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

Anna Karin Hedström,Dragana Obradovic,Lisa F Barcellos,Jan Hillert,Annette Oturai,Ola Hössjer,Hanne F Harbo,Helle Bach Sondergaard,Tomas Olsson,Lars Alfredsson,Marte Wendel Gustavsen,Michail Katsoulis,Milena A Gianfrancesco,Izaura L Bomfim,Ingrid Kockum,Lise Wegner Thørner,Henrik Ullum,Catherine A Schaefer,Finn Sellebjerg

doi:10.1007/s10654-017-0250-2

Abstract

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.

Highlights

Multiple sclerosis (MS) arises from a combination of a complex genetic predisposition and environmental factors
Two way interactions were observed between each combination of the three variables, invariant over categories of the third
The difference in multiple sclerosis (MS) risk between the extremes was considerable; smokers carrying human leukocyte antigen (HLA)-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors

Summary

Introduction

Multiple sclerosis (MS) arises from a combination of a complex genetic predisposition and environmental factors. Well-established environmental factors associated with MS risk are Epstein–Barr virus (EBV) infection [5, 6], vitamin D status [7], sun exposure habits [8], adolescent body mass index [9, 10], and smoking [11]. Based on the Swedish project Epidemiological Investigation of Multiple Sclerosis (EIMS), an interaction between smoking and HLA complex genes regarding risk of MS was reported in 2011 [12]. Smoking increased the risk of MS by a factor of 1.5 among those without HLA associated genetic risk and a combination of the genetic risk factors presence of HLA-DRB*15 and absence of HLA-A*02 increased the risk by a factor of 5.0 among non-smokers.

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