred in ptients nd siblings using conditionl logistic regression. Results: A totl of 4494 MS ptients nd 9193 of their siblings were included in the nlyses. Level of eduction ws inversely ssocited with MS risk (p trend < 0.001) with n odds rtio (OR) of 0.73 (95% confidence intervl (CI): ) when compring the highest nd lowest levels. The effect estimtes did not vry mrkedly between prticipnts born before or fter the medin yer of birth (1958), but we observed significnt effect modifiction by prentl eduction (p = 0.047). Conclusion: Level of eduction ws inversely ssocited with MS risk, nd the estimtes were similr in the erliest nd ltest birth cohorts. Keywords: Multiple sclerosis, epidemiology, risk fctors, socioeconomic sttus, eduction, environmentl risk fctors Dte received: 22 December 2015; revised: 17 Mrch 2016; ccepted: 5 April 2016 Introduction Multiple sclerosis (MS) is demyelinting disese of the centrl nervous system with unknown etiology, nd is one of few diseses, including some llergic nd utoimmune diseses, 1 tht hve been ssocited with higher socioeconomic sttus (SES). For MS, erly studies observed higher disese risk mong professionl workers thn in unskilled workers, which suggested tht exposures ssocited with higher SES incresed disese risk. 2,3 Similrly, Kurtzke nd Pge 4 observed positive ssocition between SES nd MS risk in lrge nested cse control study. More recent studies, however, hve not been ble to reproduce these findings, nd some hve rrived t opposite conclusions. 5 7 This could reflect chnge over time in the distribution of exposures relevnt for MS or country-specific differences in ccess to eduction nd ssocitions between eduction nd such exposures. Still, the heterogeneity observed could lso be due to methodologicl limittions in previous reserch. Severl studies hve used study designs tht re prone to selection nd recll bis, which my hve contributed to the pprently conflicting results. To ddress this, we conducted lrge popultionbsed study using ntionl registries to collect objective nd relible informtion on level of completed eduction, vlid mrker of SES, 8 on close to 4500 Multiple Sclerosis Journl 2017, Vol. 23(2) DOI: / The Author(s), Reprints nd permissions: journlspermissions.nv Correspondence to: K Bjørnevik Deprtment of Globl Public Helth nd Primry Cre, University of Bergen, Klfrveien 31, Bergen 5020, Norwy. kjetil.bjornevik@uib.no Kjetil Bjørnevik Trond Riise Deprtment of Globl Public Helth nd Primry Cre, University of Bergen, Bergen, Norwy/The Norwegin Multiple Sclerosis Competence Center, Hukelnd University Hospitl, Bergen, Norwy Espen Benjminsen Nordlnd Hospitl Trust, Bodø, Norwy Elisbeth G Celius Oslo University Hospitl, Ullevål, Oslo, Norwy/ Institute of Helth nd Society, Fculty of Medicine, University of Oslo, Oslo, Norwy Ole P Dhl Nmsos Hospitl, Nmsos, Norwy Mrgitt T Kmpmn University Hospitl of North Norwy, Tromsø, Norwy Kristin I Løken-Amsrud Innlndet Hospitl Trust, Lillehmmer, Norwy Rune Midgrd Molde Hospitl, Molde, Norwy/Unit for Applied Clinicl Reserch, Norwegin University of Science nd Technology, Trondheim, Norwy Kjell-Morten Myhr The Kristin Gerhrd Jebsen Centre for MS Reserch, Deprtment of Clinicl Medicine, University of Bergen, Bergen, Norwy/The Norwegin Multiple Sclerosis Registry nd Biobnk, Hukelnd University Hospitl, Bergen, Norwy journls.sgepub.com/home/msj 213

2 Multiple Sclerosis Journl 23(2) Øivind Torkildsen Nin Grytten The Norwegin Multiple Sclerosis Competence Center, Hukelnd University Hospitl, Bergen, Norwy/ The Kristin Gerhrd Jebsen Centre for MS Reserch, Deprtment of Clinicl Medicine, University of Bergen, Bergen, Norwy Anit Vtne Sørlndet Hospitl Kristinsnd, Kristinsnd, Norwy MS ptients, their siblings nd their prents over period of 50 yers. Methods Study popultion nd design We used The Norwegin MS Registry 9 s the primry source to identify MS ptients. This registry ws estblished in 2001, enrols MS ptients in ll of Norwy nd currently includes close to 6000 ptients, which corresponds to pproximtely 60% of ll MS ptients in Norwy. We further used the Oslo MS Registry, 10 registry tht ws estblished in 1990, which enrols MS ptients living in Oslo nd included pproximtely 1200 MS ptients who were not registered in the ntionl MS registry t the time of dt extrction. Moreover, vilble prevlence nd hospitl record studies were used to identify ptients not registered in the registries, s described in previous studies using the sme cohort of ptients. 16,17 All ptients hd been dignosed ccording to the criteri of Poser et l. 18 or McDonld 19 nd were born between 1930 nd In totl, the cohort included 6928 MS ptients. Identified ptients were linked to the Norwegin Popultion registry (Sttistics Norwy). This registry ws estblished in 1964 nd includes ntionl identifiction numbers for the totl Norwegin popultion live since We used the ptients identifiction number to retrieve informtion on sex nd birth yer of their unffected siblings nd prents. A totl of 9346 siblings without MS, 5711 mothers nd 5611 fthers were identified nd included in the cohort. The number of siblings per MS ptients rnged from 1 to 13. The siblings were included s controls, while the prents were included in nlyses of effect modifiction. The ntionl identifiction numbers of ll study prticipnts were then linked to the Ntionl Eduction Registry, nd informtion on levels of completed eduction ws retrieved for ll prticipnts for whom this informtion ws vilble. This registry ws estblished in 1970 nd contins informtion on the highest level of completed eduction on the totl Norwegin popultion live on or fter this yer. 21 Use of the ntionl identifiction number ensured tht no prticipnt ws included more thn once. Due to the dependency between the cses nd controls in our study, the eductionl level of ech MS cse ws compred to the level of their own siblings. Thus, ptients with no siblings were excluded from the nlyses. A totl of 4502 MS ptients hd one or more siblings. Among those, informtion on completed eduction ws vilble for 4494 ptients. Eductionl level ws vilble for 9193 of the siblings. In the fmilies tht were included in the nlyses, eductionl level ws vilble for 4297 of the fthers nd 4384 of the mothers. Prentl eduction from t lest one of the prents ws vilble for 4429 of these fmilies. Sttisticl nlysis Ctegories for highest level of completed eduction were generted bsed on the informtion provided by the Ntionl Eduction Registry. The new vrible took vlue 1 for primry level (10 yers or less), 2 for secondry level (11 13 yers), 3 for undergrdute level (14 17 yers) nd 4 for grdute level (18 yers or more). A vrible tht combined prentl eduction ws generted, nd it took level 1 if t lest one of the prents hd higher eduction nd 0 otherwise. Higher eduction ws defined s undergrdute nd grdute levels. The ssocition between disese nd exposure ws estimted s odds rtios (OR) with 95% confidence intervls (CIs) mtching the cses with their siblings using conditionl logistic regression. Level of eduction ws included s ctegoricl vrible in this model, nd we compred the different levels of eduction to the reference level, which ws the lowest level. As we re using conditionl regression model compring cses with their own siblings, the nlyses re djusted for prentl eduction nd fmily size by design. In multivrite model, we djusted for birth order (1, 2, 3 nd >3) nd residency t birth (North nd South). North ws defined s one of the three most Northern counties in Norwy (Nordlnd, Troms nd Finmrk) nd South ws defined s ny of the other counties. We tested for interction on the multiplictive scle by introducing n interction term into the regression model. Specificlly, we tested for interction between level of eduction nd sex, prentl eduction nd time periods for yer of births. The time periods included birth yers before nd fter 1958, which ws the medin birth yer for the prticipnts. We tested for p trend by including level of eduction s continuous vrible in the model. All nlyses were djusted for sex nd ge in 5-yer intervls. The sttisticl nlyses were performed in Stt Sttisticl Softwre: Relese 14. College Sttion, TX: SttCorp Ethicl pprovl The study ws pproved by the Regionl Committee for Medicl nd Helth Reserch Ethics (REK Nord). 214 journls.sgepub.com/home/msj

3 K Bjørnevik, T Riise et l. Tble 1. Bseline chrcteristics of the study popultion ccording to the level of eduction in lrge registry-bsed sibling study in Norwy. Primry Secondry Undergrdute Grdute Cses No. of prticipnts Yer of birth, men No. of siblings, men First born, % Femle, % Born in North tier, % Prents with higher eduction, b % Controls No. of prticipnts Yer of birth, men No. of siblings, men First born, % Femle, % Born in North tier, % Prents with higher eduction, b % Born in one of the three most Northern counties in Norwy (Nordlnd, Troms nd Finmrk). b Defined s t lest one prent with undergrdute or grdute level of eduction. Tble 2. Overll distribution of eductionl level mong MS ptients, their siblings nd their prents in lrge registrybsed sibling study in Norwy. Level of eduction Primry Secondry Undergrdute Grdute Missing Cses, % Fmily Siblings, % Mothers, % Fthers, % MS: multiple sclerosis. Missing vlues on level of eduction. Results Tble 1 provides the bseline chrcteristics of the study popultion ccording to the level of eduction. Those with highest level of eduction hd fewer siblings nd were more likely to be first born nd to hve prents with higher eduction. The overll distribution of level of eduction mong ptients, siblings nd prents is provided in Tble 2. We found sttisticlly significnt inverse ssocition between level of eduction nd risk of MS (p trend < 0.001; Tble 3). Prticipnts with the highest level of eduction hd lower MS risk compred to those with the lowest level (OR: 0.73, 95% CI: ). Undergrdute level of eduction ws lso significntly ssocited with lower MS risk (OR: 0.82, 95% CI: ). We observed significnt effect modifiction by prentl eduction (p = 0.047). The highest level of eduction ws significntly ssocited with decresed MS risk mong prticipnts who hd no prents with higher eduction (OR highest vs lowest level: 0.65, 95% CI: ; Tble 4), but not mong those with one or more prents with higher eduction (OR highest vs lowest level: 1.29, 95% CI: ; Tble 4). We further restricted the nlyses to those born before nd fter the medin yer of birth (1958), nd observed tht there ws only significnt effect modifiction by prentl eduction in the lst period journls.sgepub.com/home/msj 215

4 Multiple Sclerosis Journl 23(2) Tble 3. The OR of MS ccording to level of eduction in lrge registry-bsed sibling study in Norwy. No. of cses/controls OR (95% CI) Multivrite djusted b Multivrite djusted c Level of eduction Primry 1003/2104 Ref. Ref. Secondry 2186/ ( ) 0.96 ( ) Undergrdute 1050/ ( ) 0.82 ( ) Grdute 255/ ( ) 0.73 ( ) p trend <0.001 <0.001 MS: multiple sclerosis; OR: odds rtio; CI: confidence intervl. Effect estimtes clculted using conditionl logistic regression compring level of eduction in ptients with the level of their own siblings. b Adjusted for ge, sex, prentl eduction nd number of siblings. c Further djusted for birth order nd residency t birth. Tble 4. The OR of MS ccording to level of self-eduction nd prentl eduction in lrge registry-bsed sibling study in Norwy. Low prentl eduction High prentl eduction No. of cses/controls OR (95% CI) b No. of cses/controls OR (95% CI) b Level of eduction Primry 924/1959 Ref. 44/103 Ref. Secondry 1926/ ( ) 237/ ( ) Undergrdute 741/ ( ) 303/ ( ) Grdute 125/ ( ) 129/ ( ) p trend < MS: multiple sclerosis; OR: odds rtio; CI: confidence intervl. Defined s t lest one prent with undergrdute or grdute level of eduction. b Effect estimtes clculted using conditionl logistic regression compring level of eduction in ptients with the level of their own siblings. All estimtes re djusted for ge, sex nd number of siblings. (p = 0.006). There ws no significnt difference between women (OR highest vs lowest level: 0.61, 95% CI: ) nd men (OR highest vs lowest level: 0.81, 95% CI: ) (p for effect modifiction = 0.36). Similrly, there ws no significnt difference between those born before 1958 (OR highest vs lowest level: 0.72, 95% CI: ; Tble 5) nd fter 1958 (OR highest vs lowest level: 0.84, 95% CI: ), (p for effect modifiction = 0.49). Discussion We observed tht the level of completed eduction ws inversely ssocited with MS risk in Norwy. The ssocition did not vry significntly during the study period of 50 yers. Our finding of n inverse reltionship between level of eduction nd MS risk is consistent with severl recent studies. A lrge Norwegin prospective study with close to 400,000 prticipnts observed higher MS risk mong the prticipnts with lowest level of eduction. 5 These findings were lter replicted by two cse control studies from the United Sttes nd Norwy. 6,7 Our observtions suggest tht currently unknown exposures re driving the ssocition between eduction nd MS. The prevlence of smoking hs declined substntilly over the study period, nd the distribution of the hbit cross levels of SES hs chnged. In the 1950s, the mjority of Norwegin doctors were smokers, 22 while smoking is primrily hbit ssocited with lower SES tody. Thus, if smoking were driving the ssocition, we would expect to observe differences between ptients born before nd fter Furthermore, lte primry infection of Epstein Brr virus (EBV), which increses the risk of infectious 216 journls.sgepub.com/home/msj

5 K Bjørnevik, T Riise et l. Tble 5. The OR of MS ccording to time period of birth in lrge registry-bsed sibling study in Norwy. Born in or before 1958 Born fter 1958 No. of cses/controls OR (95% CI) No. of cses/controls OR (95% CI) Level of eduction Primry 459/976 Ref. 544/1128 Ref. Secondry 1082/ ( ) 1104/ ( ) Undergrdute 386/ ( ) 664/ ( ) Grdute 89/ ( ) 166/ ( ) p trend MS: multiple sclerosis; OR: odds rtio; CI: confidence intervl. Effect estimtes clculted using conditionl logistic regression compring level of eduction in ptients with the level of their own siblings. All estimtes re djusted for ge, sex, prentl eduction nd number of siblings. mononucleosis (IM), 23 is ssocited with higher SES 24 nd cn therefore not explin our observtions. Two recent studies observed n inverse ssocition between eduction nd MS tht persisted fter djustment for currently known risk fctors, 6,7 which is consistent with our findings. Sibling studies re prone to overmtching s siblings shre substntil mount of both genetic nd environmentl exposures, which reduce the power to detect differences between cses nd controls. This dds weight to our findings, s we still observe significnt ssocition between eduction nd MS. Since siblings re likely to shre fewer exposures the older they get, our findings could suggest tht eduction is mrker of n exposure in or fter the dolescence. This is consistent with studies on other known risk fctors, including vitmin D 25 nd EBV, 26 which hve observed tht exposure during dolescence my be especilly importnt for future MS risk. It hs recently been suggested tht sodium intke 27 nd the intestinl microbiome 28 could be relevnt for lter MS risk. Although these suggestions re minly bsed on niml studies, both these fctors could be ssocited with SES nd provide biologiclly plusible pthwys for subsequently ltered MS risk. Furthermore, low SES itself hs lso been ssocited with incresed proinflmmtory signlling, including higher levels of the proinflmmtory cytokine interleukin 6 (IL-6), 29 which is likely to be importnt for the development of utoimmune diseses. 30 We observed significnt effect modifiction by prentl eduction. While there ws n inverse ssocition between eduction nd MS risk mong those with prents with lower levels of eduction, there ws no significnt ssocition in fmilies with higher prentl eduction. This could reflect erly life exposures ssocited with higher SES tht compete with other risk fctors lter in life tht re ssocited with lower SES. A lrge Dnish cohort study reported lower MS risk mong children of mothers with higher eduction, but this study investigted the ssocition between cses nd unrelted controls. 31 Moreover, cse control study in Northern Cliforni reported tht both low prentl nd low self-eduction were ssocited with higher MS risk. 6 Overll, this could suggest tht both childhood nd dulthood SES re importnt for subsequent MS risk. Our study ws not powered to test for effect modifiction of the eduction level of mothers nd fthers seprtely. The use of ntionl registries for exposure informtion is strength in this study, s we re not relying on reclled or self-reported informtion. Furthermore, s the registries contin informtion on the entire Norwegin popultion, we hve complete informtion on ll siblings of the ptients. This is importnt for the vlidity of the findings, s studies on eduction nd disese re especilly prone to bis when there is low prticiption rte mong the prticipnts. The likelihood of greeing to tke prt in study is ffected by the eductionl level of those invited, 32 which could induce selection of highly educted prticipnts into the study, especilly in the less-motivted control group in cse control study design. Furthermore, nother strength of this study is tht ccess to eduction ws grdully eqully distributed over the study period by the government gency, The Norwegin Stte Eductionl Lon Fund, thus providing universlly covered nd equl finncil ccess to eduction. Our study hs some limittions. First, we hd no informtion on relevnt environmentl exposures, like smoking, nd re thus not ble to djust for this in the nlysis. Still, our findings re consistent with two journls.sgepub.com/home/msj 217

6 Multiple Sclerosis Journl 23(2) recent studies tht were ble to djust for these. 6,7 Second, s we did not hve ccess to yer of MS onset, our results could be ffected by reverse cuslity. If ptient hs n erly onset of disese, it could ffect their bility tke prt in higher eduction, s cognitive impirment is common erly in the course of the disese. 33 However, erly onset of disese did not seem to drive the ssocition between eduction nd MS in previous studies. 6,7 Furthermore, we observed similr ssocition with undergrdute level of eduction, which mkes it unlikely tht reverse cuslity cn fully explin our findings. Lstly, we cnnot exclude the possibility tht some prticipnts died before the eductionl registry ws estblished, which would led to misclssifiction of their eductionl level. Still, we observed similr results in both time periods exmined, which mkes it unlikely tht this potentil misclssifiction ply mjor role in the results. In conclusion, we observed n inverse ssocition between level of completed eduction nd MS risk tht persisted over the whole study period of 50 yers in Norwy. This suggests tht there hs not been shift in the direction of the ssocition in Norwy during this period. Declrtion of Conflicting Interests The uthor(s) declred the following potentil conflicts of interest with respect to the reserch, uthorship, nd/or publiction of this rticle: EG Celius hs received funding for trvel, dvice nd speker s fees from Snofi-Aventis, Merck-Serono, Genzyme, Biogen Idec, Roche, Tev, Almirll nd Novrtis, nd received unrestricted reserch support from Biogen Idec nd Novrtis. KM Myhr hs prticipted on scientific dvisory bords for Novrtis Norwy, Biogen Idec, Genzyme nd Roche; received funding for trvel from Allergn, Byer, Novrtis, Merck-Serono nd Biogen; received speker honorri from Allergn, Almirll, Byer, Biogen, Genzyme, Novrtis, Merck- Serono nd Tev; nd received unrestricted reserch support from Byer, Genzyme, Novrtis, Merck- Serono, Biogen, Pronov Biocre nd Bergen nd Norwegin MS Society. Ø Torkildsen hs served on scientific dvisory bords for Biogen Idec, Genzyme nd Merck-Serono nd received speker honorri nd trvel grnts from Genzyme, Merck-Serono, Novrtis nd Biogen Idec. Funding The uthor(s) received no finncil support for the reserch, uthorship, nd/or publiction of this rticle. References 1. Bch JF. The effect of infections on susceptibility to utoimmune nd llergic diseses. N Engl J Med 2002; 347: Miller H, Ridley A nd Schpir K. Multiple sclerosis. A note on socil incidence. Br Med J 1960; 2: Russell WR. Multiple sclerosis: Occuption nd socil group t onset. Lncet 1971; 2: Kurtzke JF nd Pge WF. Epidemiology of multiple sclerosis in US veterns: VII. Risk fctors for MS. Neurology 1997; 48: Riise T, Kirkeleit J, Arseth JH, et l. Risk of MS is not ssocited with exposure to crude oil, but increses with low level of eduction. Mult Scler 2011; 17: Briggs FB, Acun BS, Shen L, et l. Adverse socioeconomic position during the life course is ssocited with multiple sclerosis. J Epidemiol Community Helth 2014; 68: Bjornevik K, Riise T, Cortese M, et l. Level of eduction nd multiple sclerosis risk fter djustment for known risk fctors: The EnvIMS study. Mult Scler 2016; 22: Shvers VL. Mesurement of socioeconomic sttus in helth disprities reserch. J Ntl Med Assoc 2007; 99: Myhr KM, Grytten N, Torkildsen O, et l. The Norwegin Multiple Sclerosis Registry nd Biobnk. Act Neurol Scnd Suppl 2015; 132: Celius EG nd Smestd C. Chnge in sex rtio, disese course nd ge t dignosis in Oslo MS ptients through seven decdes. Act Neurol Scnd Suppl 2009; 189: Benjminsen E, Olvsen J, Krlberg M, et l. Multiple sclerosis in the fr north Incidence nd prevlence in Nordlnd County, Norwy, BMC Neurol 2014; 14: Dhl OP, Arseth JH, Myhr KM, et l. Multiple sclerosis in Nord-Trondelg County, Norwy: A prevlence nd incidence study. Act Neurol Scnd 2004; 109: Grytten N, Arseth JH, Lunde HM, et l. A 60-yer follow-up of the incidence nd prevlence of multiple sclerosis in Hordlnd County, Western Norwy. J Neurol Neurosurg Psychitry. Epub hed of print 24 Februry DOI: /jnnp Risberg G, Arseth JH, Nylnd H, et l. Prevlence nd incidence of multiple sclerosis in Opplnd County: A cross-sectionl popultion-bsed study in lndlocked county of Estern Norwy. Act Neurol Scnd 2011; 124: journls.sgepub.com/home/msj

7 K Bjørnevik, T Riise et l. 15. Vtne A, Myglnd A nd Ljostd U. Multiple sclerosis in Vest-Agder County, Norwy. Act Neurol Scnd 2011; 123: Kmpmn MT, Arseth JH, Grytten N, et l. Sex rtio of multiple sclerosis in persons born from 1930 to 1979 nd its reltion to ltitude in Norwy. J Neurol 2013; 260: Grytten N, Torkildsen O, Arseth JH, et l. Month of birth s ltitude-dependent risk fctor for multiple sclerosis in Norwy. Mult Scler 2013; 19: Poser CM, Pty DW, Scheinberg L, et l. New dignostic criteri for multiple sclerosis: Guidelines for reserch protocols. Ann Neurol 1983; 13: Polmn CH, Reingold SC, Edn G, et l. Dignostic criteri for multiple sclerosis: 2005 revisions to the McDonld Criteri. Ann Neurol 2005; 58: Furseth J nd Ljones O. 50-årsjubilnt med behov for oppgrdering. Smf/Stt sent 2015; 1: Vngen T. Nsjonl utdnningsdtbse NUDB. Dokumentsjonsrpport: dtvrehus for utdnningsdt, Stt sent 2007; 54: Aro LE, Bjrtveit K, Vellr OD, et l. Smoking hbits mong Norwegin doctors Scnd J Soc Med 1977; 5: Ascherio A, Munger KL nd Lunemnn JD. The initition nd prevention of multiple sclerosis. Nt Rev Neurol 2012; 8: Hjlgrim H, Friborg J nd Melbye M. The epidemiology of EBV nd its ssocition with mlignnt disese. In: Arvin A, Cmpdelli-Fiume G, Mocrski E, et l. (eds) Humn herpesviruses: biology, therpy, nd immunoprophylxis. Cmbridge: Cmbridge University Press, 2007, pp Cortese M, Riise T, Bjornevik K, et l. Timing of use of cod liver oil, vitmin D source, nd multiple sclerosis risk: The EnvIMS study. Mult Scler 2015; 21: Thcker EL, Mirzei F nd Ascherio A. Infectious mononucleosis nd risk for multiple sclerosis: A met-nlysis. Ann Neurol 2006; 59: Kleinewietfeld M, Mnzel A, Titze J, et l. Sodium chloride drives utoimmune disese by the induction of pthogenic TH17 cells. Nture 2013; 496: Berer K, Mues M, Koutrolos M, et l. Commensl microbiot nd myelin utontigen cooperte to trigger utoimmune demyelintion. Nture 2011; 479: Miller GE, Chen E, Fok AK, et l. Low erly-life socil clss leves biologicl residue mnifested by decresed glucocorticoid nd incresed proinflmmtory signling. Proc Ntl Acd Sci USA 2009; 106: Bettelli E, Crrier Y, Go W, et l. Reciprocl developmentl pthwys for the genertion of pthogenic effector TH17 nd regultory T cells. Nture 2006; 441: Nielsen NM, Jorgensen KT, Bger P, et l. Socioeconomic fctors in childhood nd the risk of multiple sclerosis. Am J Epidemiol 2013; 177: Sonne-Holm S, Sorensen TI, Jensen G, et l. Influence of ftness, intelligence, eduction nd sociodemogrphic fctors on response rte in helth survey. J Epidemiol Community Helth 1989; 43: Zipoli V, Goretti B, Hkiki B, et l. Cognitive impirment predicts conversion to multiple sclerosis in cliniclly isolted syndromes. Mult Scler 2010; 16: Visit SAGE journls online home/msj SAGE journls journls.sgepub.com/home/msj 219