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Worldwide prevalence of familial multiple sclerosis: A systematic review and meta-analysis
Multiple Sclerosis and Related Disorders 20 (2018) 43–47
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Review article
Worldwide prevalence of familial multiple sclerosis: A systematic review and meta-analysis
T
Mohammad Hossein Harirchiana, Farzad Fatehia, Payam Sarrafa, ⁎ Niyaz Mohammadzadeh Honarvara,b, Sama Bitarafana, a b
Iranian Center of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran Cellular and Molecular Nutrition Department, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Keywords: Familial multiple sclerosis Prevalence Systematic review and meta-analysis
Background: Several studies have suggested that the existence of a history of multiple sclerosis (MS) in family, is one of the predisposing factors for MS. Based on our knowledge, the review and estimation of the prevalence of familial multiple sclerosis (FMS) in the world has not been reported up to now. This study is a systematic review and a meta-analysis of FMS prevalence in the world. Methods: Two researchers searched “epidemiology” or “prevalence” or “incidence” and “familial multiple sclerosis” as relevant keywords in international databases such as PubMed, web of science and Scopus up to 2016. MedCalc Version 15.8 was used to estimate the pooled prevalence of FMS. (PROSPERO ID = CRD42016033016) Results: From the 184 total articles found from 1954 to 2016, we pooled and analyzed the data of 17 final eligible studies, according to the inclusion criteria. The prevalence of FMS was estimated as 12.6% within a total sample size of 14,619 MS patients in the world as of 95% confidence interval (CI: 9.6–15.9). Conclusion: We detected significant heterogeneity from Hungary to Saskatchewan for FMS prevalence that was not latitude and ethnicity dependent. This highlighted the accumulation effects of genetic and environment on FMS prevalence. Pooled prevalence of FMS in MS population was calculated 12.6% by random effect in the world.
1. Introduction Multiple Sclerosis (MS) is the most common inflammatory demyelinating disease involving the central nervous system with various clinical types (Guaschino et al., 2014; Young et al., 2015; Leray et al., 2016). It is a potentially debilitating condition with different complications resulting in the high burden of the disease (Young et al., 2015). The prevalence of MS varies from high rates in North America and Europe (more than 100 cases per 100,000 population) to low levels in Eastern Asia and Sub-Saharan Africa (2 cases per 100,000 population) (Leray et al., 2016). The first report of familial cases of MS was by Curtius in 1933 (Curtius and Speer, 1933). Familial MS (FMS) defined as cases of MS having at least one family member in the first, second, third degree or other relatives of probands that affected by MS (Fricska-Nagy et al., 2007; Hader and Yee, 2014). Certain etiology and pathogenesis of MS remain vague up to now,
therefore, it is really clear that complex interactions between genetic background and environmental factors result in MS presentations (Maver et al., 2017). There are more than 100 confirmed genes or gene loci associated with MS. Many studies have shown high concordance among twins, familial aggregation of the disease and increased risk of the disease among relatives of MS patients (Sawcer et al., 2014). Some rare gene variations were studied in the members of families with MS but there were no definite findings related to type of genes involved in FMS (Maver et al., 2017). Scientifics reported that a complex genetic etiology is involved in susceptibility of MS such as genes encoding myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), and myelin oligodendrocyte glycoprotein (MOG). These are candidate locus for disease susceptibility in FMS, however, there are some controversies in the linkage of them and FMS (Rose et al., 1993; Haines et al., 1998; Seboun et al., 1999).
⁎ Correspondence to: Iranian Centre of Neurological Research, Department of Neurology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Keshavarz Blvd, Tehran Postal code: 1419733141, Iran. E-mail address: [email protected] (S. Bitarafan).
https://doi.org/10.1016/j.msard.2017.12.015 Received 26 September 2017; Received in revised form 18 December 2017; Accepted 21 December 2017 2211-0348/ © 2017 Published by Elsevier B.V.
Multiple Sclerosis and Related Disorders 20 (2018) 43–47
M.H. Harirchian et al.
Some findings showed HLA-DR2 allele may be explain MHC genetic linkage in 17–62% of the genetic etiology in FMS patients (Seboun et al., 1999). One study for the first time reported that MicroRNA or miRNAs (small and non-coding RNAs mediated mRNA translation) are useful factors for exploring differentiation between FMS and sporadic MS. This study also showed that miR-5100 is increased in familial MS, miR-432-3p is decreased and miR-548-v is increased only in sporadic MS (Altun et al., 2017). However, According to other studies, some environmental factors such as EBV, smoking and geographical latitude due to present the different level of ambient UVR and serum vitamin D are attributed to the etiology of MS (Leray et al., 2016). Several studies were conducted in different geographical locations around the world and reported the magnitude of prevalence of familial MS, which are unfortunately so discrepant. Therefore, our knowledge about the epidemiology of FMS remains limited in many other parts of the world. Hence, it appears that it is necessary to estimate the epidemiology of FMS, in order to conduct etiologic and demographic research projects on it. We intended to conduct the review systematically and pool the results of publications (all over the world) which reported the prevalence of FMS in the world.
included. The title and abstract of these studies were reviewed and 136 irrelevant articles were excluded. The full texts of the remaining 31 articles were studied and 11 studies did not meet the requirements for inclusion. At the end, we found 17 articles published between 1954 and 2014, which reported the prevalence of FMS. These 17 articles mentioned the number of probands with at least one affected relative and filled an all inclusion criteria of the present study (Fig. 1). The entered studies were conducted with 14,619 MS patients who varied from 51 to 3911 in studies (Table 1). The prevalence of FMS has been extremely discrepant with significant heterogeneity in the present study (Q = 476.4, I2: 96.6%, CI = 95.6–97.4%, P < 0.0001). Therefore, the prevalence of FMS was 12.6%, as calculated by random effect (CI = 95%. 9.6–15.9) (Fig. 2). 4. Discussion Many studies have considered that one of the predictive factors for MS is the existence of a familial history. The review and estimation of FMS prevalence in MS population in the world has not been elucidated up to now. In the present study, we reviewed systematically and calculated pooled prevalence of FMS. We found a considering and significant heterogeneity from 2% in Hungary to 32.7% in Saskatchewan for FMS prevalence and estimated that at about 12.6% in the MS population between 1954 and 2014 (Table 1) (Fig. 2). Since in this study to calculate the average frequencies, we pooled the frequencies of MS and FMS patients, there is the possibility of biases to the larger studies; however, we used random effects model to improve this estimation and reducing such bias. The methods of all the included studies were cross sectional except the two studies conducted by Hader et al. and Ebers et al. The former had run a cohort study of 150 MS cases ascertained on 1977 Saskatchewan, and the search for new familial cases of MS affected relatives continued for 35 years until 2012. At first, 26 cases (17.3%) of the 150 unrelated MS patients and after 35-year longitudinal natural history study, 49 cases (32.7%) of them were reported of having at least one family member with MS. This study showed an increase in the frequency of cases with family members (Hader and Yee, 2014). Ebers et al. reported the information obtained from 1044 patients with MS in a 25-year follow-up duration from London,Ontario. Finally, this study reported that 19.8% of the total MS patients were with affected family members (Ebers et al., 2000). In present review of 17 studies we detected that Saskatchewan with 32.7%, Finland with 29% and Croatia-Slovenia with 28.7% prevalence of FMS in MS population, are the areas with the same and higher prevalence. Conversely, Hungary with 2%, Mexico with 3.3% and Brazil with 6.12% prevalence of FMS, are the regions with nearly similar and lower prevalence (Table 1). We were interested to explore that which factors are corresponded for these diversities all over the world. In this way, we found study of Albor et al.; that have shown the different ethnicities in the study population in east London included Black, South Asian and White. This study found that Black and South Asian people had a significant lower prevalence of MS compared to the White people (Albor et al., 2017). We know that Black ethnicity is in African descent, South Asian ethnicity is in Indian, Sri Lankan, Bangladeshi, or Pakistani descent and White ethnicity is in European or American descent. According to this division by ethnicity, the Saskatchewan, Finland and Croatia- Slovenia are in European or American descent with the same ethnicity. We observed the similar and higher FMS prevalence in these regions. However, the Hungary; Mexico and Brazil with lower prevalence of FMS are European or American with the same ethnicity with previous group. On the other hand, we did not detect any similarity in latitude among the areas with lower prevalence, Hungary; Mexico and Brazil. Also, latitude among the regions with higher prevalence of FMS,
2. Methods A pervasive literature search was conducted separately by two expert researchers. On January 20, 2016, international databases were searched for the relevant key words: “epidemiology” or “prevalence” or “incidence” and “Familial multiple sclerosis” within the title/abstract in PubMed, title in Web of science and title/abstract/keywords in Scopus without any limitations. We searched Google Scholar to find further results. (PROSPERO ID = CRD42016033016) (Ethic code = IR.TUMS.VCR.REC.1396.3352) In order to run a meta-analysis, inclusion and exclusion criteria were considered for articles selection: 1. In all the studies, a neurologist should have assessed and made the diagnosis of MS for the study populations. 2. Patients should have completed a questionnaire or have been followed up by a personal or telephone interview to collect information or their information would have been made available through a registry system. 3. Patients with FMS should have been described whether there were one or many MS patients in the first or second degree or other relatives of probands (proband means a person that introduce a genetic susceptibility for a disease in family members). 4. All included articles should have been published in English. A total of 184 articles were found in our searches that were published from 1954 to 2014, and duplicate articles were removed. Irrelevant articles were excluded from the study at first by screening the titles/abstracts and then by screening the full texts. Finally, 17 articles reporting the prevalence of FMS and satisfying our inclusion criteria were enrolled in this study (Fig. 1). These articles explain the number of probands with at least one affected relative. Discrepancy of data was detected by MedCalc Version 15.8. According to the discrepancy of data; the random effect model was used to estimate the prevalence of FMS using MedCalc. 3. Results A total of 184 articles were found in initial searches including 10 articles in PubMed, 159 articles in web of science, and 15 articles in Scopus. The search of Google Scholar did not add more articles to our findings. After exclusion of duplicate findings, 167 studies were 44
Multiple Sclerosis and Related Disorders 20 (2018) 43–47
M.H. Harirchian et al.
Fig. 1. diagram of selection of studies about FMS prevalence between 1954 and 2014.
more common variant. The increased risk of MS in families is due to the greater role of genetic factors. It is necessary to understand and predict familial MS aggregation that designs some studies with focus on rare variants and environmental risk factors for MS in families. One study revealed two genetic variants with a modest effect, CYP27B1 and TYK2, on the risk of MS in some families with several affected members (Maver et al., 2017). These studies show the predictive effect of genetic factors on MS prevalence in family. On the other hand whereas some studies have reported that the prevalence of MS has recently increased in the Mediterranean Basin, Europe and Latin America and in this area environmental triggers were more important in MS pathogenesis than genetic factors (Abbasiet al, 2017). We observed that included studies conducted in the same regions, with presumably similar populations and genetic, such as studies from Saudi Arabia and Qatar, Saskatoon and London in Canada, or Brazil and Argentina that showed markedly different FMS prevalence estimates. But the three studies in Iran with the same FMS prevalence between 11% and 12.2%, are more consistent between studies. Our review showed that there is a challengeable and ambiguous discussion about effectiveness of genetic and environmental factors in the prevalence of MS in families. There are not significant differences between familial MS and sporadic MS in clinical signs. Ebers, showed that the demography and outcomes of familial MS patients were very similar to sporadic MS patients except in early onset and greater male to female ratio (Ebers et al., 2000). Peterlin, confirmed the results obtained by Ebers but in contrast to that, the primary progressive course of the disease was highly prevalent (Peterlin et al., 2006).
Saskatchewan, Finland and Croatia-Slovenia was not similar according to Table 1. Therefore, it seems that diversity of FMS prevalence is not ethnicity and latitude dependent. Many researches indicated that MS is caused by the cumulative effects and interactions between some predisposing genetic and environmental factors. Sunlight exposure which mediates the synthesis of vitamin D and EBV as the infectious agent are the most likely environmental factors associated with MS susceptibility (Milo and Kahana, 2010). Also, the increase in prevalence of MS can be due to some other factors such as longer survival of patients, higher tendency to cigarette smoking, occupation, birth control, and later childbirth (Baranzini et al., 2008). However, another study have shown that shared maternal environments such as breastfeeding, intrauterine and perinatal factors does not account for familial risk in MS lonely as well as genomic imprinting (Sadovnick et al., 1996). Milo et al. study reported that the risk of MS incidence in first-degree relatives is increased (3.4–5.13%) in Canada, England, Scotland and Belgium. Twin studies demonstrated genetic susceptibility in monozygotic twins with 25–30% concordance rate and 0.25–0.76 heritability index (Milo and Kahana, 2010; Akkad et al., 2016). Therefore, some studies showed in different regions of the world that there are different recurrence risks for MS in the first and second degree family members according to genetic sharing (O'Gorman et al., 2011) and major differences in HLA-DRB1*1501 (Mescheriakova et al., 2016). Also, there is a positive family history in nearly 20% of patients with multiple sclerosis. Common genetic variants are found in patients with familial MS more than sporadic cases. One study reported that patients with multiplex MS families have HLA-DRB1*1501 variants as a 45
Cross sectional
Cross sectional Cohort
1999
–
(Peterlin et al., 2006)
(Jumah et al., 2011) (Ebers et al., 2000) (Carton et al., 1997) (O'Gorman et al., 2011)
46
Cross sectional Cross sectional Cross sectional Cross sectional Cross sectional Cross sectional Cross sectional Cross sectional cross sectional
2013
(Rezaali et al., 2013) (Toghianifar et al., 2014) (Farez et al., 2014) (Deleu et al., 2013) (Hashemilar et al., 2011) (Cendrowski, 1967) (Papais-Alvarenga et al., 2015) (Gonzalez and Sotelo, 1995) (Fricska-Nagy et al., 2007) Investigate the frequency and type of familial MS To determine familial MS prevalence and MS recurrence risk Investigate the prevalence and clinical characteristics of MS Investigate the current prevalence of MS Determining the pattern of distribution of FMS To describe frequency of familial forms of MS Studying the trend of MS prevalence in Mexico Detecting familial accumulation of MS
Comparing demographic and longterm outcome of familial MS Calculating age adjusted risk for MS in relatives of patients Investigation the environmental and genetic causative factors interaction in MS and determination familial recurrence risk in 3 latitudinal distinct sits of Australia. Determine the clinical features of MS in subgroups (early‐onset, late‐onset, familial) Determine the epidemiology of MS.
Determining the prevalence of MS and clinical characteristics and occurrence of FMS Calculating the prevalence of FMS
Determining the occurrence of FMS and frequency of MS among the relatives Studying the epidemiology of MS
Objectives
* With at least one affected relative, # % Patients of MS cases.
2004
1992
2011
1964
2009
2010
2014
2014
Cross sectional
2006
(Saadatnia et al., 2007)
2006
1994
Cross sectional Cross sectional
Cross sectional
1979
(Kinnunen et al., 1984)
1997
Cohort
2012
(Hader and Yee, 2014)
Design
Prevalence date/period
Study (Year)
Table 1 Information about studies entered in systematic review and meta-analysis.
Hungary
Rio de Janeiro State, Brazil Mexico
Poland
East Azerbaijan, Iran
Qatar
Buenos Aires, Argentina
Isfahan, Iran
Qom, Iran
McDonald
Poser's
2005 McDonald
not mentioned
McDonald
Revised McDonald McDonald
McDonald
McDonald
McDonald
Revised McDonald
Australia (total)
Isfahan, Iran
Poser's
Flanders, Belgium
London, Ontario, Canada
Revised McDonald Poser's
87
Poser's
Saudi Arabia
51
Schumacher committee's
A small rural area of five communities in western province of Vaasa, Finland Croatia and Slovenia
1500
272
653
616
1000
154
219
3911
592
1718
1837
674
1044
141
150
Not mentioned
Saskatoon, Saskatchewan, Canada
Sample size
Diagnostic criteria
Location
33
9
40
38
71
16
23
430
66
209
265
104
208
30
25
15
49
Number of probands*
11% 10.5 10.4
34.25 – – –
–
6.17
– 28.5 27 –
– – – –
2
3.3
6.12
7.1
33.4
34.7
40.03
36.9
11.2
25.36
12.2
14.42
–
–
50.50
15.4
19.8 32.6
30.6
– 47.6
–
–
21
28.7
–
29.1
29
–
–
32.7
–
Onset
FMS prevalence #
29.4
Patients
Mean age
62
30
30
110
27.7
31–55
19.8
–
50.4
43.8
84.6
88
91
31–55
151.9
19.8
110
MS Prevalence
34.6° N, 50.8° E 32.6° N, 51.6° E 34.6° S, 58.3° W 25.3° N, 51.1° E 37.9° N, 46.2° E 51.9° N, 19.1° E 22.3° S, 42.7° W 23.6° N, 102.5° W 47.1° N, 19.5° E
32.6° N, 51.6° E
23.8° N, 45.0° E 51.2° N, 85.3° W 50.5° N, 4.4° E 25.2° S, 133.7° E
45.1° N, 15.2° E
63.0° N, 21.6° E
52.1° N, 106.6° W
Latitude
M.H. Harirchian et al.
Multiple Sclerosis and Related Disorders 20 (2018) 43–47
Multiple Sclerosis and Related Disorders 20 (2018) 43–47
M.H. Harirchian et al.
Fig. 2. Forest plot showed result of meta-analysis of the FMS prevalence.
Finally, we mention to a probable limitation of study in selection of key words in the method of our study. It was better that search was done with "familial recurrence" plus other key words.
Neurol. 88 (P3. 383). Baranzini, S.E., Wang, J., Gibson, R., et al., 2008. Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum. Mol. Genet. 18, 767–778. Carton, H., Vlietinck, R., Debruyne, J., et al., 1997. Risks of multiple sclerosis in relatives of patients in Flanders, Belgium. J. Neurol. Neurosurg. Psychiatry 62, 329–333. Cendrowski, W.S., 1967. Familial multiple sclerosis in Poland: Part 1. Geographical distribution of the disease. J. Neurol. Sci. 4, 95–99. Curtius, F., Speer, H., 1933. Multiple Sklerose und Erbanlage. Z. Gesamt. Neurologie Psychiatr. 60, 226–245. Deleu, D., Mir, D., Al Tabouki, A., et al., 2013. Prevalence, demographics and clinical characteristics of multiple sclerosis in Qatar. Mult. Scler. J. 19, 816–819. Ebers, G., Koopman, W., Hader, W., et al., 2000. The natural history of multiple sclerosis: a geographically based study. Brain 123, 641–649. Farez, M.F., Aguirre, M.E.B., Francisco, V., et al., 2014. Low familial risks for multiple sclerosis in Buenos Aires, Argentina. J. Neurol. Sci. 346, 268–270. Fricska-Nagy, Z., Bencsik, K., Rajda, C., et al., 2007. Epidemiology of familial multiple sclerosis in Hungary. Mult. Scler. J. 13, 260–261. Gonzalez, O., Sotelo, J., 1995. Is the frequency of multiple sclerosis increasing in Mexico? J. Neurol. Neurosurg. Psychiatry 59, 528–530. Guaschino, C., Esposito, F., Liberatore, G., et al., 2014. Familial clustering in Italian progressiveonset and bout-onset multiple sclerosis. Neurol. Sci. 35, 789–791. Hader, W.J., Yee, I.M., 2014. The prevalence of familial multiple sclerosis in saskatoon, Saskatchewan. Mult. Scler. Int. 2014. Haines, J.L., Terwedow, H.A., Burgess, K., et al., 1998. Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. Hum. Mol. Genet. 7, 1229–1234. Hashemilar, M., Savadi Ouskui, D., Farhoudi, M., et al., 2011. Multiple sclerosis in EastAzerbaijan, north west Iran. Neurol. Asia 16, 127–131. Jumah, M.A., Kojan, S., Khathaami, A., et al., 2011. Familial multiple sclerosis: does consanguinity have a role? Mult. Scler. J. 17, 487–489. Kinnunen, E., Wikström, J., Porras, J., et al., 1984. Prevalence, incidence and familial risk of multiple sclerosis. Acta Neurol. Scand. 69, 378–379. Leray, E., Moreau, T., Fromont, A., et al., 2016. Epidemiology of multiple sclerosis. Rev. Neurol. 172, 3–13. Maver, A., Lavtar, P., Smiljana, R., et al., 2017. Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis. Sci. Rep. 7, 3715. Mescheriakova, J.Y., Broer, L., Wahedi, S., et al., 2016. Burden of genetic risk variants in multiple sclerosis families in the Netherlands. Mult. Scler. J. Exp. Transl. Clin. 2, 1–8. Milo, R., Kahana, E., 2010. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun. Rev. 9, A387–A394. O'Gorman, C., Freeman, S., Taylor, B.V., et al., 2011. Familial recurrence risks for multiple sclerosis in Australia. J. Neurol. Neurosurg. Psychiatry 82, 1351–1354. Papais-Alvarenga, R.M., Pereira, F.C., Bernardes, M.S., et al., 2015. Familial forms of multiple sclerosis and neuromyelitis optica at an MS center in Rio de Janeiro State, Brazil. J. Neurol. Sci. 356, 196–201. Peterlin, B., Ristiæ, S., Juraj, S., et al., 2006. Region with persistent high frequency of multiple sclerosis in Croatia and Slovenia. Neurol. Sci. 247, 169–172. Rezaali, S., Khalilnezhad, A., Moghadasi, A.N., et al., 2013. Epidemiology of multiple sclerosis in Qom: demographic study in Iran. Iran. J. Neurol. 12, 136–143. Rose, J., Lynch, S., Pisan, P., et al., 1993. Genetic susceptibility in familial multiple sclerosis not linked to the myelin basic protein gene. Lancet 341, 1179–1181. Saadatnia, M., Etemadifar, M., Maghzi, A.H., et al., 2007. Multiple sclerosis in Isfahan, Iran. Int. Rev. Neurobiol. 79, 357–375. Sadovnick, A., Dyment, D., Ebers, G.C., et al., 1996. Evidence for genetic basis of multiple sclerosis. Lancet 347, 1728–1730. Sawcer, S., Franklin, R.J., Ban, M., 2014. Multiple sclerosis genetics. Lancet Neurol. 13, 700–709. Seboun, E., Oksenberg, J.R., Rombos, A., et al., 1999. Linkage analysis of candidate myelin genes in familial multiple sclerosis. Neurogenetics 2, 155–162. Toghianifar, N., Etemadifar, M., Sharifzadeh, A., et al., 2014. Characteristics of familial multiple sclerosis in Isfahan, Iran: a cross-sectional study. Neurol. Asia 19, 59–62. Young, L., Healey, K., Charlton, M., et al., 2015. A home-based comprehensive care model in patients with multiple sclerosis: a study pre-protocol. F1000Research 4, 872–883.
5. Conclusion In the present systematic review, we detected a significant heterogeneity from 2% in Hungary to 32.7% in Saskatchewan for FMS prevalence in the world. Prevalence of FMS was not dependent on latitude and ethnicity and dominant effect of genetic or environment on FMS prevalence was not derived definitely. Consequently our review highlighted the accumulation effects of genetic contents and environmental agents on prevalence of MS in families. In the mata-analysis the pooled prevalence of FMS in MS population was calculated 12.6% by random effect in the world (CI = 95%. 9.60–15.88). We recommend designing further studies to find the prevalence of FMS in different regions of the world with focus on effective factors (genes and environments) in FMS prevalence. Acknowledgment This research was supported by Tehran University of Medical Sciences and Health Services, Neuroscience Institute, Iran (grant number 95-02-54-34673). The authors are grateful for all colleagues in Iranian Center of Neurological Research specially Miss Maryam Rashidi for her kind collaborations. Conflict of interest The authors declare no conflict of interest in present study. Funding source Our funding source was Tehran University of Medical Sciences and Health Services, Neuroscience Institute. References Abbasi, M., Nabavi, S.M., Fereshtehnejad, S.M., et al., 2017. Multiple sclerosis and environmental risk factors: a case-control study in Iran. Neurol. Sci. 1–11. Akkad, D.A., Lee, D.H., Bruch, K., et al., 2016. Multiple sclerosis in families: risk factors beyond known genetic polymorphisms. Neurogenetics 17, 131–135. Albor, C., Sautoy, T., du., Kali Vanan, N., et al., 2017. Ethnicity and prevalence of multiple sclerosis in east London. Mult. Scler. J. 23, 36–42. Altun, Z., Idiman, E., Özçelik, P., et al., 2017. The differences of microRNA expressions profiles in peripheral blood cells in familial and sporadic multiple sclerosis patients (P3. 383). J.
47
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Review article
Worldwide prevalence of familial multiple sclerosis: A systematic review and meta-analysis
T
Mohammad Hossein Harirchiana, Farzad Fatehia, Payam Sarrafa, ⁎ Niyaz Mohammadzadeh Honarvara,b, Sama Bitarafana, a b
Iranian Center of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran Cellular and Molecular Nutrition Department, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Keywords: Familial multiple sclerosis Prevalence Systematic review and meta-analysis
Background: Several studies have suggested that the existence of a history of multiple sclerosis (MS) in family, is one of the predisposing factors for MS. Based on our knowledge, the review and estimation of the prevalence of familial multiple sclerosis (FMS) in the world has not been reported up to now. This study is a systematic review and a meta-analysis of FMS prevalence in the world. Methods: Two researchers searched “epidemiology” or “prevalence” or “incidence” and “familial multiple sclerosis” as relevant keywords in international databases such as PubMed, web of science and Scopus up to 2016. MedCalc Version 15.8 was used to estimate the pooled prevalence of FMS. (PROSPERO ID = CRD42016033016) Results: From the 184 total articles found from 1954 to 2016, we pooled and analyzed the data of 17 final eligible studies, according to the inclusion criteria. The prevalence of FMS was estimated as 12.6% within a total sample size of 14,619 MS patients in the world as of 95% confidence interval (CI: 9.6–15.9). Conclusion: We detected significant heterogeneity from Hungary to Saskatchewan for FMS prevalence that was not latitude and ethnicity dependent. This highlighted the accumulation effects of genetic and environment on FMS prevalence. Pooled prevalence of FMS in MS population was calculated 12.6% by random effect in the world.
1. Introduction Multiple Sclerosis (MS) is the most common inflammatory demyelinating disease involving the central nervous system with various clinical types (Guaschino et al., 2014; Young et al., 2015; Leray et al., 2016). It is a potentially debilitating condition with different complications resulting in the high burden of the disease (Young et al., 2015). The prevalence of MS varies from high rates in North America and Europe (more than 100 cases per 100,000 population) to low levels in Eastern Asia and Sub-Saharan Africa (2 cases per 100,000 population) (Leray et al., 2016). The first report of familial cases of MS was by Curtius in 1933 (Curtius and Speer, 1933). Familial MS (FMS) defined as cases of MS having at least one family member in the first, second, third degree or other relatives of probands that affected by MS (Fricska-Nagy et al., 2007; Hader and Yee, 2014). Certain etiology and pathogenesis of MS remain vague up to now,
therefore, it is really clear that complex interactions between genetic background and environmental factors result in MS presentations (Maver et al., 2017). There are more than 100 confirmed genes or gene loci associated with MS. Many studies have shown high concordance among twins, familial aggregation of the disease and increased risk of the disease among relatives of MS patients (Sawcer et al., 2014). Some rare gene variations were studied in the members of families with MS but there were no definite findings related to type of genes involved in FMS (Maver et al., 2017). Scientifics reported that a complex genetic etiology is involved in susceptibility of MS such as genes encoding myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), and myelin oligodendrocyte glycoprotein (MOG). These are candidate locus for disease susceptibility in FMS, however, there are some controversies in the linkage of them and FMS (Rose et al., 1993; Haines et al., 1998; Seboun et al., 1999).
⁎ Correspondence to: Iranian Centre of Neurological Research, Department of Neurology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Keshavarz Blvd, Tehran Postal code: 1419733141, Iran. E-mail address: [email protected] (S. Bitarafan).
https://doi.org/10.1016/j.msard.2017.12.015 Received 26 September 2017; Received in revised form 18 December 2017; Accepted 21 December 2017 2211-0348/ © 2017 Published by Elsevier B.V.
Multiple Sclerosis and Related Disorders 20 (2018) 43–47
M.H. Harirchian et al.
Some findings showed HLA-DR2 allele may be explain MHC genetic linkage in 17–62% of the genetic etiology in FMS patients (Seboun et al., 1999). One study for the first time reported that MicroRNA or miRNAs (small and non-coding RNAs mediated mRNA translation) are useful factors for exploring differentiation between FMS and sporadic MS. This study also showed that miR-5100 is increased in familial MS, miR-432-3p is decreased and miR-548-v is increased only in sporadic MS (Altun et al., 2017). However, According to other studies, some environmental factors such as EBV, smoking and geographical latitude due to present the different level of ambient UVR and serum vitamin D are attributed to the etiology of MS (Leray et al., 2016). Several studies were conducted in different geographical locations around the world and reported the magnitude of prevalence of familial MS, which are unfortunately so discrepant. Therefore, our knowledge about the epidemiology of FMS remains limited in many other parts of the world. Hence, it appears that it is necessary to estimate the epidemiology of FMS, in order to conduct etiologic and demographic research projects on it. We intended to conduct the review systematically and pool the results of publications (all over the world) which reported the prevalence of FMS in the world.
included. The title and abstract of these studies were reviewed and 136 irrelevant articles were excluded. The full texts of the remaining 31 articles were studied and 11 studies did not meet the requirements for inclusion. At the end, we found 17 articles published between 1954 and 2014, which reported the prevalence of FMS. These 17 articles mentioned the number of probands with at least one affected relative and filled an all inclusion criteria of the present study (Fig. 1). The entered studies were conducted with 14,619 MS patients who varied from 51 to 3911 in studies (Table 1). The prevalence of FMS has been extremely discrepant with significant heterogeneity in the present study (Q = 476.4, I2: 96.6%, CI = 95.6–97.4%, P < 0.0001). Therefore, the prevalence of FMS was 12.6%, as calculated by random effect (CI = 95%. 9.6–15.9) (Fig. 2). 4. Discussion Many studies have considered that one of the predictive factors for MS is the existence of a familial history. The review and estimation of FMS prevalence in MS population in the world has not been elucidated up to now. In the present study, we reviewed systematically and calculated pooled prevalence of FMS. We found a considering and significant heterogeneity from 2% in Hungary to 32.7% in Saskatchewan for FMS prevalence and estimated that at about 12.6% in the MS population between 1954 and 2014 (Table 1) (Fig. 2). Since in this study to calculate the average frequencies, we pooled the frequencies of MS and FMS patients, there is the possibility of biases to the larger studies; however, we used random effects model to improve this estimation and reducing such bias. The methods of all the included studies were cross sectional except the two studies conducted by Hader et al. and Ebers et al. The former had run a cohort study of 150 MS cases ascertained on 1977 Saskatchewan, and the search for new familial cases of MS affected relatives continued for 35 years until 2012. At first, 26 cases (17.3%) of the 150 unrelated MS patients and after 35-year longitudinal natural history study, 49 cases (32.7%) of them were reported of having at least one family member with MS. This study showed an increase in the frequency of cases with family members (Hader and Yee, 2014). Ebers et al. reported the information obtained from 1044 patients with MS in a 25-year follow-up duration from London,Ontario. Finally, this study reported that 19.8% of the total MS patients were with affected family members (Ebers et al., 2000). In present review of 17 studies we detected that Saskatchewan with 32.7%, Finland with 29% and Croatia-Slovenia with 28.7% prevalence of FMS in MS population, are the areas with the same and higher prevalence. Conversely, Hungary with 2%, Mexico with 3.3% and Brazil with 6.12% prevalence of FMS, are the regions with nearly similar and lower prevalence (Table 1). We were interested to explore that which factors are corresponded for these diversities all over the world. In this way, we found study of Albor et al.; that have shown the different ethnicities in the study population in east London included Black, South Asian and White. This study found that Black and South Asian people had a significant lower prevalence of MS compared to the White people (Albor et al., 2017). We know that Black ethnicity is in African descent, South Asian ethnicity is in Indian, Sri Lankan, Bangladeshi, or Pakistani descent and White ethnicity is in European or American descent. According to this division by ethnicity, the Saskatchewan, Finland and Croatia- Slovenia are in European or American descent with the same ethnicity. We observed the similar and higher FMS prevalence in these regions. However, the Hungary; Mexico and Brazil with lower prevalence of FMS are European or American with the same ethnicity with previous group. On the other hand, we did not detect any similarity in latitude among the areas with lower prevalence, Hungary; Mexico and Brazil. Also, latitude among the regions with higher prevalence of FMS,
2. Methods A pervasive literature search was conducted separately by two expert researchers. On January 20, 2016, international databases were searched for the relevant key words: “epidemiology” or “prevalence” or “incidence” and “Familial multiple sclerosis” within the title/abstract in PubMed, title in Web of science and title/abstract/keywords in Scopus without any limitations. We searched Google Scholar to find further results. (PROSPERO ID = CRD42016033016) (Ethic code = IR.TUMS.VCR.REC.1396.3352) In order to run a meta-analysis, inclusion and exclusion criteria were considered for articles selection: 1. In all the studies, a neurologist should have assessed and made the diagnosis of MS for the study populations. 2. Patients should have completed a questionnaire or have been followed up by a personal or telephone interview to collect information or their information would have been made available through a registry system. 3. Patients with FMS should have been described whether there were one or many MS patients in the first or second degree or other relatives of probands (proband means a person that introduce a genetic susceptibility for a disease in family members). 4. All included articles should have been published in English. A total of 184 articles were found in our searches that were published from 1954 to 2014, and duplicate articles were removed. Irrelevant articles were excluded from the study at first by screening the titles/abstracts and then by screening the full texts. Finally, 17 articles reporting the prevalence of FMS and satisfying our inclusion criteria were enrolled in this study (Fig. 1). These articles explain the number of probands with at least one affected relative. Discrepancy of data was detected by MedCalc Version 15.8. According to the discrepancy of data; the random effect model was used to estimate the prevalence of FMS using MedCalc. 3. Results A total of 184 articles were found in initial searches including 10 articles in PubMed, 159 articles in web of science, and 15 articles in Scopus. The search of Google Scholar did not add more articles to our findings. After exclusion of duplicate findings, 167 studies were 44
Multiple Sclerosis and Related Disorders 20 (2018) 43–47
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Fig. 1. diagram of selection of studies about FMS prevalence between 1954 and 2014.
more common variant. The increased risk of MS in families is due to the greater role of genetic factors. It is necessary to understand and predict familial MS aggregation that designs some studies with focus on rare variants and environmental risk factors for MS in families. One study revealed two genetic variants with a modest effect, CYP27B1 and TYK2, on the risk of MS in some families with several affected members (Maver et al., 2017). These studies show the predictive effect of genetic factors on MS prevalence in family. On the other hand whereas some studies have reported that the prevalence of MS has recently increased in the Mediterranean Basin, Europe and Latin America and in this area environmental triggers were more important in MS pathogenesis than genetic factors (Abbasiet al, 2017). We observed that included studies conducted in the same regions, with presumably similar populations and genetic, such as studies from Saudi Arabia and Qatar, Saskatoon and London in Canada, or Brazil and Argentina that showed markedly different FMS prevalence estimates. But the three studies in Iran with the same FMS prevalence between 11% and 12.2%, are more consistent between studies. Our review showed that there is a challengeable and ambiguous discussion about effectiveness of genetic and environmental factors in the prevalence of MS in families. There are not significant differences between familial MS and sporadic MS in clinical signs. Ebers, showed that the demography and outcomes of familial MS patients were very similar to sporadic MS patients except in early onset and greater male to female ratio (Ebers et al., 2000). Peterlin, confirmed the results obtained by Ebers but in contrast to that, the primary progressive course of the disease was highly prevalent (Peterlin et al., 2006).
Saskatchewan, Finland and Croatia-Slovenia was not similar according to Table 1. Therefore, it seems that diversity of FMS prevalence is not ethnicity and latitude dependent. Many researches indicated that MS is caused by the cumulative effects and interactions between some predisposing genetic and environmental factors. Sunlight exposure which mediates the synthesis of vitamin D and EBV as the infectious agent are the most likely environmental factors associated with MS susceptibility (Milo and Kahana, 2010). Also, the increase in prevalence of MS can be due to some other factors such as longer survival of patients, higher tendency to cigarette smoking, occupation, birth control, and later childbirth (Baranzini et al., 2008). However, another study have shown that shared maternal environments such as breastfeeding, intrauterine and perinatal factors does not account for familial risk in MS lonely as well as genomic imprinting (Sadovnick et al., 1996). Milo et al. study reported that the risk of MS incidence in first-degree relatives is increased (3.4–5.13%) in Canada, England, Scotland and Belgium. Twin studies demonstrated genetic susceptibility in monozygotic twins with 25–30% concordance rate and 0.25–0.76 heritability index (Milo and Kahana, 2010; Akkad et al., 2016). Therefore, some studies showed in different regions of the world that there are different recurrence risks for MS in the first and second degree family members according to genetic sharing (O'Gorman et al., 2011) and major differences in HLA-DRB1*1501 (Mescheriakova et al., 2016). Also, there is a positive family history in nearly 20% of patients with multiple sclerosis. Common genetic variants are found in patients with familial MS more than sporadic cases. One study reported that patients with multiplex MS families have HLA-DRB1*1501 variants as a 45
Cross sectional
Cross sectional Cohort
1999
–
(Peterlin et al., 2006)
(Jumah et al., 2011) (Ebers et al., 2000) (Carton et al., 1997) (O'Gorman et al., 2011)
46
Cross sectional Cross sectional Cross sectional Cross sectional Cross sectional Cross sectional Cross sectional Cross sectional cross sectional
2013
(Rezaali et al., 2013) (Toghianifar et al., 2014) (Farez et al., 2014) (Deleu et al., 2013) (Hashemilar et al., 2011) (Cendrowski, 1967) (Papais-Alvarenga et al., 2015) (Gonzalez and Sotelo, 1995) (Fricska-Nagy et al., 2007) Investigate the frequency and type of familial MS To determine familial MS prevalence and MS recurrence risk Investigate the prevalence and clinical characteristics of MS Investigate the current prevalence of MS Determining the pattern of distribution of FMS To describe frequency of familial forms of MS Studying the trend of MS prevalence in Mexico Detecting familial accumulation of MS
Comparing demographic and longterm outcome of familial MS Calculating age adjusted risk for MS in relatives of patients Investigation the environmental and genetic causative factors interaction in MS and determination familial recurrence risk in 3 latitudinal distinct sits of Australia. Determine the clinical features of MS in subgroups (early‐onset, late‐onset, familial) Determine the epidemiology of MS.
Determining the prevalence of MS and clinical characteristics and occurrence of FMS Calculating the prevalence of FMS
Determining the occurrence of FMS and frequency of MS among the relatives Studying the epidemiology of MS
Objectives
* With at least one affected relative, # % Patients of MS cases.
2004
1992
2011
1964
2009
2010
2014
2014
Cross sectional
2006
(Saadatnia et al., 2007)
2006
1994
Cross sectional Cross sectional
Cross sectional
1979
(Kinnunen et al., 1984)
1997
Cohort
2012
(Hader and Yee, 2014)
Design
Prevalence date/period
Study (Year)
Table 1 Information about studies entered in systematic review and meta-analysis.
Hungary
Rio de Janeiro State, Brazil Mexico
Poland
East Azerbaijan, Iran
Qatar
Buenos Aires, Argentina
Isfahan, Iran
Qom, Iran
McDonald
Poser's
2005 McDonald
not mentioned
McDonald
Revised McDonald McDonald
McDonald
McDonald
McDonald
Revised McDonald
Australia (total)
Isfahan, Iran
Poser's
Flanders, Belgium
London, Ontario, Canada
Revised McDonald Poser's
87
Poser's
Saudi Arabia
51
Schumacher committee's
A small rural area of five communities in western province of Vaasa, Finland Croatia and Slovenia
1500
272
653
616
1000
154
219
3911
592
1718
1837
674
1044
141
150
Not mentioned
Saskatoon, Saskatchewan, Canada
Sample size
Diagnostic criteria
Location
33
9
40
38
71
16
23
430
66
209
265
104
208
30
25
15
49
Number of probands*
11% 10.5 10.4
34.25 – – –
–
6.17
– 28.5 27 –
– – – –
2
3.3
6.12
7.1
33.4
34.7
40.03
36.9
11.2
25.36
12.2
14.42
–
–
50.50
15.4
19.8 32.6
30.6
– 47.6
–
–
21
28.7
–
29.1
29
–
–
32.7
–
Onset
FMS prevalence #
29.4
Patients
Mean age
62
30
30
110
27.7
31–55
19.8
–
50.4
43.8
84.6
88
91
31–55
151.9
19.8
110
MS Prevalence
34.6° N, 50.8° E 32.6° N, 51.6° E 34.6° S, 58.3° W 25.3° N, 51.1° E 37.9° N, 46.2° E 51.9° N, 19.1° E 22.3° S, 42.7° W 23.6° N, 102.5° W 47.1° N, 19.5° E
32.6° N, 51.6° E
23.8° N, 45.0° E 51.2° N, 85.3° W 50.5° N, 4.4° E 25.2° S, 133.7° E
45.1° N, 15.2° E
63.0° N, 21.6° E
52.1° N, 106.6° W
Latitude
M.H. Harirchian et al.
Multiple Sclerosis and Related Disorders 20 (2018) 43–47
Multiple Sclerosis and Related Disorders 20 (2018) 43–47
M.H. Harirchian et al.
Fig. 2. Forest plot showed result of meta-analysis of the FMS prevalence.
Finally, we mention to a probable limitation of study in selection of key words in the method of our study. It was better that search was done with "familial recurrence" plus other key words.
Neurol. 88 (P3. 383). Baranzini, S.E., Wang, J., Gibson, R., et al., 2008. Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum. Mol. Genet. 18, 767–778. Carton, H., Vlietinck, R., Debruyne, J., et al., 1997. Risks of multiple sclerosis in relatives of patients in Flanders, Belgium. J. Neurol. Neurosurg. Psychiatry 62, 329–333. Cendrowski, W.S., 1967. Familial multiple sclerosis in Poland: Part 1. Geographical distribution of the disease. J. Neurol. Sci. 4, 95–99. Curtius, F., Speer, H., 1933. Multiple Sklerose und Erbanlage. Z. Gesamt. Neurologie Psychiatr. 60, 226–245. Deleu, D., Mir, D., Al Tabouki, A., et al., 2013. Prevalence, demographics and clinical characteristics of multiple sclerosis in Qatar. Mult. Scler. J. 19, 816–819. Ebers, G., Koopman, W., Hader, W., et al., 2000. The natural history of multiple sclerosis: a geographically based study. Brain 123, 641–649. Farez, M.F., Aguirre, M.E.B., Francisco, V., et al., 2014. Low familial risks for multiple sclerosis in Buenos Aires, Argentina. J. Neurol. Sci. 346, 268–270. Fricska-Nagy, Z., Bencsik, K., Rajda, C., et al., 2007. Epidemiology of familial multiple sclerosis in Hungary. Mult. Scler. J. 13, 260–261. Gonzalez, O., Sotelo, J., 1995. Is the frequency of multiple sclerosis increasing in Mexico? J. Neurol. Neurosurg. Psychiatry 59, 528–530. Guaschino, C., Esposito, F., Liberatore, G., et al., 2014. Familial clustering in Italian progressiveonset and bout-onset multiple sclerosis. Neurol. Sci. 35, 789–791. Hader, W.J., Yee, I.M., 2014. The prevalence of familial multiple sclerosis in saskatoon, Saskatchewan. Mult. Scler. Int. 2014. Haines, J.L., Terwedow, H.A., Burgess, K., et al., 1998. Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. Hum. Mol. Genet. 7, 1229–1234. Hashemilar, M., Savadi Ouskui, D., Farhoudi, M., et al., 2011. Multiple sclerosis in EastAzerbaijan, north west Iran. Neurol. Asia 16, 127–131. Jumah, M.A., Kojan, S., Khathaami, A., et al., 2011. Familial multiple sclerosis: does consanguinity have a role? Mult. Scler. J. 17, 487–489. Kinnunen, E., Wikström, J., Porras, J., et al., 1984. Prevalence, incidence and familial risk of multiple sclerosis. Acta Neurol. Scand. 69, 378–379. Leray, E., Moreau, T., Fromont, A., et al., 2016. Epidemiology of multiple sclerosis. Rev. Neurol. 172, 3–13. Maver, A., Lavtar, P., Smiljana, R., et al., 2017. Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis. Sci. Rep. 7, 3715. Mescheriakova, J.Y., Broer, L., Wahedi, S., et al., 2016. Burden of genetic risk variants in multiple sclerosis families in the Netherlands. Mult. Scler. J. Exp. Transl. Clin. 2, 1–8. Milo, R., Kahana, E., 2010. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun. Rev. 9, A387–A394. O'Gorman, C., Freeman, S., Taylor, B.V., et al., 2011. Familial recurrence risks for multiple sclerosis in Australia. J. Neurol. Neurosurg. Psychiatry 82, 1351–1354. Papais-Alvarenga, R.M., Pereira, F.C., Bernardes, M.S., et al., 2015. Familial forms of multiple sclerosis and neuromyelitis optica at an MS center in Rio de Janeiro State, Brazil. J. Neurol. Sci. 356, 196–201. Peterlin, B., Ristiæ, S., Juraj, S., et al., 2006. Region with persistent high frequency of multiple sclerosis in Croatia and Slovenia. Neurol. Sci. 247, 169–172. Rezaali, S., Khalilnezhad, A., Moghadasi, A.N., et al., 2013. Epidemiology of multiple sclerosis in Qom: demographic study in Iran. Iran. J. Neurol. 12, 136–143. Rose, J., Lynch, S., Pisan, P., et al., 1993. Genetic susceptibility in familial multiple sclerosis not linked to the myelin basic protein gene. Lancet 341, 1179–1181. Saadatnia, M., Etemadifar, M., Maghzi, A.H., et al., 2007. Multiple sclerosis in Isfahan, Iran. Int. Rev. Neurobiol. 79, 357–375. Sadovnick, A., Dyment, D., Ebers, G.C., et al., 1996. Evidence for genetic basis of multiple sclerosis. Lancet 347, 1728–1730. Sawcer, S., Franklin, R.J., Ban, M., 2014. Multiple sclerosis genetics. Lancet Neurol. 13, 700–709. Seboun, E., Oksenberg, J.R., Rombos, A., et al., 1999. Linkage analysis of candidate myelin genes in familial multiple sclerosis. Neurogenetics 2, 155–162. Toghianifar, N., Etemadifar, M., Sharifzadeh, A., et al., 2014. Characteristics of familial multiple sclerosis in Isfahan, Iran: a cross-sectional study. Neurol. Asia 19, 59–62. Young, L., Healey, K., Charlton, M., et al., 2015. A home-based comprehensive care model in patients with multiple sclerosis: a study pre-protocol. F1000Research 4, 872–883.
5. Conclusion In the present systematic review, we detected a significant heterogeneity from 2% in Hungary to 32.7% in Saskatchewan for FMS prevalence in the world. Prevalence of FMS was not dependent on latitude and ethnicity and dominant effect of genetic or environment on FMS prevalence was not derived definitely. Consequently our review highlighted the accumulation effects of genetic contents and environmental agents on prevalence of MS in families. In the mata-analysis the pooled prevalence of FMS in MS population was calculated 12.6% by random effect in the world (CI = 95%. 9.60–15.88). We recommend designing further studies to find the prevalence of FMS in different regions of the world with focus on effective factors (genes and environments) in FMS prevalence. Acknowledgment This research was supported by Tehran University of Medical Sciences and Health Services, Neuroscience Institute, Iran (grant number 95-02-54-34673). The authors are grateful for all colleagues in Iranian Center of Neurological Research specially Miss Maryam Rashidi for her kind collaborations. Conflict of interest The authors declare no conflict of interest in present study. Funding source Our funding source was Tehran University of Medical Sciences and Health Services, Neuroscience Institute. References Abbasi, M., Nabavi, S.M., Fereshtehnejad, S.M., et al., 2017. Multiple sclerosis and environmental risk factors: a case-control study in Iran. Neurol. Sci. 1–11. Akkad, D.A., Lee, D.H., Bruch, K., et al., 2016. Multiple sclerosis in families: risk factors beyond known genetic polymorphisms. Neurogenetics 17, 131–135. Albor, C., Sautoy, T., du., Kali Vanan, N., et al., 2017. Ethnicity and prevalence of multiple sclerosis in east London. Mult. Scler. J. 23, 36–42. Altun, Z., Idiman, E., Özçelik, P., et al., 2017. The differences of microRNA expressions profiles in peripheral blood cells in familial and sporadic multiple sclerosis patients (P3. 383). J.
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