- Email: [email protected]
The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis
NEUROL-2112; No. of Pages 4 revue neurologique xxx (2019) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Environmental Neurology
The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis D. Sadovnick a,b,* a b
Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, Canada Department of Medical Genetics, University of British Columbia, Vancouver, Canada
info article
abstract
Article history:
The relative roles of genes and environment (not intra-familial environment) and inter-
Received 3 April 2019
actions thereof continue to confound better understanding of the pathogenesis of multiple
Received in revised form
sclerosis (MS) and can also impact recurrence risks for family members as well as genetic
21 June 2019
family studies. Strong evidence for non-familial environmental factors is suggested by the
Accepted 13 July 2019
change in the sex ratio (female:male) of MS patients over the last four decades.
Available online xxx
# 2019 Published by Elsevier Masson SAS.
Keywords: Multiple sclerosis Genes Environment Recurrence risks Sex ratio
All subjects involved in the Canadian studies discussed here signed informed consents prior to inclusion and only deidentified data were used in analyses. The relative roles of genes and environment in the etiology of multiple sclerosis (MS) have long been a topic of debate as familial clustering has been noted for decades [1]–see Fig. 1 to illustrate familial clustering in MS. However, the first population-based study on the familial nature of multiple sclerosis was conducted at the MS Clinic at the University of British Columbia (UBC) and was published in 1988 [2]. MS patients attending the UBC MS Clinic in Vancouver had genetic histories taken as part of routine protocol at first visit (i.e. no selection bias based on family history of MS or any
other disease). These family histories were updated annually during routine clinical follow-ups. Initially, data were first available for 815 MS index cases and 11,345 of their biological relatives. Age-specific MS risks were calculated for first-degree relatives of MS index cases. In general, first-degree relatives of MS index cases (parents, siblings) had recurrence risks that were 30–50 times greater than the 0.1% risk for the general population. Note this was a relatively young population so accurate risks for children needed age-adjustment for remaining risk [2]. It is recognized that familial aggregation does not necessarily presume genetic sharing. Close biological relatives, especially siblings, often share similar familial environments
* Correspondence. University of British Columbia, S200-2211 Wesbrook Mall, Vancouver, BC V6T2B5, Canada. E-mail address: [email protected]. https://doi.org/10.1016/j.neurol.2019.08.003 0035-3787/# 2019 Published by Elsevier Masson SAS.
Please cite this article in press as: Sadovnick D. The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.08.003
NEUROL-2112; No. of Pages 4
2
revue neurologique xxx (2019) xxx–xxx
Fig. 1 – Familial aggregation of multiple sclerosis [4].
[e.g. diet, time spent outdoors in the sun, physical activity, quality of health care during childhood, exposure to or protection from specific viruses, smoking (second-hand exposure or actually smoking), etc.]. These data, while interesting, were based on a relatively small sample size and were limited to the population attending the UBC MS Clinic. Thus, there was a need for a larger population-based study. The Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS) was initiated with funding by the MS Society of Canada Scientific Research Foundation. Study design is described in detail in Sadovnick et al. [3]. Briefly, this Canada-wide study had many unique factors as outlined in Box 1. All Canadian MS Clinics were involved in case ascertainment and data collection. The CCPGSMS had five phases and clearly showed that both genes and environment were important in the etiology of MS. The study included more than 30,000 unique families ascertained and for whom data could be entered into the
Box 1. Unique characteristics of the CCPGSMS Living database (not static in one point in time) Longitudinal nature (e.g. maternal effect; prevalence changes) Ongoing contact with families & ability to update both clinically and with biological samples Family cooperation Clinical & molecular information on affected & unaffected, including various degrees of affected individuals & intervening relatives Spouse controls Sib controls Many individuals past ‘‘risk age range’’ for MS Ethnic diversity Essentially ‘‘equal access’’ to clinics thus wide range of socioeconomic status
CCPGSMS living database. The database included more than 8000 spouse controls for whom early life information could also be collected from the spouse’s mother. As well, there were more than 4000 unique families in which at least two persons were diagnosed with MS > 8000 with data on ‘‘spouse’’ controls; Specifically, CCPGSMS studies were designed to regulate genetic sharing (e.g. twins, adoptees) as well as environment, both familial and maternal versus paternal. A study of adoptees clearly showed that being raised from infancy in the same family environment with a non-biological sibling who developed MS did not increase the adoptees risk to develop MS over the general population [4] compared to biological siblings of individuals who develop MS. Adoptee recurrence risk for MS was the same as that for the general population. Similarly, a study of half-siblings of MS index cases [5] was done to identify the impact of reducing genetic sharing (50% for full siblings, 25% for half-siblings) as well as various environmental sharing (half-siblings raised apart compared to those raised together). The age-adjusted full-sibling risk was 3.11%. By contrast, half-sibling risk in the same families was significantly lower at 1.89% (P = 0.006), but higher than expected if familial risk was simply polygenic. For maternal half-siblings, the risk was 2.35% (34 affected siblings of 1859), and 1.31% for paternal half-siblings (15 of 1577), (P = 0.048). The difference in risk suggests a maternal parent-of-origin effect in multiple sclerosis susceptibility. This cannot be quantified and should not be taken in any way to infer that a ‘‘mother causes MS’’. The maternal effect has also been suggested by the CCPGSMS month of birth data [6]. Month of birth data were collected for 11,465 index cases with relapsing remitting (RRMS) or secondary progressive (SPMS). Month of birth was used as a surrogate for vitamin D levels during pregnancy [6]. Using May/November births as comparison ratios, data showed MS patients studied were more often born in May than November for a birth ratio of 1.43:1 compared to a birth ratio of 1.18 in population controls (P = 0.000032). Driving this difference is the nadir of births during November in the RRMS
Please cite this article in press as: Sadovnick D. The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.08.003
NEUROL-2112; No. of Pages 4 revue neurologique xxx (2019) xxx–xxx
group compared to the population control group (6.7 versus 7.7%, P = 0.000076). Thus, adoptee and half-sibling findings further indicate that a shared family environment does not account for the increased familial risk in MS among biological relatives. Nevertheless, this does not exclude environmental factors in general for the overall risk to develop MS. Twin studies clearly illustrated this point by showing that even in monozygotic female twins (females having a higher rate for MS than males (vide infra), MS concordance is only about 34% despite the excessive genetic sharing by monozygotic twins [7]. While genetic sharing remains important in familial MS and there are several ongoing approaches to try to identify genetic factors by studying populations [8] and multiplex families [9] there may even be a subgroup in which an autosomal gene is important [9], the majority of MS is still believed to represent an interaction of genes and environment [10]. Identification of these environmental factors is in progress. Candidates include vitamin D [11], Epstein Barr virus [12], smoking [13] and body mass index [14,15]. Further evidence for environmental risk factors comes from the observation in many regions that the sex ratio (female: male) of MS is increasing, especially in individuals born in the last four decades. Historically, it was only in the 1950s that the female preponderance in MS was recognized [16]. A review of 14 prevalence surveys undertaken before 1977 concluded that the sex ratio was 14:1 [17]. This sex ratio continued to increase and reached 2 females:1 male during the 1980s and 1990s [18,19]. For more detailed review, see Sadovnick [20]. Temporal changes in the female:male ratio of Canadian MS patients born since 1970 have been noted with the female:male ratio approaching 3:1 [21]. This increase has also been noted in other regions. Despite much speculation [22], the reason for this increase in female preponderance remains unknown. It is likely not genetics, given the short evolutionary period, and must reflect environmental changes. It is interesting to speculate what effect, if any, changes in the female:male ratio will have on family studies and risk counselling for families of people with MS. Empiric recurrence risks (RRs), based on observed data rather than theoretical models, are used in genetic counselling when the exact mode of inheritance is unknown, but biological relatives of affected individuals are at a higher risk compared with the general population. The UBC MS Clinic and the subsequent CCPGSMS remain the only resources to have systematically documented family history data (as previously discussed). See Table 1 for CCPGSMS recurrence risk data by genetic sharing.
Table 1 – Recurrence Risk of MS by Increasing Genetic (DNA) Sharing. General Population Adopted Sibs Step-sibs 1st cousin has MS (1/8 DNA sharing) Half sib (1/4 DNA sharing) Full sib has MS (1/2 DNA sharing) HLA identical sib has MS Sib has MS & consanguineous mating Parents represent conjugal MS pair Female MZ twin has MS (all genes in common)
2/1000 2/1000 2/1000 7/1000 1/1000 35/1000 80/1000 90/1000 300/1000 340/1000
3
These cohorts were largely born before 1970 when the sex ratio was about 2:1 (Table 1). These RRs became used for standard genetic counselling as well as the basis on which to conduct familial genetic studies in MS. Research is in progress to update RR data keeping in mind the changes to the female:male ratio. It is possible that within multiplex families, there may be MS individuals for whom the genetic and environmental loading varies with respect to the cause of the disease. This is well reflected in Alzheimer disease [23,24].
Funding The author is currently funded for research and travel by Biogen Idec and has received research funds from Novartis, Teva Neurosciences, and Novartis. Much of the Canadian work discussed in this paper was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation.
Disclosure of interest The author declares that he has no competing interest.
references
[1] Schapira K, Poskanzer DC, Miller H. Familial and conjugal multiple sclerosis. Brain 1963;86:315–32. [2] Sadovnick AD, Baird PA, Ward RH. Multiple sclerosis: updated risks for relatives. Am J Med Genet 1988;29:533–41. [3] Sadovnick AD, Risch NJ, Ebers GC, The Canadian Collaborative Study Group. Canadian Collaborative Project on Genetic Susceptibility to MS, phase 2: rationale and method. Can J Neurol Sci 1998;25:216–21. [4] Ebers GC, Sadovnick AD, Risch NJ. A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature 1995;377:150–1. [5] Ebers GC, Sadovnick AD, Dyment DA, Yee IM, Willer CJ, Risch N. Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet 2004;363:1773–4. [6] Sadovnick AD, Duquette P, Herrera B, Yee IM, Ebers GC. A timing-of-birth effect on multiple sclerosis clinical phenotype. Neurol 2007;69:60–2. [7] Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC. The Canadian Collaborative Study Group Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A 2003;100:12877–82. [8] International Multiple Sclerosis Genetics Consortium (IMSGC), Wellcome Trust Case Control Consortium 2 (WTCCC2). et al. Genetic risk and a primary role for cellmediated immune mechanisms in multiple sclerosis. Nature 2011;476:214–9. [9] Wang A, Sadovnick AD, Traboulsee L, Ross JP, Bernales CQ, Encarnacion M, et al. Nuclear receptor NR1H3 in familial multiple sclerosis. Neuron 2016;90:948–54. [10] Xia Z, White CC, Owens EK, Von Korff A, Clarkson SR, McCabe CA, et al. GEMS Project: a platform to investigate multiple sclerosis risk. Ann Neurol 2016;79:178–89. [11] Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol 2007;61:504–13.
Please cite this article in press as: Sadovnick D. The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.08.003
NEUROL-2112; No. of Pages 4
4
revue neurologique xxx (2019) xxx–xxx
[12] Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 2007;61:288–99. [13] Degelman ML, Herman KM. Smoking and multiple sclerosis: a systematic review and meta-analysis using the Bradford Hill criteria for causation. Mult Scler Relat Disord 2017;17:207–16. [14] Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurol 2013;80:548–52. [15] Munger KL, Bentzen J, Laursen B, et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Multiple Sclerosis Journal 2013;19:1323–9. [16] Buckley OE. The status of multiple sclerosis. Ann NY Acad Sci 1954;58:541–720. [17] Acheson ED. Epidemiology of multiple sclerosis. Br Med Bull 1977;33:9–14.
[18] Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980;103:281–300. [19] Steinman L. Autoimmune disease. Sci Am 1993;269:106–14. [20] Sadovnick AD. European Charcot Foundation Lecture: the natural history of multiple sclerosis and gender. J Neurol Sci 2009;286:1–5. [21] Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 2006;5:932–6. [22] Magyari M. Gender differences in multiple sclerosis epidemiology and treatment response. Dan Med J 2016 [pii:B5212 Review]. [23] Zhu JB, Tan CC, Tan L, Yu JT. State of Play in Alzheimer’s disease genetics. J Alzheimers Dis 2017;58:631–59. [24] Stocker H, Mo¨llers T, Perna L, Brenner H. The genetic risk of Alzheimer’s disease beyond APOE e4: systematic review of Alzheimer’s genetic risk scores. Transl Psychiatry 2018;8:166.
Please cite this article in press as: Sadovnick D. The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.08.003
Available online at
ScienceDirect www.sciencedirect.com
Environmental Neurology
The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis D. Sadovnick a,b,* a b
Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, Canada Department of Medical Genetics, University of British Columbia, Vancouver, Canada
info article
abstract
Article history:
The relative roles of genes and environment (not intra-familial environment) and inter-
Received 3 April 2019
actions thereof continue to confound better understanding of the pathogenesis of multiple
Received in revised form
sclerosis (MS) and can also impact recurrence risks for family members as well as genetic
21 June 2019
family studies. Strong evidence for non-familial environmental factors is suggested by the
Accepted 13 July 2019
change in the sex ratio (female:male) of MS patients over the last four decades.
Available online xxx
# 2019 Published by Elsevier Masson SAS.
Keywords: Multiple sclerosis Genes Environment Recurrence risks Sex ratio
All subjects involved in the Canadian studies discussed here signed informed consents prior to inclusion and only deidentified data were used in analyses. The relative roles of genes and environment in the etiology of multiple sclerosis (MS) have long been a topic of debate as familial clustering has been noted for decades [1]–see Fig. 1 to illustrate familial clustering in MS. However, the first population-based study on the familial nature of multiple sclerosis was conducted at the MS Clinic at the University of British Columbia (UBC) and was published in 1988 [2]. MS patients attending the UBC MS Clinic in Vancouver had genetic histories taken as part of routine protocol at first visit (i.e. no selection bias based on family history of MS or any
other disease). These family histories were updated annually during routine clinical follow-ups. Initially, data were first available for 815 MS index cases and 11,345 of their biological relatives. Age-specific MS risks were calculated for first-degree relatives of MS index cases. In general, first-degree relatives of MS index cases (parents, siblings) had recurrence risks that were 30–50 times greater than the 0.1% risk for the general population. Note this was a relatively young population so accurate risks for children needed age-adjustment for remaining risk [2]. It is recognized that familial aggregation does not necessarily presume genetic sharing. Close biological relatives, especially siblings, often share similar familial environments
* Correspondence. University of British Columbia, S200-2211 Wesbrook Mall, Vancouver, BC V6T2B5, Canada. E-mail address: [email protected]. https://doi.org/10.1016/j.neurol.2019.08.003 0035-3787/# 2019 Published by Elsevier Masson SAS.
Please cite this article in press as: Sadovnick D. The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.08.003
NEUROL-2112; No. of Pages 4
2
revue neurologique xxx (2019) xxx–xxx
Fig. 1 – Familial aggregation of multiple sclerosis [4].
[e.g. diet, time spent outdoors in the sun, physical activity, quality of health care during childhood, exposure to or protection from specific viruses, smoking (second-hand exposure or actually smoking), etc.]. These data, while interesting, were based on a relatively small sample size and were limited to the population attending the UBC MS Clinic. Thus, there was a need for a larger population-based study. The Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS) was initiated with funding by the MS Society of Canada Scientific Research Foundation. Study design is described in detail in Sadovnick et al. [3]. Briefly, this Canada-wide study had many unique factors as outlined in Box 1. All Canadian MS Clinics were involved in case ascertainment and data collection. The CCPGSMS had five phases and clearly showed that both genes and environment were important in the etiology of MS. The study included more than 30,000 unique families ascertained and for whom data could be entered into the
Box 1. Unique characteristics of the CCPGSMS Living database (not static in one point in time) Longitudinal nature (e.g. maternal effect; prevalence changes) Ongoing contact with families & ability to update both clinically and with biological samples Family cooperation Clinical & molecular information on affected & unaffected, including various degrees of affected individuals & intervening relatives Spouse controls Sib controls Many individuals past ‘‘risk age range’’ for MS Ethnic diversity Essentially ‘‘equal access’’ to clinics thus wide range of socioeconomic status
CCPGSMS living database. The database included more than 8000 spouse controls for whom early life information could also be collected from the spouse’s mother. As well, there were more than 4000 unique families in which at least two persons were diagnosed with MS > 8000 with data on ‘‘spouse’’ controls; Specifically, CCPGSMS studies were designed to regulate genetic sharing (e.g. twins, adoptees) as well as environment, both familial and maternal versus paternal. A study of adoptees clearly showed that being raised from infancy in the same family environment with a non-biological sibling who developed MS did not increase the adoptees risk to develop MS over the general population [4] compared to biological siblings of individuals who develop MS. Adoptee recurrence risk for MS was the same as that for the general population. Similarly, a study of half-siblings of MS index cases [5] was done to identify the impact of reducing genetic sharing (50% for full siblings, 25% for half-siblings) as well as various environmental sharing (half-siblings raised apart compared to those raised together). The age-adjusted full-sibling risk was 3.11%. By contrast, half-sibling risk in the same families was significantly lower at 1.89% (P = 0.006), but higher than expected if familial risk was simply polygenic. For maternal half-siblings, the risk was 2.35% (34 affected siblings of 1859), and 1.31% for paternal half-siblings (15 of 1577), (P = 0.048). The difference in risk suggests a maternal parent-of-origin effect in multiple sclerosis susceptibility. This cannot be quantified and should not be taken in any way to infer that a ‘‘mother causes MS’’. The maternal effect has also been suggested by the CCPGSMS month of birth data [6]. Month of birth data were collected for 11,465 index cases with relapsing remitting (RRMS) or secondary progressive (SPMS). Month of birth was used as a surrogate for vitamin D levels during pregnancy [6]. Using May/November births as comparison ratios, data showed MS patients studied were more often born in May than November for a birth ratio of 1.43:1 compared to a birth ratio of 1.18 in population controls (P = 0.000032). Driving this difference is the nadir of births during November in the RRMS
Please cite this article in press as: Sadovnick D. The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.08.003
NEUROL-2112; No. of Pages 4 revue neurologique xxx (2019) xxx–xxx
group compared to the population control group (6.7 versus 7.7%, P = 0.000076). Thus, adoptee and half-sibling findings further indicate that a shared family environment does not account for the increased familial risk in MS among biological relatives. Nevertheless, this does not exclude environmental factors in general for the overall risk to develop MS. Twin studies clearly illustrated this point by showing that even in monozygotic female twins (females having a higher rate for MS than males (vide infra), MS concordance is only about 34% despite the excessive genetic sharing by monozygotic twins [7]. While genetic sharing remains important in familial MS and there are several ongoing approaches to try to identify genetic factors by studying populations [8] and multiplex families [9] there may even be a subgroup in which an autosomal gene is important [9], the majority of MS is still believed to represent an interaction of genes and environment [10]. Identification of these environmental factors is in progress. Candidates include vitamin D [11], Epstein Barr virus [12], smoking [13] and body mass index [14,15]. Further evidence for environmental risk factors comes from the observation in many regions that the sex ratio (female: male) of MS is increasing, especially in individuals born in the last four decades. Historically, it was only in the 1950s that the female preponderance in MS was recognized [16]. A review of 14 prevalence surveys undertaken before 1977 concluded that the sex ratio was 14:1 [17]. This sex ratio continued to increase and reached 2 females:1 male during the 1980s and 1990s [18,19]. For more detailed review, see Sadovnick [20]. Temporal changes in the female:male ratio of Canadian MS patients born since 1970 have been noted with the female:male ratio approaching 3:1 [21]. This increase has also been noted in other regions. Despite much speculation [22], the reason for this increase in female preponderance remains unknown. It is likely not genetics, given the short evolutionary period, and must reflect environmental changes. It is interesting to speculate what effect, if any, changes in the female:male ratio will have on family studies and risk counselling for families of people with MS. Empiric recurrence risks (RRs), based on observed data rather than theoretical models, are used in genetic counselling when the exact mode of inheritance is unknown, but biological relatives of affected individuals are at a higher risk compared with the general population. The UBC MS Clinic and the subsequent CCPGSMS remain the only resources to have systematically documented family history data (as previously discussed). See Table 1 for CCPGSMS recurrence risk data by genetic sharing.
Table 1 – Recurrence Risk of MS by Increasing Genetic (DNA) Sharing. General Population Adopted Sibs Step-sibs 1st cousin has MS (1/8 DNA sharing) Half sib (1/4 DNA sharing) Full sib has MS (1/2 DNA sharing) HLA identical sib has MS Sib has MS & consanguineous mating Parents represent conjugal MS pair Female MZ twin has MS (all genes in common)
2/1000 2/1000 2/1000 7/1000 1/1000 35/1000 80/1000 90/1000 300/1000 340/1000
3
These cohorts were largely born before 1970 when the sex ratio was about 2:1 (Table 1). These RRs became used for standard genetic counselling as well as the basis on which to conduct familial genetic studies in MS. Research is in progress to update RR data keeping in mind the changes to the female:male ratio. It is possible that within multiplex families, there may be MS individuals for whom the genetic and environmental loading varies with respect to the cause of the disease. This is well reflected in Alzheimer disease [23,24].
Funding The author is currently funded for research and travel by Biogen Idec and has received research funds from Novartis, Teva Neurosciences, and Novartis. Much of the Canadian work discussed in this paper was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation.
Disclosure of interest The author declares that he has no competing interest.
references
[1] Schapira K, Poskanzer DC, Miller H. Familial and conjugal multiple sclerosis. Brain 1963;86:315–32. [2] Sadovnick AD, Baird PA, Ward RH. Multiple sclerosis: updated risks for relatives. Am J Med Genet 1988;29:533–41. [3] Sadovnick AD, Risch NJ, Ebers GC, The Canadian Collaborative Study Group. Canadian Collaborative Project on Genetic Susceptibility to MS, phase 2: rationale and method. Can J Neurol Sci 1998;25:216–21. [4] Ebers GC, Sadovnick AD, Risch NJ. A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature 1995;377:150–1. [5] Ebers GC, Sadovnick AD, Dyment DA, Yee IM, Willer CJ, Risch N. Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet 2004;363:1773–4. [6] Sadovnick AD, Duquette P, Herrera B, Yee IM, Ebers GC. A timing-of-birth effect on multiple sclerosis clinical phenotype. Neurol 2007;69:60–2. [7] Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC. The Canadian Collaborative Study Group Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A 2003;100:12877–82. [8] International Multiple Sclerosis Genetics Consortium (IMSGC), Wellcome Trust Case Control Consortium 2 (WTCCC2). et al. Genetic risk and a primary role for cellmediated immune mechanisms in multiple sclerosis. Nature 2011;476:214–9. [9] Wang A, Sadovnick AD, Traboulsee L, Ross JP, Bernales CQ, Encarnacion M, et al. Nuclear receptor NR1H3 in familial multiple sclerosis. Neuron 2016;90:948–54. [10] Xia Z, White CC, Owens EK, Von Korff A, Clarkson SR, McCabe CA, et al. GEMS Project: a platform to investigate multiple sclerosis risk. Ann Neurol 2016;79:178–89. [11] Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol 2007;61:504–13.
Please cite this article in press as: Sadovnick D. The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.08.003
NEUROL-2112; No. of Pages 4
4
revue neurologique xxx (2019) xxx–xxx
[12] Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 2007;61:288–99. [13] Degelman ML, Herman KM. Smoking and multiple sclerosis: a systematic review and meta-analysis using the Bradford Hill criteria for causation. Mult Scler Relat Disord 2017;17:207–16. [14] Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurol 2013;80:548–52. [15] Munger KL, Bentzen J, Laursen B, et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Multiple Sclerosis Journal 2013;19:1323–9. [16] Buckley OE. The status of multiple sclerosis. Ann NY Acad Sci 1954;58:541–720. [17] Acheson ED. Epidemiology of multiple sclerosis. Br Med Bull 1977;33:9–14.
[18] Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980;103:281–300. [19] Steinman L. Autoimmune disease. Sci Am 1993;269:106–14. [20] Sadovnick AD. European Charcot Foundation Lecture: the natural history of multiple sclerosis and gender. J Neurol Sci 2009;286:1–5. [21] Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 2006;5:932–6. [22] Magyari M. Gender differences in multiple sclerosis epidemiology and treatment response. Dan Med J 2016 [pii:B5212 Review]. [23] Zhu JB, Tan CC, Tan L, Yu JT. State of Play in Alzheimer’s disease genetics. J Alzheimers Dis 2017;58:631–59. [24] Stocker H, Mo¨llers T, Perna L, Brenner H. The genetic risk of Alzheimer’s disease beyond APOE e4: systematic review of Alzheimer’s genetic risk scores. Transl Psychiatry 2018;8:166.
Please cite this article in press as: Sadovnick D. The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.08.003