Introduction 1 2 3 4 DRB1 DQA1 DQB1 INS CTLA4 PTPN22 5 8 2 3 9 INS 10 18 INS 19 2 20 21 INS 14 15 13 15 13 14 17 PTPN22 CTLA4 22 23 24 27 INS CTLA4 PTPN22 Methods Participants 28 29 30 Genomic DNA extraction and genotyping 31 HLA-DRB1 −DQA1 DQB1 32 33 34 DQB1 DQA1 DRB1 DRB1*04 DRB1*04-DQA1*0301-DQB1*0302 DRB1*0401 0404 35 DRB1*04XX INS-VNTR −23 HphI HphI INS-VNTR. 23 HphI VNTR −23 HphI VNTR PTPN22 Arg620Trp JO27_1 CTLA4 1 Data analysis DRB1*0401/04XX DQA1*03-DQB1*0302/DRB1*03-DQA1*05-DQB1*0201 DR4 DQ8/DR3-DQ2 DQB1 DRB1*0404-DQ8/DR3-DQ2 DR3-DQ2/DR3-DQ2 DR4-DQ8/DR4-DQ8 DRB1 0404-DQ8 DRB1*0401 040XX-DQ8/X DQB1 0602 DR3-DQ2 INS PTPN22 CTLA4 INS PTPN22 CTLA4 JO27_1 36 37 38 p Results 2 3 INS PTPN22 CTLA4 INS PTPN22 CTLA4 JO27_1 JO27_1 3 Joint effect of HLA and PTPN22 PTPN22 df PTPN22 p  PTPN22 4 5 PTPN22 df p  df p  PTPN22 df p  39 Joint effect of HLA and INS df INS p  p  4 df p  5 df p  INS df p  Joint effect of HLA and CTLA4 CTLA4 1 df p  4 5 df p  df p  Table 1 HLA-INS -23HphI HLA-PTPN22 Arg620Trp HLA-CTLA4 JO27_1 a Non-HLA genotypes Cases Controls OR 95% CI p n n %  INS b     0.67 High risk I-I 218 (25.2) 20 (2.8) 1.56 0.76–3.21   III+ 98 (28.6) 14 (2.5) 1   Intermediate risk I-I 412 (47.6) 122 (17.1) 2.10 1.52–2.89   III+ 160 (46.8) 99 (17.4) 1   Neutral risk I-I 221 (25.5) 346 (48.5) 2.34 1.74–3.15   III+ 81 (23.7) 299 (52.6) 1   Low risk I-I 14 (1.6) 225 (31.6) 3.26 0.92–11.54   III+ 3 (0.9) 156 (27.5) 1   Total  1207 1281     PTPN22     0.024 High risk TT + TC 89 (23.2) 8 (3.1) 1.26 0.55–2.88   CC 237 (27.8) 27 (2.6) 1   Intermediate risk TT + TC 177 (46.1) 55 (21.2) 1.31 0.91–1.86   CC 406 (47.7) 164 (15.6) 1   Neutral risk TT + TC 111 (28.9) 121 (46.7) 2.44 1.80–3.31   CC 199 (23.4) 536 (51.0) 1   Low risk TT + TC 7 (1.8) 75 (29.0) 3.27 1.18–9.06   CC 9 (1.1) 323 (30.8) 1   Total  1235 1309     CTLA4     0.53 High risk TT 122 (24.9) 14 (3.6) 0.90 0.45–1.84   TC-CC 210 (27.9) 22 (2.5) 1   Intermediate risk TT 241 (49.2) 65 (16.5) 1.59 1.14–2.23   TC-CC 346 (46.0) 148 (16.7) 1   Neutral risk TT 121 (24.7) 212 (53.8) 1.34 1.01–1.77   TC-CC 187 (24.9) 439 (49.7) 1   Low risk TT 6 (1.2) 103 (26.1) 1.80 0.63–5.18   TC-CC 9 (1.2) 275 (31.1) 1   Total  1242 1278    n a DQA1*03-DQB1*0302/DQA1*05-DQB1*0201 DQ8/DQ2 DRB1≠0404 DQB1*0602 DRB1*0404-DQ8/DR3-DQ2 DR3-DQ2/DR3-DQ2 DR4-DQ8/DR4-DQ8 DRB1 0404 DRB1*0401 040x-DQ8/X DQB1*0602 DR3 b Joint effects of non-HLA loci PTPN22-INS INS CTLA4 PTPN22-CTLA4 2 5 p  PTPN22 CTLA4 p  6 CTLA4 PTPN22 Table 2 INS-PTPN22 INS-CTLA4 PTPN22-CTLA4 Non-HLA genotypes Cases Controls OR 95% CI a p n n INS PTPN         0.67 I-I TT+TC 274 (72.9) 156 (58.4) 1.74 1.38–2.18 I-I CC 594 (71.6) 587 (54.8) 1   III+ TT+TC 102 (27.1) 111 (41.6) 1.89 1.38–2.58 III+ CC 236 (28.4) 485 (45.2) 1   n   1,206 1,339     INS CTLA4         0.42 I-I TT 354 (73.1) 222 (53.9) 1.51 1.23–1.86 I-I TC-CC 520 (71.0) 492 (54.8) 1   III+ TT 130 (26.9) 190 (46.1) 1.31 0.99–1.73 III+ TC-CC 212 (29.0) 405 (45.2) 1   n   1,216 1,309     PTPN CTLA4         0.78 TT+TC TT 143 (29.7) 75 (17.7) 1.46 1.04–2.05 TT+TC TC-CC 239 (31.7) 183 (20.1) 1   CC TT 339 (70.3) 348 (82.3) 1.4 1.15–1.67 CC TC-CC 514 (68.3) 729 (79.9) 1   n   1,235 1,335     The low-risk genotypes were used as reference (CC, TC-CC, TC-CC) a n Joint effects of more than two susceptibility loci p  7 ROC curve 40 1 Fig. 1 CTLA4 PTPN22 INS INS PTPN22 INS PTPN22 CTLA4  Age of disease onset and sex 8 9 Discussion PTPN22 HLA-INS HLA-CTLA4 INS-CTLA4 INS-PTPN22 PTPN22-CTLA4 1 PTPN22 25 27 22 PTPN22 41 http://hydra.usc.edu/gxe CTLA4 22 INS 11 12 16 18 INS HLA-DR4 10 14 15 10 12 13 16 16 18 22 25 DR4-DQ8 DR3-DQ2 42 43 locus1 locus2. INS PTPN22 44 18 INS INS 40 45 INS PTPN22 PTPN22 HLA-INS HLA-CTLA PTPN-INS INS-CTLA4 PTPN-CTLA4 - Electronic supplementary material Below is the link to the electronic supplementary material.
 ESM Table 1 (PDF 14.3 kb) ESM Table 2 (PDF 110 kb) ESM Table 3 (PDF 69.2 kb) ESM Table 4 (PDF 51.2 kb) ESM Table 5 (PDF 31.9 kb) ESM Table 6 (PDF 48.8 kb) ESM Table 7 (PDF 25.9 kb) ESM Table 8 (PDF 68.0 kb) ESM Table 9 (PDF 25.1 kb)