Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk

Abstract

Objective: To examine the interplay between smoking, serum antibody titers to the Epstein-Barr virus nuclear antigens (anti-EBNA), and HLA-DR15 on multiple sclerosis (MS) risk.Methods: Individual and pooled analyses were conducted among 442 cases and 865 controls from 3 MS case-control studies-a nested case-control study in the Nurses' Health Study/Nurses' Health Study II, the Tasmanian MS Study, and a Swedish MS Study. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for the association between smoking, anti-EBNA titers, HLA-DR15, and MS risk. Study estimates were pooled using inverse variance weights to determine a combined effect and p value.Results: Among MS cases, anti-EBNA titers were significantly higher in ever smokers compared to never smokers. The increased risk of MS associated with high anti-EBNA Ab titers was stronger among ever smokers (OR ϭ 3.9, 95% CI ϭ 2.7-5.7) compared to never smokers (OR ϭ 1.8, 95% CI ϭ 1.4 -2.3; p for interaction ϭ 0.001). The increased risk of MS associated with a history of smoking was no longer evident after adjustment for anti-EBNA Ab titers. No modification or confounding by HLA-DR15 was observed. The increased risk of MS associated with ever smoking was only observed among those who had high anti-EBNA titers (OR ϭ 1.7, 95% CI ϭ 1.1-2.6).Conclusions: Smoking appears to enhance the association between high anti-EBNA titer and increased multiple sclerosis (MS) risk. The association between HLA-DR15 and MS risk is independent of smoking. Further work is necessary to elucidate possible biologic mechanisms to explain this finding. Neurology Multiple sclerosis (MS) is the most common nontraumatic disabling neurologic disease among young adults in the United States.1 The exact mechanism resulting in disease progression is unknown, though likely autoimmune in origin. Risk factors that have been consistently associated with increased MS risk include the HLA-DRB1*1501 haplotype in Caucasian populations, 2 high antibody levels against the Epstein-Barr virus (EBV), 3 and a smoking history. 4Whether these factors are independently associated with risk of MS or are related, possibly suggesting a common biologic mechanism, is unclear. We recently observed that the associations between HLA-DR15 positivity and EBV infection are independent MS risk factors. 5,6 However, the risk of MS associated with smoking independent of the other 2 factors and potential 3-way relationships have not been investigated.

Epstein-Barr virus and multiple sclerosis: interaction with HLA

“…These interactions have been suggested by previous smaller studies but have not been formally tested. 14,15 The interaction between EBNA1: 385-420 IgG and absence of A*02 is instead a novel finding.…”

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

“…As already emphasized in the preceding chapters, risk factors for MS are multiple and smoking may, therefore, interact with genetics and the main two other identified environmental risk factors. Smoking is associated with higher levels of EBNA1 [Nielsen et al 2007a] and enhances the association between high EBNA1 titres and increased MS risk [Simon et al 2010]. An interaction with HLA-DRB1*15 was also observed in smoker but not in nonsmoker patients with MS [Hedström et al 2011b].…”

Environmental triggers of multiple sclerosis

“…Vitamin D is a potent immunomodulator affecting proinflammatory pathways [55,56] as well as the number and activity of regulatory T cells [57]. Epidemiological studies have shown an increase in MS frequency with increasing distance from the equator, which inversely correlates with duration and intensity of sunlight [58][59][60][61][62]. Interestingly, populations situated at high latitudes but having high consumption of vitamin D rich food were observed to have reduced MS prevalence [63][64][65], while the risk of MS incidence decreased with movement from high to low altitudes [2].…”