- Email: [email protected]
Smoking and multiple sclerosis, cause or coincidence?
Multiple Sclerosis and Related Disorders 1 (2012) 106–107
Contents lists available at SciVerse ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Commentary
Smoking and multiple sclerosis, cause or coincidence? Natalia Palacios a,n, Kelly Claire Simon a,b a b
Department of Nutrition, Harvard School of Public Health, 655 Huntington Avenue, Building 2, 3rd Floor, Boston, MA 02115, USA Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
a r t i c l e i n f o Article history: Received 10 January 2012 Received in revised form 7 March 2012 Accepted 11 March 2012
An increased risk of MS among smokers has been consistently found in numerous longitudinal studies with excess rates ranging from 1.3 to 1.7 for heavy long-term smokers as compared to never smokers (Hernan et al., 2005, Herna´n et al., 2001). Smoking has also been associated with an increased risk of MS progression from a relapsing-remitting clinical course into a secondary progressive course (Healy et al., 2009; Hernan et al., 2005). Recently, Hedstrom et al. (2011) found that exposure to passive smoking was also associated with a similar 30% increased MS risk and an even greater MS risk was associated with longer exposure to passive smoking (80% increased risk among those exposed for more than 20 years). However, it is still unclear if the relationship between smoking and MS is causal, and if so, what are the relevant components of cigarette smoking for MS risk. To provide some evidence of causation, Palacios et al. (2011) compared published data on MS incidence and smoking rates among men and women over the past several decades to determine if there were similarities consistent with a causal interpretation (Palacios et al., 2011). Correlating female to male ratios of prevalence of smoking from numerous birth cohorts within several countries with the corresponding female to male ratios of MS incidence demonstrated that a significant proportion of the increase in the female/male ratio of MS incidence could potentially be explained by the change over time in the rates of smoking in women as compared to men. The change in the smoking ratio was primarily due to a steady decrease in smoking among men over the past decades from approximately 80% to approximately 20%, while smoking among women remained relatively stable. The female to male smoking ratio was
n
Corresponding author. Fax: þ617 432 2435. E-mail address: [email protected] (N. Palacios).
2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/doi:10.1016/j.msard.2012.03.001
significantly correlated to that of MS (r ¼0.16; 95% confidence interval [CI]: 0.06, 0.26; p¼0.002). While the Palacios et al. study shows that smoking could partly explain the increasing female to male ratio of MS, it does not explain the increasing incidence of MS among women (Orton et al., 2006). It is thus possible that another exposure is resulting in increased incidence in both sexes that may be offset in men by smoking cessation. One possibility discussed by Palacios et al. is the increase in use of sunscreen products that would decrease vitamin D exposure, and result in an overall increased incidence of MS. However, there are many other potential exposures that may explain this disparity and ongoing research is aimed at determining these factors. Studies of genetics and gene-environment interactions could bring us closer to unraveling the biological relationship between smoking and MS, as the cause of this complex disorder likely involves interactions between environmental factors and genetic susceptibility. To address how smoking may influence MS risk in the context of known MS susceptibility alleles, Hedstrom et al. (2011) examined the interaction between smoking and the HLA-DRB1*15 and HLA-A*02 alleles. The increased risk of MS associated with HLA-DRB1*15 has been long known and remains the strongest genetic risk factor. (Lincoln et al., 2009). More recently, the independent effects of other HLA alleles has been examined with HLA-A*02 (Brynedal et al., 2007), among others, showing a protective effect. It has been previously shown that smoking and HLA-DRB1*15 appear to exert independent effects on MS risk (Simon et al., 2010); however, additional HLA alleles were not considered. In the Hedstrom study, smoking alone was associated with an increased risk of MS (OR¼ 1.6, 95% CI 1.3–2.0) consistent with previous estimates (Ascherio and Munger, 2007; Handel et al., 2011). Smokers with both genetic risk factors (HLA-DRB1*15 positive and HLA-A*02 negative) were at an over 13-fold increased risk of MS compared to non-smokers with neither risk factor. Non-smokers
N. Palacios, K. Claire Simon / Multiple Sclerosis and Related Disorders 1 (2012) 106–107
with both genetic risk factors had approximately a five-fold higher risk of MS. That the combined effect was greater than the expected increased risk assuming the risk factors were independent, suggests a three-way interaction between HLA–DRB1*15, HLA-A*02 and smoking. Specifically, an interaction between the two HLA alleles was only observed in smokers. This finding requires replication and more work needs to be done to determine the biological relevance underlying this statistical interaction. Central to elucidating a role for smoking in predisposing to MS would be determining a definitive biological mechanism. Smoking has been shown to have immunomodulatory effects, (Sopori, 2002) but how they relate to MS is unclear. Two studies have shown that tobacco smoking, but not moist snuff use, was associated with increased MS risk providing evidence against a role for nicotine. (Carlens et al., 2010; Hedstrom et al., 2009). Given this finding, it has been hypothesized that lung irritation may be an important event linking smoking to MS susceptibility (Hedstrom et al., 2011), additionally, smoking may increase the frequency and persistence of respiratory infections resulting in increased MS risk (Hedstrom et al., 2009). Understanding the relevant time period of exposure is also important and deserves further attention. Continued work on the specific biological mechanisms linking the observational findings of increased MS risk associated smoking is warranted. Importantly, understanding risk factors in the context of genetic susceptibility is relevant for our understanding so continued study and replication of gene-environment interactions are necessary. Understanding the relationship between smoking and MS in the context of the changing epidemiology of MS will require joint contributions from epidemiological, genetic and gene–environment interaction studies. References Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: noninfectious factors. Annals of Neurology 2007;61:504–13.
107
Brynedal B, Duvefelt K, Jonasdottir G, Roos IM, Akesson E, Palmgren J, et al. HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS One 2007;2:e664. Carlens, C., Hergens, M.P., Grunewald, J., Ekbom, A., Eklund, A., Olgart Hoglund, C., et al. Smoking, use of moist snuff and risk of chronic inflammatory diseases. American Journal of Respiratory Critical Care Medicine. 2010. Handel AE, Williamson AJ, Disanto G, Dobson R, Giovannoni G, Ramagopalan SV. Smoking and multiple sclerosis: an updated meta-analysis. PLoS One 2011; 6:e16149. Healy BC, Ali EN, Guttman CRG, Chitnis T, Glanz BI, Buckle G, et al. Smoking and disease progression in multiple sclerosis. Archives of Neurology 2009;66:858–64. Hedstrom A, Baarnhielm M, Olsson T, Alfredsson L. Exposure to environmental tobacco smoke is associated with increased risk for multiple sclerosis. Multiple Sclerosis 2011;17:788–93. Hedstrom AK, Baarnhielm M, Olsson T, Alfredsson L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology 2009;73: 696–701. Hernan MA, Jick SS, Logroscino G, Olek MJ, Ascherio A, Jick H. Cigarette smoking and the progression of multiple sclerosis. Brain 2005;128:1461–5. Herna´n MA, Olek MJ, Ascherio A. Cigarette smoking and incidence of multiple sclerosis. American Journal of Epidemiology 2001;154:69–74. Lincoln MR, Ramagopalan SV, Chao MJ, Herrera BM, Deluca GC, Orton SM, et al. Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility. Proceedings of the National Academy of Sciences USA 2009;106:7542–7. 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 Neurology 2006;5:932–6. Palacios N, Alonso A, Bronnum-Hansen H, Ascherio A. Smoking and increased risk of multiple sclerosis: parallel trends in the sex ratio reinforce the evidence. Annals of Epidemiology 2011;21:536–42. Simon KC, Van der Mei IA, Munger KL, Ponsonby AL, Dickinson JL, Dwyer T, et al. Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB11501 on multiple sclerosis risk. Neurology 2010;74:1365–71. Sopori M. Effects of cigarette smoke on the immune system. Nature Reviews Immunology 2002;2:372–7.
Contents lists available at SciVerse ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Commentary
Smoking and multiple sclerosis, cause or coincidence? Natalia Palacios a,n, Kelly Claire Simon a,b a b
Department of Nutrition, Harvard School of Public Health, 655 Huntington Avenue, Building 2, 3rd Floor, Boston, MA 02115, USA Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
a r t i c l e i n f o Article history: Received 10 January 2012 Received in revised form 7 March 2012 Accepted 11 March 2012
An increased risk of MS among smokers has been consistently found in numerous longitudinal studies with excess rates ranging from 1.3 to 1.7 for heavy long-term smokers as compared to never smokers (Hernan et al., 2005, Herna´n et al., 2001). Smoking has also been associated with an increased risk of MS progression from a relapsing-remitting clinical course into a secondary progressive course (Healy et al., 2009; Hernan et al., 2005). Recently, Hedstrom et al. (2011) found that exposure to passive smoking was also associated with a similar 30% increased MS risk and an even greater MS risk was associated with longer exposure to passive smoking (80% increased risk among those exposed for more than 20 years). However, it is still unclear if the relationship between smoking and MS is causal, and if so, what are the relevant components of cigarette smoking for MS risk. To provide some evidence of causation, Palacios et al. (2011) compared published data on MS incidence and smoking rates among men and women over the past several decades to determine if there were similarities consistent with a causal interpretation (Palacios et al., 2011). Correlating female to male ratios of prevalence of smoking from numerous birth cohorts within several countries with the corresponding female to male ratios of MS incidence demonstrated that a significant proportion of the increase in the female/male ratio of MS incidence could potentially be explained by the change over time in the rates of smoking in women as compared to men. The change in the smoking ratio was primarily due to a steady decrease in smoking among men over the past decades from approximately 80% to approximately 20%, while smoking among women remained relatively stable. The female to male smoking ratio was
n
Corresponding author. Fax: þ617 432 2435. E-mail address: [email protected] (N. Palacios).
2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/doi:10.1016/j.msard.2012.03.001
significantly correlated to that of MS (r ¼0.16; 95% confidence interval [CI]: 0.06, 0.26; p¼0.002). While the Palacios et al. study shows that smoking could partly explain the increasing female to male ratio of MS, it does not explain the increasing incidence of MS among women (Orton et al., 2006). It is thus possible that another exposure is resulting in increased incidence in both sexes that may be offset in men by smoking cessation. One possibility discussed by Palacios et al. is the increase in use of sunscreen products that would decrease vitamin D exposure, and result in an overall increased incidence of MS. However, there are many other potential exposures that may explain this disparity and ongoing research is aimed at determining these factors. Studies of genetics and gene-environment interactions could bring us closer to unraveling the biological relationship between smoking and MS, as the cause of this complex disorder likely involves interactions between environmental factors and genetic susceptibility. To address how smoking may influence MS risk in the context of known MS susceptibility alleles, Hedstrom et al. (2011) examined the interaction between smoking and the HLA-DRB1*15 and HLA-A*02 alleles. The increased risk of MS associated with HLA-DRB1*15 has been long known and remains the strongest genetic risk factor. (Lincoln et al., 2009). More recently, the independent effects of other HLA alleles has been examined with HLA-A*02 (Brynedal et al., 2007), among others, showing a protective effect. It has been previously shown that smoking and HLA-DRB1*15 appear to exert independent effects on MS risk (Simon et al., 2010); however, additional HLA alleles were not considered. In the Hedstrom study, smoking alone was associated with an increased risk of MS (OR¼ 1.6, 95% CI 1.3–2.0) consistent with previous estimates (Ascherio and Munger, 2007; Handel et al., 2011). Smokers with both genetic risk factors (HLA-DRB1*15 positive and HLA-A*02 negative) were at an over 13-fold increased risk of MS compared to non-smokers with neither risk factor. Non-smokers
N. Palacios, K. Claire Simon / Multiple Sclerosis and Related Disorders 1 (2012) 106–107
with both genetic risk factors had approximately a five-fold higher risk of MS. That the combined effect was greater than the expected increased risk assuming the risk factors were independent, suggests a three-way interaction between HLA–DRB1*15, HLA-A*02 and smoking. Specifically, an interaction between the two HLA alleles was only observed in smokers. This finding requires replication and more work needs to be done to determine the biological relevance underlying this statistical interaction. Central to elucidating a role for smoking in predisposing to MS would be determining a definitive biological mechanism. Smoking has been shown to have immunomodulatory effects, (Sopori, 2002) but how they relate to MS is unclear. Two studies have shown that tobacco smoking, but not moist snuff use, was associated with increased MS risk providing evidence against a role for nicotine. (Carlens et al., 2010; Hedstrom et al., 2009). Given this finding, it has been hypothesized that lung irritation may be an important event linking smoking to MS susceptibility (Hedstrom et al., 2011), additionally, smoking may increase the frequency and persistence of respiratory infections resulting in increased MS risk (Hedstrom et al., 2009). Understanding the relevant time period of exposure is also important and deserves further attention. Continued work on the specific biological mechanisms linking the observational findings of increased MS risk associated smoking is warranted. Importantly, understanding risk factors in the context of genetic susceptibility is relevant for our understanding so continued study and replication of gene-environment interactions are necessary. Understanding the relationship between smoking and MS in the context of the changing epidemiology of MS will require joint contributions from epidemiological, genetic and gene–environment interaction studies. References Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: noninfectious factors. Annals of Neurology 2007;61:504–13.
107
Brynedal B, Duvefelt K, Jonasdottir G, Roos IM, Akesson E, Palmgren J, et al. HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS One 2007;2:e664. Carlens, C., Hergens, M.P., Grunewald, J., Ekbom, A., Eklund, A., Olgart Hoglund, C., et al. Smoking, use of moist snuff and risk of chronic inflammatory diseases. American Journal of Respiratory Critical Care Medicine. 2010. Handel AE, Williamson AJ, Disanto G, Dobson R, Giovannoni G, Ramagopalan SV. Smoking and multiple sclerosis: an updated meta-analysis. PLoS One 2011; 6:e16149. Healy BC, Ali EN, Guttman CRG, Chitnis T, Glanz BI, Buckle G, et al. Smoking and disease progression in multiple sclerosis. Archives of Neurology 2009;66:858–64. Hedstrom A, Baarnhielm M, Olsson T, Alfredsson L. Exposure to environmental tobacco smoke is associated with increased risk for multiple sclerosis. Multiple Sclerosis 2011;17:788–93. Hedstrom AK, Baarnhielm M, Olsson T, Alfredsson L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology 2009;73: 696–701. Hernan MA, Jick SS, Logroscino G, Olek MJ, Ascherio A, Jick H. Cigarette smoking and the progression of multiple sclerosis. Brain 2005;128:1461–5. Herna´n MA, Olek MJ, Ascherio A. Cigarette smoking and incidence of multiple sclerosis. American Journal of Epidemiology 2001;154:69–74. Lincoln MR, Ramagopalan SV, Chao MJ, Herrera BM, Deluca GC, Orton SM, et al. Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility. Proceedings of the National Academy of Sciences USA 2009;106:7542–7. 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 Neurology 2006;5:932–6. Palacios N, Alonso A, Bronnum-Hansen H, Ascherio A. Smoking and increased risk of multiple sclerosis: parallel trends in the sex ratio reinforce the evidence. Annals of Epidemiology 2011;21:536–42. Simon KC, Van der Mei IA, Munger KL, Ponsonby AL, Dickinson JL, Dwyer T, et al. Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB11501 on multiple sclerosis risk. Neurology 2010;74:1365–71. Sopori M. Effects of cigarette smoke on the immune system. Nature Reviews Immunology 2002;2:372–7.