HLA Class I and Genetic Susceptibility to Type 1 Diabetes
Results From the Type 1 Diabetes Genetics Consortium
Article Figures & Tables
Figures
- FIG. 1.
LD diagram for selected HLA alleles. The r2 × 100 value of LD between pairs of alleles is shown.
Tables
- TABLE 1
Descriptive statistics of sample studied
Cohort Origin Collection Pedigrees Type 1 diabetic sibs per pedigree Type 1 diabetic offspring in cohort Type 1 diabetic male Type 1 diabetic female Male (%) Age of onset (years) Age of onset (range) AP Asia Pacific New 150 2.02 ± 0.24 303 153 150 50.50 10.06 ± 7.43 0–37 DAN Denmark Extant 94 2.05 ± 0.33 194 105 90 54.12 11.73 ± 8.30 0.8–49 EUR Europe New 470 2.01 ± 0.10 945 513 432 54.29 10.76 ± 7.26 1–35 HBDI U.S. Extant 416 2.10 ± 0.42 879 471 410 53.58 11.90 ± 8.22 0.8–50 JOS U.S. Extant 57 2.14 ± 0.58 122 60 62 49.18 11.22 ± 7.31 1–31 NA U.S. New 407 2.01 ± 0.21 819 435 384 53.11 8.763 ± 6.45 0–34 SAR Sardinia Extant 52 1.98 ± 0.14 101 47 54 46.53 12.34 ± 7.90 0.7–34 UK U.K. New 107 2.00 ± 0.13 214 97 117 45.33 7.65 ± 4.48 0–23 Total 1,753 2.03 ± 0.28 3,577 1,881 1,699 52.59 10.44 ± 7.41 0–50 Data are means ± SD unless otherwise indicated.
- TABLE 2
HLA class I allele frequencies in 3,506 chromosomes from 1,753 type 1 diabetic probands and 1,585 affected family-based control chromosomes
Allele Type 1 diabetes (n) AFBAC (n) P A*0101 17.7 (621) 16.1 (256) 0.214 A*0102 0.1 (4) 0 (0) 0.179 A*0103 0 (0) 0.1 (2) 0.035 A*0201 30.6 (1,074) 27.6 (438) 0.069 A*0202 0.2 (8) 0 (0) 0.057 A*0205 2.1 (73) 1.2 (19) 0.030 A*0206 0.3 (9) 0.2 (3) 0.646 A*0211 0 (1) 0 (0) 0.501 A*0220 0 (0) 0.1 (1) 0.137 A*0234 0 (0) 0.1 (1) 0.137 A*0235 0 (0) 0.1 (1) 0.137 A*0301 11.9 (417) 13.1 (207) 0.271 A*0302 0.5 (16) 0.3 (4) 0.282 A*0305 0 (0) 0.1 (1) 0.137 A*1101 3.4 (119) 6.9 (109) 5.E-08 A*1105 0 (0) 0.1 (1) 0.137 A*2301 1.2 (43) 1.8 (29) 0.094 A*2401 0 (0) 0.1 (1) 0.137 A*2402 11.3 (396) 7.8 (123) 2.E-04 A*2403 0.3 (10) 0.1 (1) 0.114 A*2501 2.3 (80) 2.6 (42) 0.432 A*2601 2.6 (90) 2.8 (44) 0.671 A*2607 0 (0) 0.1 (1) 0.137 A*2608 0.1 (2) 0 (0) 0.342 A*2901 0.3 (12) 0.4 (6) 0.840 A*2902 2.3 (80) 3.4 (54) 0.022 A*3001 0.7 (25) 1.1 (17) 0.191 A*3002 3.3 (117) 1.7 (27) 0.001 A*3004 0.1 (2) 0.1 (1) 0.934 A*3010 0 (1) 0 (0) 0.501 A*3101 2.1 (74) 1.9 (30) 0.614 A*3201 2.1 (73) 4.2 (67) 2.E-05 A*3204 0 (0) 0.1 (1) 0.137 A*3301 0.8 (27) 1 (16) 0.390 A*3303 0.4 (14) 0.3 (5) 0.650 A*3402 0.2 (6) 0.1 (1) 0.336 A*3601 0 (1) 0.1 (2) 0.184 A*6601 0.1 (3) 0.6 (10) 4.E-04 A*6602 0.1 (2) 0 (0) 0.342 A*6801 2.6 (91) 2.7 (43) 0.811 A*6802 0.4 (14) 1.3 (20) 5.E-04 A*6901 0 (0) 0.1 (1) 0.137 A*7401 0 (0) 0.1 (1) 0.137 A*8001 0 (1) 0 (0) 0.501 B*0702 7 (244) 14.7 (233) 7.E-17 B*0704 0 (0) 0.1 (1) 0.137 B*0705 0.7 (26) 0.3 (4) 0.035 B*0707 0 (0) 0.1 (1) 0.137 B*0801 21 (735) 10.9 (173) 4.E-15 B*0809 0 (0) 0.1 (1) 0.137 B*1302 1.8 (64) 2 (31) 0.752 B*1401 0.2 (8) 0.6 (9) 0.052 B*1402 1.7 (60) 2.6 (41) 0.040 B*1501 12.3 (432) 4.5 (71) 2.E-16 B*1502 0.1 (2) 0 (0) 0.342 B*1503 0.1 (5) 0.1 (1) 0.444 B*1507 0.1 (3) 0 (0) 0.244 B*1508 0 (1) 0 (0) 0.501 B*1509 0.1 (2) 0.1 (1) 0.934 B*1510 0.1 (4) 0 (0) 0.179 B*1515 0 (1) 0 (0) 0.501 B*1516 0 (1) 0.1 (1) 0.564 B*1517 0.4 (15) 0.3 (4) 0.343 B*1518 0.2 (6) 0.3 (5) 0.305 B*1524 0.1 (3) 0 (0) 0.244 B*1525 0 (0) 0.1 (1) 0.137 B*1537 0 (1) 0 (0) 0.501 B*1571 0 (0) 0.1 (1) 0.137 B*1573 0 (0) 0.1 (1) 0.137 B*1801 10.2 (357) 6.3 (100) 2.E-05 B*1812 0 (1) 0 (0) 0.501 B*2701 0 (0) 0.1 (1) 0.137 B*2702 0.3 (9) 0.4 (6) 0.458 B*2703 3.2 (113) 3.1 (49) 0.807 B*2707 0 (1) 0.1 (2) 0.184 B*3501 3.6 (126) 6.3 (100) 2.E-05 B*3502 0.3 (12) 1.5 (23) 1.E-05 B*3503 1.6 (56) 1.5 (23) 0.698 B*3508 0.3 (12) 0.5 (8) 0.392 B*3512 0 (0) 0.1 (1) 0.137 B*3701 0.7 (23) 1 (16) 0.182 B*3801 1.8 (63) 2.5 (40) 0.091 B*3901 1.2 (42) 1.2 (19) 0.998 B*3906 3.2 (112) 0.4 (7) 3.E-09 B*4001 5.6 (198) 4.4 (69) 0.062 B*4002 0.6 (20) 1.6 (25) 4.E-04 B*4006 0.1 (3) 0.2 (3) 0.318 B*4009 0 (1) 0 (0) 0.501 B*4014 0 (0) 0.1 (2) 0.035 B*4101 1 (34) 0.3 (4) 0.006 B*4102 0.1 (2) 0.4 (6) 0.007 B*4201 0 (1) 0 (0) 0.501 B*4202 0 (0) 0.1 (1) 0.137 B*4402 6 (210) 9 (143) 1.E-04 B*4403 2 (69) 5.7 (91) 2.E-12 B*4404 0 (0) 0.1 (1) 0.137 B*4405 0.2 (7) 0.1 (1) 0.255 B*4501 0.5 (17) 0.4 (7) 0.835 B*4701 0.3 (10) 0.4 (6) 0.582 B*4702 0 (1) 0 (0) 0.501 B*4801 0.1 (2) 0.1 (1) 0.934 B*4901 2.2 (77) 1.1 (17) 0.006 B*5001 2.1 (75) 1.2 (19) 0.022 B*5002 0.1 (2) 0.1 (1) 0.934 B*5101 3 (104) 4.2 (67) 0.023 B*5102 0 (0) 0.1 (1) 0.137 B*5105 0 (0) 0.1 (1) 0.137 B*5107 0 (1) 0.1 (1) 0.564 B*5108 0.1 (4) 0.1 (1) 0.591 B*5201 0.3 (12) 1.1 (18) 0.001 B*5301 0.1 (5) 0.5 (8) 0.018 B*5501 0.9 (30) 1.6 (26) 0.013 B*5601 0.6 (20) 0.6 (10) 0.795 B*5701 0.5 (19) 3.5 (56) 4.E-16 B*5703 0 (1) 0.3 (5) 0.006 B*5801 0.9 (31) 1.1 (18) 0.397 B*7301 0.3 (9) 0.1 (1) 0.149 B*8101 0 (1) 0 (0) 0.501 C*0102 2 (69) 3 (48) 0.021 C*0202 3.9 (136) 4.4 (69) 0.435 C*0206 0 (1) 0.1 (1) 0.564 C*0302 0.3 (12) 0.4 (7) 0.591 C*0303 5.5 (194) 3.9 (62) 0.017 C*0304 13.5 (475) 6.6 (105) 1.E-11 C*0305 0.1 (3) 0 (0) 0.244 C*0314 0 (1) 0 (0) 0.501 C*0401 6 (212) 11.6 (184) 4.E-11 C*0403 0 (0) 0.1 (1) 0.137 C*0501 11.3 (397) 9.5 (150) 0.061 C*0602 5.9 (208) 8.4 (133) 0.002 C*0606 0 (1) 0 (0) 0.501 C*0701 25.7 (900) 15 (238) 1.E-13 C*0702 10.8 (378) 15.6 (247) 6.E-06 C*0704 1 (34) 1.9 (30) 0.007 C*0801 0.1 (5) 0.1 (2) 0.884 C*0802 1.9 (66) 3.2 (50) 0.005 C*1202 0.3 (12) 1.1 (17) 0.001 C*1203 5.7 (200) 6.4 (102) 0.322 C*1402 0.7 (25) 1.2 (19) 0.084 C*1502 1.4 (50) 2 (32) 0.123 C*1504 0.2 (8) 0.1 (2) 0.447 C*1505 0.8 (27) 0.3 (5) 0.058 C*1601 1.2 (43) 3.8 (60) 3.E-09 C*1602 0.5 (17) 0.2 (3) 0.119 C*1604 0.1 (4) 0.4 (6) 0.049 C*1701 0.8 (27) 0.7 (11) 0.771 C*1801 0 (1) 0.1 (1) 0.564 P values lower than 0.1 are shown in boldface type.
- TABLE 3
HLA class I alleles significantly different from expected values when accounting for LD with DRB1-DQB1
Allele Type 1 diabetes observed (%) Type 1 diabetes expected (%)† OR (95% CI) P A*0101 17.7 21.9 0.77 (0.66–0.88) 0.002 A*0201 30.6 24.7 1.35 (1.17–1.54) 3.E-04 A*1101 3.4 6.2 0.53 (0.40–0.70) 8.E-06 A*2402 11.4 7.0 1.71 (1.37–2.12) 5.E-06 A*3201 2.1 3.8 0.54 (0.37–0.75) 4.E-04 A*6601 0.1 0.6 0.16 (0.04–0.57) 9.E-04 A*6802 0.4 1.2 0.34 (0.17–0.69) 0.002 B*0702 7.0 11.4 0.58 (0.47–0.70) 3.E-07 B*0705 0.7 0.2 3.42 (1.11–10.5) 0.023 B*1501 12.3 9.4 1.36 (1.11–1.65) 0.004 B*1801 10.2 5.2 2.05 (1.59–2.61) 3.E-08 B*3501 3.6 4.9 0.72 (0.53–0.96) 0.028 B*3502 0.3 1.2 0.29 (0.14–0.60) 5.E-04 B*3906 3.2 0.3 10.31 (4.21–25.1) 4.E-10 B*4002 0.5 1.2 0.45 (0.23–0.84) 0.012 B*4101 1.0 0.2 4.49 (1.48–13.6) 0.004 B*4102 0.1 0.3 0.19 (0.03–0.96) 0.020 B*4403 1.9 4.5 0.42 (0.30–0.59) 4.E-07 B*4901 2.2 0.9 2.6 (1.45–4.63) 0.001 B*5001 2.1 1.0 2.27 (1.30–3.94) 0.003 B*5201 0.3 0.9 0.37 (0.17–0.80) 0.009 B*5301 0.1 0.4 0.33 (0.10–1.06) 0.055 B*5701 0.5 2.8 0.19 (0.11–0.32) 4.E-11 B*5703 0.0 0.3 0.11 (0.01–0.96) 0.013 C*0303 5.5 3.8 1.48 (1.10–1.99) 0.010 C*0401 6.0 9.3 0.63 (0.50–0.78) 6.E-05 C*0501 11.3 7.6 1.56 (1.26–1.93) 9.E-05 C*1202 0.3 0.9 0.39 (0.17–0.83) 0.014 C*1402 0.7 1.4 0.52 (0.29–0.93) 0.027 C*1505 0.8 0.3 2.78 (1.01–7.62) 0.039 C*1601 1.2 3.0 0.39 (0.25–0.58) 5.E-06 †Expected values calculated based on LD of class I alleles with DR-DQ–encoding loci in this population.
- TABLE 4
Protective effect of C*1601 appears to be caused by LD with B*4403
DR HLA-B HLA-C Not trans Trans Trans proportion (%) P All B*4403 All 282 118 29.50 All B*4403 C*1601 156 66 29.73 All B*4403 not C*1601 115 40 25.81 NS All All C*1601 173 80 31.62 All B*4403 C*1601 156 66 29.73 All not B*4403 C*1601 17 14 45.16 <0.13 DR7† B*4403 not C*1601 81 10 10.99 DR7 not B*4403 C*1601 3 4 57.14 <0.0074 DR7 B*4403 C*1601 124 36 22.50 DR7 B*4403 not C*1601 81 10 10.99 <0.023 DR7 B*4403 C*1601 124 36 22.50 DR7 not B*4403 C*1601 3 4 57.14 <0.036 †DRB1*0701 DQB1*0201.
- TABLE 5
Summary of statistically significant relative ORs on specific haplotypes for class I alleles
Allele DR3 DR4 DR8 DR1 DR2 Number Consistent effect A*0101 0.69 (0.59–0.78) 0.75 (0.57–0.98) 2 Yes A*0201 0.58 (0.38–0.89) A*0301 1.47 (1.14–1.88) A*1101 X 0.60 (0.38–0.91) A*2402 1.69 (1.25–2.28) 1.52 (1.15–2.01) 3.31 (1.90–5.74) 2.18 (1.51–3.14) 4 Yes A*2601 0.65 (0.46–0.89) X A*2902 2.22 (1.03–4.78) A*3101 0.57 (0.41–0.79) A*3201 0.57 (0.36–0.88) 0.19 (0.04–0.89) X 2 Yes A*6601 X 0.10 (0.01–0.98) A*6801 0.62 (0.38–0.99) 3.32 (1.14–9.64) 4.83 (1.02–22.6) 3 No B*0801 0.68 (0.62–0.74) B*1801 1.58 (1.31–1.90) 1.74 (1.19–2.53) 2 Yes B*3501 X 4.79 (1.07–21.4) 4.79 (1.07–21.4) 2 No B*3503 X X 14.54 (2.66–79.3) B*3801 X 0.70 (0.49–0.97) X B*3901 X X 2.44 (1.01–5.88) B*3906 11.56 (0.68–195.0)† 2.70 (1.16–6.29) 14.03 (5.55–35.4) 7.15 (3.89–13.1) 14.54 (2.66–79.3) 4 Yes B*4001 0.71 (0.56–0.88) B*4402 0.34 (0.13–0.84) B*4403 4.83 (1.12–20.6) 0.5 (0.32–0.77) X X 2 No B*4901 X 1.61 (1.01–2.53) X X X B*5001 1.95 (1.22–3.11) X X X B*5101 0.36 (0.13–0.96) B*5301 X X X X 28.11 (1.75–449.0) B*5601 0.10 (0.01–0.81) X X X X C*0102 0.30 (0.11–0.77) C*0401 4.82 (1.87–12.3) C*0501 1.48 (1.21–1.81) 0.29 (0.12–0.68) 2 No C*0602 1.56 (1.09–2.21) X C*0701 0.70 (0.60–0.80) 0.26 (0.08–0.80) 0.51 (0.28–0.92) 3 Yes C*0702 1.31 (1.00–1.70) 3.65 (2.42–5.48) 1.94 (1.41–2.65) 3 Yes C*1202 X 0.15 (0.03–0.61) X X X C*1402 X 0.33 (0.11–0.92) X C*1502 0.57 (0.37–0.87) X C*1604 X 0.38 (0.15–0.90) For each allele, the relative OR value represents a comparison of the DR haplotype carrying the allele to that DR haplotype carrying any class I allele. X = total n in contingency table ≤12.
†Although the confidence interval overlaps 1, this result, with relative OR of 11.56, has been included for comparison. Data for seven alleles that exhibit a consistent disease association on more than one haplotype are indicated in boldface type.
In this Issue
November 2010, 59(11)
