Table 5.
Selected significant HLA alleles and haplotypes
| ADA | Allele/HT | AF (KI) | AF (TUM) | OR/β (Disc.) | p (Disc.) | OR/β (Repl.) | p(one-sided) (Repl.) | OR/β (Pool.) | p (Pool.) |
|---|---|---|---|---|---|---|---|---|---|
| All preparations: risk alleles | |||||||||
| bADA levels | HLA-DQA1*01:02 | 0.42 | 0.36 | 0.18β | 1.6 × 10−08 | 0.17β | 3.7 × 10−04 | 0.17β | 4.8 × 10−11 |
| bADA levels | B7-DQ6 | 0.18 | 0.17 | 0.17β | 8.6 × 10−06 | 0.21β | 3.8 × 10−04 | 0.18β | 2.7 × 10−08 |
| All preparations: protective alleles | |||||||||
| bADA levels | DR3-DQ2 | 0.13 | 0.12 | − 0.23β | 9.6 × 10−08 | − 0.21β | 6.7 × 10−04 | − 0.23β | 5.0 × 10−10 |
| IFNβ-1a s.c.: risk alleles | |||||||||
| nADA pres. | DR15-DQ6 | 0.34 | 0.30 | 2.73OR | 3.1 × 10−14 | 3.41OR | 1.5 × 10−07 | 2.89OR | 7.4 × 10−20 |
| nADA titer | DR15-DQ6 | 0.34 | 0.30 | 0.36β | 1.3 × 10−15 | 0.32β | 2.3 × 10−07 | 0.35β | 3.6 × 10−21 |
| bADA levels | DR15-DQ6 | 0.34 | 0.30 | 0.44β | 6.8 × 10−15 | 0.45β | 4.4 × 10−08 | 0.44β | 3.5 × 10−21 |
| IFNβ-1a s.c.: protective alleles | |||||||||
| nADA pres. | DR3-DQ2 | 0.13 | 0.12 | 0.40OR | 9.1 × 10−07 | 0.29OR | 4.0 × 10−04 | 0.37OR | 3.7 × 10−09 |
| nADA titer | DR3-DQ2 | 0.13 | 0.12 | − 0.31β | 8.6 × 10−08 | − 0.28β | 5.0 × 10−04 | − 0.30β | 3.4 × 10−10 |
| bADA levels | DR3-DQ2 | 0.13 | 0.12 | − 0.41β | 2.1 × 10−08 | − 0.40β | 1.5 × 10−04 | − 0.41β | 2.5 × 10−11 |
| IFNβ-1b s.c.: risk alleles | |||||||||
| nADA pres. | HLA-DRB1*04:01 | 0.09 | 0.07 | 6.82OR | 3.4 × 10−13 | 14.7OR | 1.7 × 10−07 | 7.95OR | 1.4 × 10−18 |
| nADA pres. | DR4-DQ3 | 0.07 | 0.05 | 6.23OR | 1.2 × 10−09 | 14.7OR | 6.1 × 10−06 | 7.35OR | 1.5 × 10−13 |
| nADA titer | HLA-DRB1*04:01 | 0.09 | 0.07 | 0.56β | 4.1 × 10−15 | 0.56β | 9.2 × 10−06 | 0.56β | 3.7 × 10−19 |
| nADA titer | DR4-DQ3 | 0.07 | 0.05 | 0.50β | 1.6 × 10−09 | 0.54β | 1.3 × 10−04 | 0.51β | 1.9 × 10−12 |
| bADA levels | HLA-DRB1*04:01 | 0.09 | 0.07 | 0.62β | 4.6 × 10−15 | 0.61β | 1.8 × 10−06 | 0.62β | 8.7 × 10−20 |
| bADA levels | DR4-DQ3 | 0.07 | 0.05 | 0.56β | 4.9 × 10−10 | 0.53β | 2.2 × 10−04 | 0.56β | 9.0 × 10−13 |
Selected four-digit HLA alleles and extended haplotypes that were significantly associated (p < 3 × 10−4) with an ADA measurement and replicated (pone-sided < 1 × 10−3). Alleles that are part of one of the listed extended haplotypes and showed a similar or weaker association than the haplotypes and which did not remain significant when conditioning for the haplotypes are not displayed separately. For nADA presence, odds ratios are provided (marked by OR), and for quantitative ADA measures effect sizes (marked by β). For a detailed table of all results, see Additional file 22. For forest plots of each association, including treatment preparation-specific effects, see Additional files 14, 19, and 21. HT haplotype; AF allele frequency; KI Karolinska Institutet, Sweden; TUM Technical University of Munich, Germany; β effect size; OR odds ratio; Disc discovery; Repl. replication; Pool. pooled; pres.presence. Abbreviations of the haplotypes: B7-DQ6, HLA-B*07:02 + HLA-DRB1*15:01 + HLA-DQA1*01:02 + HLA-DQB1*06:02; DR15-DQ6, HLA-DRB1*15:01 + HLA-DQA1*01:02 + HLA-DQB1*06:02; DR3-DQ2, HLA-DRB1*03:01 + HLA-DQA1*05:01 + HLA-DQB1*02:01; DR4-DQ3, HLA-DRB1*04:01 + HLA-DQA1*03:01 + HLA-DQB1*03:02