Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis

Abstract

Gene-environment interactions may shed light on the mechanisms underlying multiple sclerosis (MS). We pooled data from two case-control studies on incident demyelination and used different methods to assess interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). Individuals exposed to both factors were at substantially increased risk of disease (OR=7.32, 95% CI=4.92-10.90). In logistic regression models, DRB1-15 and IM status were independent predictors of disease while their interaction term was not (DRB1-15*IM: OR=1.35, 95% CI=0.79-2.23). However, interaction on an additive scale was evident (Synergy index=2.09, 95% CI=1.59-2.59; excess risk due to interaction=3.30, 95%CI=0.47-6.12; attributable proportion due to interaction=45%, 95% CI=22-68%). This suggests, if the additive model is appropriate, the DRB1-15 and IM may be involved in the same causal process leading to MS and highlights the benefit of reporting gene-environment interactions on both a multiplicative and additive scale.

Population attributable fractions and joint effects of key risk factors for multiple sclerosis

“…The significant interaction on the additive scale between HLA-DR15 and IM is in line with reports from two previous case-control studies, 26–28 and a case-only study. 29 Putting the evidence critically together, and using stringent criteria as suggested by Boffetta and colleagues, 30 including the evidence on the main and interaction effects (replication, protection from bias, plausibility), suggests that at this stage there is moderate evidence for a true interaction.…”

Low sun exposure increases multiple sclerosis risk both directly and indirectly

“…Interactions have been demonstrated between several lifestyle and environmental risk factors for MS and presence of the strongest genetic risk factor, the HLA-DRB1*15:01 allele [5][6][7][8]. A synergistic effect between vitamin D and DRB1*15:01 has been suggested [9], whereas we found no such interaction in a previous study comprising a relatively small case-control sample [10].…”

Combining HLA-DR risk alleles and anti-Epstein-Barr virus antibody profiles to stratify multiple sclerosis risk

“…Previous studies have identified statistical interactions between HLA-DRB1*15 and anti-EBNA-1 antibody levels 12 or history of EBV-associated infectious mononucleosis, 27 suggesting that these risk factors may share a common pathway in disease susceptibility. Our data would support this view, particularly the finding that the strong independent effect of high-risk HLA-DR alleles (Model 1, p = 0.0009) on MS risk (Table 2) was substantially abrogated after incorporation of the influence of anti-EBNA-1 (long) antibody levels (Model 2, (EBNA-1 (long) , p = 1.8 × 10 −14 ; high-risk HLA-DR alleles, p = 0.26).…”