Multivariable GLMMs results.

<p>Multivariable GLMMs results.</p

Results of principal component analysis (PCA).

<p>Results of principal component analysis (PCA).</p

Scree plots of the principal component analysis (with and without copper).

<p>Scree plots of the principal component analysis (with and without copper).</p

The 25 municipalities forming the study area, the sampling sites and the ore bodies.

<p>The 25 municipalities forming the study area, the sampling sites and the ore bodies.</p

Transmission disequilibrium test of the not-transmitted parental haplotype in multiple sclerosis patients carrying (DR3+) or not carrying (DR3−) the HLA-DRB1*03∶01-*02∶01 haplotype.

<p>NA = no mating of this type was available.</p><p>Rare haplotypes belonging to the same haplogroup were grouped together: as *11 were designed *11∶01-02-03-04 -*03∶01, *11∶01-*03∶03-*05∶02 and *11∶04-*06∶03; as *07 were designed *07∶01- *02∶01 and *07∶01-*03∶03; as *13 were designed *13∶01-*06∶03-*03∶03, *13∶02-*05∶01-*05∶031-*06∶02-*06∶04-*06∶05-*06∶09, *13∶05-*03∶01 and *13∶16-DQB1*06∶04; as *04 were designed *04∶01-*03∶01-*03∶02, *04∶02-*03∶02, *04∶03– *03∶01-02-04-05, *04∶04-*03∶02-*04∶02, *04∶05-*02∶01, *04∶05-*03∶02, *04∶06-*03∶02, *04∶07-*03∶01 and *04∶08-*03∶01; as *15 were designed *15∶01-*05∶01-02 and *15∶01-*06∶01-03; as *08 were designed *08∶01-*03∶01-*04∶02, *08∶03-*03∶01 and *08∶04-*03∶01-*04∶02; as *01 were designed *01∶01 *05∶01, *01∶02-*05∶01 and *01∶03- *05∶01.</p

Binding region for the MHC-peptide complex for DRB1*14∶01 allele.

<p>MHC is shown in cartoon representation (black), MBP peptide backbone is shown in ball-stick representation. The residues in pocket P4, and P9 are shown in surface representation and are colored based on residue type (blue: basic, red: acidic, green: polar).</p

Relative predispositional effect: the overall frequency distribution of all haplotypes at the DRB1-DQB1 loci in MS patients (n = 2,555) compared with the distribution in controls (N = 1,365).

<p>DRB1-DQB1 haplotypes in MS patients (col.1), the number observed (col. 2) and expected from controls on the basis of the assumption that there were no differential predispositional effects on the DRB1-DQB1 haplotypes (col. 3), and the contribution of each haplotype to the overall <b>χ</b>2 (col.4). The overall <b>χ</b>2 distribution was considered statistically significant at P<0.001 (col. 5).</p><p>Rare haplotypes belonging to the same haplogroup were grouped together: as *04 were designed *04∶01-*03∶01-*03∶02, *04∶02-*03∶02, *04∶03– *03∶01-02-04-05, *04∶04-*03∶02-*04∶02, *04∶05-*02∶01, *04∶05-*03∶02, *04∶06-*03∶02, *04∶07-*03∶01 and *04∶08-*03∶01; as *08 were designed *08∶01-*03∶01-*04∶02, *08∶03-*03∶01 and *08∶04-*03∶01-*04∶02.</p

Case-control analysis of HLA-DRB1-DQB1 genotype from 2,555 multiple sclerosis patients and 1,365 healthy ethnically matched controls.

<p>Only genotypes represented in at least 1% of the sample were considered. Pc = P corrected for the 28 considered genotypes. NS = not significant.</p><p>Rare haplotypes belonging to the same haplogroup were grouped together: as *11 were designed *11∶01-02-03-04 -*03∶01, *11∶01-*03∶03-*05∶02 and *11∶04-*06∶03; as *07 were designed *07∶01- *02∶01 and *07∶01-*03∶03; as *13 were designed *13∶01-*06∶03-*03∶03, *13∶02-*05∶01-*05∶031-*06∶02-*06∶04-*06∶05-*06∶09, *13∶05-*03∶01 and *13∶16-*06∶04; as *04 were designed *04∶01-*03∶01-*03∶02, *04∶02-*03∶02, *04∶03– *03∶01-02-04-05, *04∶04-*03∶02-*04∶02, *04∶05-*02∶01, *04∶05-*03∶02, *04∶06-*03∶02, *04∶07-*03∶01 and *04∶08-*03∶01; as *08 were designed *08∶01-*04∶02, *08∶03-*03∶01 and *08∶04-*03∶01-*04∶02; as *01 were designed *01∶01 *05∶01, *01∶02-*05∶01 and *01∶03- *05∶01.</p

Sequence alignment of the eight MS associated DRB1 alleles.

<p>Only positions with different residues are considered. The first line reports the residue position and the last line the pocket or pockets to which it belongs.</p

Binding region for the MHC-peptide complex for DRB1*03∶01 allele.

<p>MHC binding region is shown in cartoon representation (black), MBP peptide backbone is shown in ball-stick representation. The residues in pocket P4, and P9 are shown in surface representation and are colored based on residue type (blue: basic, red: acidic, green: polar).</p