Supplementary figure 1: Median time to reach EDSS 6 for all patients and patients stratified according to gender. pvalue= 0.43

Supplementary table 1: P values from multiple comparison of time to reach EDSS 6.0 according to age at onset.

Age at onset / 20-29 years / 30-39 years / ³40 years
£ 19 years / 0.855 / 0.863 / 0.025
20-29 years / / / 0.800 / 0.000435*
30-39 years / / / / / 0.00812*

Among the 38 patients with age at onset ³40 years, 13 PP, 19RR, 6SP and 17 DR15 carriers, 21 DR15 non-carriers.

Supplementary table 2: TDT analysis of French MS patients

All transmissions / Without DR15 transmissions
HLA Allele / T / NT / TDT / p / T / NT / Chisq / p
15 / 323 / 87 / 135.844 / 2.16E-31 / -- / -- / -- / --
1 / 89 / 137 / 10.195 / 0.001 / 80 / 90 / 0.588 / 0.443
3 / 133 / 138 / 0.092 / 0.761 / 114 / 88 / 3.347 / 0.067
4 / 132 / 162 / 3.061 / 0.080 / 114 / 109 / 0.112 / 0.738
7 / 109 / 143 / 4.587 / 0.032 / 94 / 94 / 0.000 / 1.000
8 / 45 / 46 / 0.011 / 0.917 / 40 / 33 / 0.671 / 0.413
9 / 11 / 13 / 0.167 / 0.683 / 9 / 5 / 1.143 / 0.285
10 / 8 / 7 / 0.067 / 0.796 / 7 / 4 / 0.818 / 0.366
11 / 98 / 133 / 5.303 / 0.021 / 87 / 98 / 0.654 / 0.419
12 / 10 / 23 / 5.121 / 0.024 / 8 / 15 / 2.130 / 0.144
13 / 118 / 168 / 8.741 / 0.003 / 104 / 113 / 0.373 / 0.541
14 / 22 / 43 / 6.785 / 0.009 / 19 / 34 / 4.245 / 0.039
16 / 27 / 25 / 0.077 / 0.782 / 27 / 20 / 1.043 / 0.307

T and NT: number of times alleles is transmitted or not by a heterozygous parent. TDT: values of the TDT statistic. P: nominal p-value of the TDT statistic. As expected, a very strong association with HLA DRB *1501 allele was observed in our sample (p= 2.16E-31). To identify other alleles of interest, either predisposing or protective, the analysis was repeated, after exclusion of all informative DR15 transmissions from parent to children. The HLA DRB1*14 allele was found to have a protective effect (p=0.04) although this association was no more significant after correction for the multiple tests.

Supplementary table 3: Genotype Relative Risk (GRR) for the total Sample and after stratification on the form of the disease.

MS Form / Genotype / GRR / 95% CI
All / DR15/DR15 / 10.16 / [5.87-17.58]
All / DR15/DRX / 4.39 / [3.28-5.86]
Relapsing Remitting / DR15/DR15 / 8.60 / [4.58-16.16]
Relapsing Remitting / DR15/DRX / 3.61 / [2.61-5.00]
Secondary Progressive / DR15 carriers / 10.97 / [4.39-27.36]
Primary Progressive / DR15 carriers / 5.17 / [1.99-13.43]

In our data, the hypothesis of a dominant model was rejected (p =0.0005). An additive model, with a GRR of 4.39 and 10.16 for DR15 heterozygotes and homozygotes respectively, was compatible with a dose effect of HLA DR15 (p=0.55).

Supplementary table 4: P values from comparison of time to reach EDSS 6.0 according to HLA*DRB1 alleles using log-rank-test among DR15 non-carriers patients

Alleles / Number of carriers / Pvalues
1 / 42 / 0.478
3 / 63 / 0.590
4 / 76 / 0.892
7 / 43 / 0.130
8 / 21 / 0.508
9 / 4 / ND
10 / 6 / ND
11 / 44 / 0.308
12 / 4 / ND
13 / 64 / 0.381
14 / 9 / 0.413
16 / 14 / 0.100