The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement

• Published in: European journal of epidemiology Vol. 32; no. 10; pp. 909 - 919
• Main Authors: Hedström, Anna Karin, Katsoulis, Michail, Hössjer, Ola, Bomfim, Izaura L., Oturai, Annette, Sondergaard, Helle Bach, Sellebjerg, Finn, Ullum, Henrik, Thørner, Lise Wegner, Gustavsen, Marte Wendel, Harbo, Hanne F., Obradovic, Dragana, Gianfrancesco, Milena A., Barcellos, Lisa F., Schaefer, Catherine A., Hillert, Jan, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer 2017; Springer Netherlands; Springer Nature B.V
• Subjects: Adaptive immunity; Antigens; Cardiology; Case-Control Studies; Drb1 protein; Epidemiology; Female; Gene-Environment Interaction; Genes; Genetic Predisposition to Disease; Genetics; Genotype; Genotypes; Histocompatibility antigen HLA; HLA; HLA-A Antigens - genetics; HLA-DRB1 Chains - genetics; Humans; Immunity; Infectious Diseases; Lymphocytes; Lymphocytes T; Male; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Middle Aged; Multiple sclerosis; Multiple Sclerosis - epidemiology; Multiple Sclerosis - genetics; Multiple Sclerosis - immunology; NEURO-EPIDEMIOLOGY; Oncology; Population genetics; Population studies; Populations; Public Health; Replication; Risk analysis; Risk Factors; Smoking; Smoking - adverse effects; Smoking - immunology; Sweden - epidemiology; Multiple sclerosis; Gene–environment interaction; HLA; Smoking
• ISSN: 0393-2990; 1573-7284; 1573-7284
• DOI: 10.1007/s10654-017-0250-2

Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLADRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.