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

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10654-017-0250-2) contains supplementary material, which is available to authorized users.

The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years

“…These studies have been limited to HLA genes so far, with positive results reported for active and passive smoking, EBV infection and infectious mononucleosis, and childhood/adolescent obesity [reviewed in [5]]. For example, in a pooled analysis of six datasets, smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased disease risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8–14.9) [69]. Novel modeling approaches will afford the analysis of gene-environment interactions genome-wide [70], potentially addressing an important knowledge gap in the understanding of MS heritability.…”

“…Emerging evidence suggests that while some risk loci are conserved, ethnic-specific variants may contribute to shaping disease susceptibility in different populations (50, 69–72). …”

Effects of smoking on the association of human leukocyte antigen with ulcerative colitis

“…In rheumatoid arthritis, the risk of developing antibodies to citrullinated proteins has been associated with gene–environment interactions between HLA‐DRB1 shared epitope alleles and smoking . Other diseases showing associations between HLA and smoking include idiopathic inflammatory myopathies, Parkinson disease, multiple sclerosis, and lymphoma …”

“…30 In rheumatoid arthritis, the risk of developing antibodies to citrullinated proteins has been associated with gene-environment interactions between HLA-DRB1 shared epitope alleles and smoking. [30][31][32][33][34] Other diseases showing associations between HLA and smoking include idiopathic inflammatory myopathies, 35 Parkinson disease, 36,37 multiple sclerosis, [38][39][40][41] and lymphoma. 42 In the current study, the strong effects of HLA-DRB1*15:02 on the risk of UC were observed in never smokers.…”

Quantifying and estimating additive measures of interaction from case-control data

“…The additive odds measures of joint effects and interaction are defined in Section 3, and the procedures for estimating them are given in Section 4. Our methodology is illustrated in Section 5 for a multiple sclerosis (MS) dataset from Hedström et al [14], and a concluding discussion appears in Section 6.…”