MS Speaks

Effect of smoking, a NAT1 genetic variant and HLA genes on disease activity in MS patients before and during interferon-beta treatment

E.R. Petersen1, A.B. Oturai1, N. Koch-Henriksen2,3, M. Magyari1,3, P.S. Sørensen1, F. Sellebjerg1, H.B. Søndergaard1

1Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, 2Department of Clinical Epidemiology, University of Aarhus, Clinical Institute, Aarhus, 3The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Background:

Increased risk of MS was previously found in smokers and interaction between HLA genes, a NAT1 variant, and smoking has been reported. However, the effect of this interaction on treatment response has not yet been investigated.

Objective:

To investigate if smoking before and during treatment with interferon-beta (IFN-beta) is associated with relapse rate, and whether the treatment response is influenced by the interaction between smoking and HLA-DRB1*15:01, HLA-A*02:01 and the NAT1 variant rs7388368.

Methods:

DNA from 2723 MS patients was stored in the Danish MS Biobank from 2006 to 2013; all were given a questionnaire. IFN-beta treated patients (n=2031) who had completed the questionnaire (n=1445) were selected. Progressive MS patients (n=126), patients treated less than 3 months (n=26), patients with missing HLA data (n=41) and patients with other ancestry than Nordic (n=107) were excluded.

Clinical data from two years before treatment start to either treatment stop or to the last follow-up examination was obtained from the Danish MS Treatment Register. Smoking status was obtained through the questionnaire survey and smoking intensity was determined as cigarette packs per day (1 pack contains 20 cigarettes). Tag-SNPs for HLA-DRB1*15:01 and HLA-A*02:01 genes and the NAT1 rs7388368 variant were genotyped using TaqMan allelic discrimination. Age and sex were included as covariates in the primary analyses and the association between treatment response and smoking intensity was analyzed by Poisson regression and negative binomial models.

Results:

1145 relapsing-remitting MS (RRMS) patients were included in the study; 323 men and 822 women. Two time periods were evaluated; two year prior IFN-beta treatment and during treatment, with number of smokers of 615 and 389, respectively. Analysis of the two year prior treatment start showed no association between smoking and the number of relapses.

 During IFN-beta treatment smoking intensity was significantly associated with treatment response. The incidence rate ratio per one additional pack of cigarettes per day was 1.25 (95% CI:1.04-1.50, p=0. 019). We did not observe interaction between smoking and HLA genes or the NAT1 variant in the analysis.

Conclusion:

This study demonstrates for the first time that smoking is associated with increased disease activity in RRMS patients treated with IFN-beta. Interaction between smoking and HLA genes or the NAT1 gene variant and disease activity was not observed.

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Disclosure:

Eva Rosa Petersen has received support for congress participation from Teva and Genzyme.
Annette Bang Oturai has served on scientific advisory boards for Biogen Idec and Genzyme; has received research support from Novartis and Biogen Idec; has received speaker honoraria from Biogen Idec, Novartis and TEVA; and has received support for congress participation from, Merck Serono, Teva, Biogen, Novartis and Genzyme.
Nils Koch-Henriksen has received honoraria for lecturing and participation in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish MS Treatment Register from Bayer-Schering, Merck-Serono, BiogenIdec, TEVA, Sanofi-Avensis, and Novartis for the Danish MS Treatment Register.
Melinda Magyari has served on scientific advisory board for Biogen Idec and Novartis, Merck Serono, has received honoraria for lecturing from Biogen Idec, Merck Serono, Novartis, Genzyme, has received support for congress participation from Biogen Idec, Novartis, Genzyme, Teva.
P. S. Sørensen has received personal compensation for serving on scientific advisory boards, steering committees or independent data monitoring boards for Biogen Idec, Merck Serono, Novartis, Genzyme, Teva Pharmaceutical Industries Ltd., GlaxoSmithKline, medDay Pharmaceuticals and Forward Pharma and has received speaker honoraria from Biogen Idec, Merck Serono, Teva Pharmaceutical Industries Ltd., Genzyme, and Novartis.
Finn Sellebjerg has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, EMD Serono, Genzyme, Lundbeck, Merck Serono, Novartis and Teva.
Helle Bach Søndergaard has received support for congress participation from Biogen Idec, Genzyme and Teva.