Smoking and Two Human Leukocyte Antigen Genes Interact to Increase the Risk for Multiple Sclerosis

Anna Karin Hedström; Emilie Sundqvist; Maria Bäärnhielm; Nina Nordin; Jan Hillert; Ingrid Kockum; Tomas Olsson; Lars Alfredsson


Brain. 2011;134(3):653-664. 

In This Article

Abstract and Introduction


Both genetic and environmental factors display low or modest associations with multiple sclerosis. Hypothetically, gene–environment interactions may exert much stronger effects. In this study, we investigated potential interactions between genetic risk factors and smoking in relation to risk of developing multiple sclerosis. A population-based case–control study involving incident cases of multiple sclerosis (843 cases, 1209 controls) was performed in Sweden. Cases and controls were classified according to their smoking status and human leukocyte antigen DRB1 as well as human leukocyte antigen A genotypes. Subjects with different genotypes and smoking habits were compared with regard to incidence of multiple sclerosis, by calculating odds ratios with 95% confidence intervals employing logistic regression. The potential interaction between different genotypes, as well as between genotype and smoking, was evaluated by calculating attributable proportion due to interaction. A significant interaction between two genetic risk factors, carriage of human leukocyte antigen DRB1*15 and absence of human leukocyte antigen A*02, was observed among smokers whereas such an interaction was absent among non-smokers. There were considerable differences in odds ratios between the various groups. Compared with non-smokers with neither of the genetic risk factors, the odds ratio was 13.5 (8.1–22.6) for smokers with both genetic risk factors. The odds ratio for smokers without genetic risk was 1.4 (0.9–2.1) and the odds ratio for non-smokers with both genetic risk factors was 4.9 (3.6–6.6). Among those with both genetic risk factors, smoking increased the risk by a factor of 2.8 in comparison with a factor of 1.4 among those without the genetic risk factors. The risk of developing multiple sclerosis associated with human leukocyte antigen genotypes may be strongly influenced by smoking status. The findings are consistent with our hypothesis that priming of the immune response in the lungs may subsequently lead to multiple sclerosis in genetically susceptible people.


Multiple sclerosis is a complex and inflammatory disease of the central nervous system causing damage to myelin and axons, and progressive neurological dysfunction often ensues. Improved therapy and prevention depend on better understanding of causes and mechanisms in multiple sclerosis. Hereby, definitions of disease-associated genes and environmental factors have begun to offer some clues. However, it is likely that studies of gene–environment interactions will provide a more complete understanding.

The familial aggregation evident in studies of twins, siblings and families proves a genetic predisposition to multiple sclerosis. The impact of discrete gene variants outside the human leukocyte antigen (HLA) complex is low (International Multiple Sclerosis Genetics Consortium, 2005, 2010) while genes of the HLA complex exert a stronger influence. The haplotype containing the HLA-DRB1*15 allele provides an increased risk with odds ratios in the order of 2–4 (Lincoln et al., 2005). In addition, evidence is mounting for an additional role of HLA class I genes (Brynedal et al., 2007; Burfoot et al., 2008; Lorentzen et al., 2009; Bergamaschi et al., 2010). In particular, the HLA-A*02 allele of the HLA-A locus has been reported to have a protective role with an odds ratio of approximately 0.5 (Brynedal et al., 2007; Burfoot et al., 2008; Bergamaschi et al., 2010). Interestingly, the combination of carriage of HLA-DRB1*15 and absence of HLA-A*02 alleles provides risk increases beyond additive effects (Brynedal et al., 2007), suggesting the existence of gene–gene and/or gene–environment interaction.

Migration studies, geographical gradients and discordancy in identical twins indicate that the environment has significant influence on the development of multiple sclerosis. Accumulating data suggest particular environmental factors in the aetiology of multiple sclerosis, such as Epstein-Barr virus infection (Bagert, 2009), vitamin D deficiency (Munger et al., 2006) and smoking (Antonowsky et al., 1965; Thorogood and Hannaford, 1998; Ghadirian et al., 2001; Hernan et al., 2001, 2005; Riise et al., 2003; Pekmezovic et al., 2006; Hedström et al., 2009). In this study, we focus on the potential interaction between smoking and the HLA-DRB1*15 and HLA-A*02 alleles.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: