TY - JOUR

T1 - The interaction between smoking and HLA genes in multiple sclerosis

T2 - replication and refinement

AU - Hedström, Anna Karin

AU - Katsoulis, Michail

AU - Hössjer, Ola

AU - Bomfim, Izaura Lima

AU - Oturai, Annette

AU - Sondergaard, Helle Bach

AU - Sellebjerg, Finn

AU - Ullum, Henrik

AU - Thørner, Lise Wegner

AU - Gustavsen, Marte Wendel

AU - Harbo, Hanne F

AU - Obradovic, Dragana

AU - Gianfrancesco, Milena A

AU - Barcellos, Lisa F

AU - Schaefer, Catherine A

AU - Hillert, Jan

AU - Kockum, Ingrid

AU - Olsson, Tomas

AU - Alfredsson, Lars

PY - 2017/10

Y1 - 2017/10

N2 - 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 HLA-DRB*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.

AB - 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 HLA-DRB*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.

KW - Journal Article

U2 - 10.1007/s10654-017-0250-2

DO - 10.1007/s10654-017-0250-2

M3 - Journal article

C2 - 28597127

VL - 32

SP - 909

EP - 919

JO - European Journal of Epidemiology

JF - European Journal of Epidemiology

SN - 0393-2990

IS - 10

ER -