Critical Amino Acid Variants in HLA-DRB1 and -DQB1 Allotypes in the Development of Classical Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Japanese Population
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Participants
2.2. Measurements
2.3. Statistical Analysis
3. Results and Discussion
3.1. Clinical Data
3.2. HLA-DRB1 and -DQB1 Allele Frequencies in Patients with Classical T1D and LADA
3.3. Polymorphic DRB1 and DQB1 Amino Acid Residue Variations in Patients with Classical T1D and LADA
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
T1D | Type 1 diabetes |
LADA | latent autoimmune diabetes in adults |
HLA | human leukocyte antigen |
GAD | glutamic acid decarboxylase |
GAD-Ab | GAD antibody |
IA-2Ab | insulinoma-associated antigen-2 antibody |
SBT | sequence-based typing |
BIGDAWG | Bridging ImmunoGenomic Data-Analysis Workflow Gaps |
BMI | body mass index |
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Allele | Allele Frequency (Number) | Classical T1D vs. Control | LADA vs. Control | ||||||
---|---|---|---|---|---|---|---|---|---|
Classical T1D (n = 144) | LADA (n = 204) | Control (n = 516) | p | Pc | OR (95%CI) | p | Pc | OR (95%CI) | |
DRB1*01:01 | 4.9 (7) | 4.9 (10) | 3.9 (20) | 0.37 | — | 1.27 (0.53–3.06) | 0.33 | — | 1.28 (0.59–2.78) |
DRB1*04:01 | 0.7 (1) | 2.0 (4) | 1.4 (7) | 0.45 | — | 0.51 (0.06–4.17) | 0.38 | — | 1.45 (0.42–5.02) |
DRB1*04:03 | 0.7 (1) | 3.4 (7) | 3.9 (20) | 0.037 | — | 0.17 (0.02–1.30) | 0.49 | — | 0.88 (0.37–2.12) |
DRB1*04:05 | 29.2 (42) | 16.2 (33) | 13.2 (68) | 1.2 × 10−5 | 6.0 × 10−5 | 2.71 (1.75–4.22) | 0.18 | — | 1.27 (0.81–2.00) |
DRB1*04:06 | 0.7 (1) | 4.4 (9) | 3.5 (18) | 0.056 | — | 0.19 (0.03–1.46) | 0.35 | — | 1.28 (0.56–2.89) |
DRB1*04:07 | 0.7 (1) | 2.9 (6) | 0.4 (2) | 0.52 | — | 1.80 (0.16–20.0) | 0.0080 | 0.0400 | 7.79 (1.56–38.9) |
DRB1*04:10 | 2.1 (3) | 3.0 (5) | 2.1 (11) | 0.64 | — | 0.98 (0.27–3.55) | 0.10 | — | 0.23 (0.03–1.76) |
DRB1*08:02 | 9.0 (13) | 6.9 (14) | 3.5 (18) | 0.0080 | 0.0183 | 2.75 (1.31–5.75) | 0.041 | 0.15 | 2.04 (0.99–4.18) |
DRB1*08:03 | 2.1 (3) | 4.4 (9) | 6.4 (33) | 0.027 | — | 0.31 (0.09–1.03) | 0.20 | — | 0.68 (0.32–1.44) |
DRB1*09:01 | 27.1 (39) | 25.0 (51) | 13.8 (71) | 2.2 × 10−4 | 7.2 × 10−4 | 2.33 (1.49–3.63) | 3.1 × 10−4 | 0.0031 | 2.09 (1.40–3.13) |
DRB1*11:01 | 0.0 (0) | 1.5 (3) | 3.7 (19) | 0.0086 | 0.0185 | 0 | 0.089 | — | 0.39 (0.11–1.33) |
DRB1*12:01 | 0.7 (1) | 3.4 (7) | 2.5 (13) | 0.15 | — | 0.27 (0.04–2.09) | 0.33 | — | 1.38 (0.54–3.50) |
DRB1*12:02 | 0.7 (1) | 0.5 (1) | 2.1 (11) | 0.22 | — | 0.32 (0.04–2.51) | 0.10 | — | 0.23 (0.03–1.76) |
DRB1*13:02 | 18.1 (26) | 6.4 (13) | 5.6 (29) | 1.0 × 10−5 | 7.5 × 10−5 | 3.70 (2.10–6.52) | 0.41 | — | 1.14 (0.58–2.25) |
DRB1*14:05 | 0.0 (0) | 1.0 (2) | 3.1 (16) | 0.0185 | 0.0370 | 0 | 0.077 | — | 0.31 (0.07–1.36) |
DRB1*14:06 | 0.7 (1) | 0.5 (1) | 2.1 (11) | 0.22 | — | 0.32 (0.04–2.51) | 0.10 | — | 0.23 (0.03–1.76) |
DRB1*14:54 | 0.7 (1) | 2.5 (5) | 4.3 (22) | 0.024 | — | 0.16 (0.02–1.18) | 0.18 | — | 0.56 (0.21–1.51) |
DRB1*15:01 | 0.0 (0) | 3.9 (8) | 11.6 (60) | 1.7 × 10−7 | 5.2 × 10−6 | 0 | 5.8 × 10−4 | 0.0043 | 0.31 (0.15–0.66) |
DRB1*15:02 | 0.7 (1) | 7.4 (15) | 8.9 (46) | 9.0 × 10−5 | 3.4 × 10−4 | 0.07 (0.01–0.52) | 0.30 | — | 0.81 (0.44–1.45) |
DQB1*03:01 | 2.8 (4) | 6.4 (13) | 12.0 (62) | 2.9 × 10−4 | 8.7 × 10−4 | 0.21 (0.08–0.59) | 0.0152 | 0.06 | 0.50 (0.27–0.93) |
DQB1*03:02 | 10.4 (15) | 17.6 (36) | 10.1 (52) | 0.51 | — | 1.04 (0.57–1.90) | 0.0046 | 0.0278 | 1.91 (1.21–3.03) |
DQB1*03:03 | 26.4 (38) | 26.0 (53) | 14.5 (75) | 0.0010 | 0.0024 | 2.11 (1.35–3.29) | 3.1 × 10−4 | 0.0046 | 2.06 (1.39–3.07) |
DQB1*04:01 | 29.2 (42) | 16.2 (33) | 13.0 (67) | 9.0 × 10−6 | 9.0 × 10−5 | 2.76 (1.77–4.29) | 0.16 | — | 1.29 (0.82–2.03) |
DQB1*04:02 | 4.2 (6) | 2.5 (5) | 3.9 (20) | 0.52 | — | 1.08 (0.43–2.74) | 0.24 | — | 0.62 (0.23–1.68) |
DQB1*05:01 | 4.9 (7) | 4.9 (10) | 4.5 (23) | 0.49 | — | 1.10 (0.46–2.61) | 0.47 | — | 1.11 (0.52–2.36) |
DQB1*05:02 | 0.7 (1) | 1.5 (3) | 3.3 (17) | 0.069 | — | 0.21 (0.03–1.56) | 0.14 | — | 0.44 (0.13–1.51) |
DQB1*05:03 | 0.0 (0) | 2.5 (5) | 5.4 (28) | 8.6 × 10−4 | 0.0024 | 0 | 0.06 | — | 0.44 (0.17–1.15) |
DQB1*06:01 | 2.8 (4) | 11.8 (24) | 14.9 (77) | 1.1 × 10−5 | 6.6 × 10−5 | 0.16 (0.06–0.45) | 0.16 | — | 0.76 (0.47–1.24) |
DQB1*06:02 | 0.0 (0) | 3.4 (7) | 11.6 (60) | 1.7 × 10−7 | 5.2 × 10−6 | 0 | 2.1 × 10−4 | 0.0064 | 0.27 (0.12–0.60) |
DQB1*06:04 | 17.4 (25) | 6.4 (13) | 5.4 (28) | 1.6 × 10−5 | 6.9 × 10−5 | 3.66 (2.06–6.51) | 0.37 | — | 1.19 (0.60–2.34) |
Amino Acid Position | Amino Acid Variants | Allele Frequency (Number) | Classical T1D vs. Control | LADA vs. Control | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Classical T1D (n = 144) | LADA (n = 204) | Control (n = 516) | p | Pc | OR (95%CI) | p | Pc | OR (95%CI) | ||
DRß13 | Phe | 31.9 (46) | 29.9 (61) | 18.2 (94) | 4.2 × 10−4 | 0.0012 | 2.11 (1.39–3.19) | 5.4 × 10−4 | 0.0020 | 1.92 (1.32–2.78) |
His | 34.7 (50) | 29.4 (60) | 24.4 (126) | 0.0099 | 0.0231 | 1.65 (1.11–2.45) | 0.10 | — | 1.29 (0.90–1.85) | |
Tyr | 0.7 (1) | 0.0 (0) | 0.8 (4) | 0.70 | — | 0.90 (0.10–8.07) | 0.26 | — | 0 | |
Gly | 12.5 (18) | 15.7 (32) | 14.5 (75) | 0.32 | — | 0.84 (0.48–1.46) | 0.39 | — | 1.09 (0.70–1.72) | |
Ser | 19.4 (28) | 13.7 (28) | 20.7 (107) | 0.42 | — | 0.92 (0.58–1.47) | 0.0177 | 0.0374 | 0.61 (0.39–0.96) | |
Arg | 0.7 (1) | 11.3 (23) | 21.3 (110) | 2.8 × 10−12 | 6.0 × 10−11 | 0.03 (0.004–0.19) | 8.9 × 10−4 | 0.0024 | 0.47 (0.29–0.76) | |
DRß31 | Ile | 31.9 (46) | 29.9 (61) | 176 (91) | 2.3 × 10−4 | 7.9 × 10−4 | 2.19 (1.45–3.33) | 2.7 × 10−4 | 0.0013 | 1.99 (1.37–2.90) |
Phe | 68.1 (98) | 70.1 (143) | 81.8 (422) | 4.2 × 10−4 | 0.0012 | 0.48 (0.31–0.72) | 5.4 × 10−4 | 0.0020 | 0.52 (0.36–0.76) | |
Val | 0.0 (0) | 0.0 (0) | 0.6 (3) | 0.48 | — | 0 | 0.37 | — | 0 | |
DRß33 | Asn | 65.3 (94) | 70.6 (144) | 75.6 (390) | 0.0099 | 0.0231 | 0.61 (0.41–0.90) | 0.10 | — | 0.78 (0.54–1.11) |
His | 34.7 (50) | 29.4 (60) | 24.4 (126) | 0.0099 | 0.0231 | 1.65 (1.11–2.45) | 0.10 | — | 1.29 (0.90–1.85) | |
DQß30 | Ser | 0.7 (1) | 0.0 (0) | 0.8 (4) | 0.70 | — | 0.90 (0.10–8.07) | 0.26 | — | 0 |
Tyr | 76.4 (110) | 83.8 (171) | 80.2 (414) | 0.19 | — | 0.80 (0.51–1.24) | 0.16 | — | 1.28 (0.83–1.97) | |
His | 22.9 (33) | 16.2 (33) | 19.0 (98) | 0.18 | — | 1.27 (0.81–1.98) | 0.22 | — | 0.82 (0.53–1.27) | |
DQß70 | Arg | 61.1 (88) | 68.1 (139) | 58.0 (299) | 0.28 | — | 1.14 (0.78–1.66) | 0.0070 | 0.0167 | 1.55 (1.10–2.19) |
Glu | 33.3 (48) | 18.6 (38) | 16.9 (87) | 2.5 × 10−5 | 1.1 × 10−4 | 2.47 (1.63–3.74) | 0.32 | — | 1.13 (0.74–1.72) | |
Gly | 5.6 (8) | 13.2 (27) | 25.2 (130) | 1.6 × 10−8 | 1.7 × 10−7 | 0.18 (0.08–0.37) | 2.2 × 10−4 | 0.0042 | 0.45 (0.29–0.71) | |
DQß75 | Val | 39.6 (57) | 27.5 (56) | 30.8 (159) | 0.0308 | 0.054 | 1.47 (1.00–2.16) | — | — | — |
Leu | 60.4 (87) | 72.5 (148) | 69.2 (357) | 0.0308 | 0.054 | 0.68 (0.46–1.00) | — | — | — | |
DQß85 | Leu | 73.6 (106) | 68.6 (140) | 54.3 (280) | 1.7 × 10−5 | 1.2 × 10−4 | 2.35 (1.56–3.54) | 2.6 × 10−4 | 0.0025 | 1.84 (1.31–2.60) |
Val | 26.4 (38) | 31.4 (64) | 45.7 (236) | 1.7 × 10−5 | 1.2 × 10−4 | 0.43 (0.28–0.64) | 2.6 × 10−4 | 0.0025 | 0.54 (0.39–0.76) |
Amino Acid Position | Amino Acid Variants | Classical T1D | LADA | ||
---|---|---|---|---|---|
Allotypes | Allotypes | ||||
DRß13 | Phe | S | (S) DRB1*09:01 | S | (S) DRB1*09:01 |
His | S | (S) DRB1*04:05 | — | ||
Ser | — | P | None | ||
Arg | P | (P) DRB1*15:01, DRB1*15:02 | P | (P) DRB1*15:01 | |
DRß31 | Ile | S | (S) DRB1*09:01 | S | (S) DRB1*09:01 |
Phe | P | (S) DRB1*04:05, DRB1*08:02, DRB1*13:02 (P) DRB1*11:01, DRB1*14:05, DRB1*15:01, DRB1*15:02 | P | (S) DRB1*04:07 (P) DRB1*15:01 | |
DRß33 | Asn | P | (S) DRB1*08:02, DRB1*09:01, DRB1*13:02 | — | |
His | S | (P) DRB1*11:01, DRB1*14:05, DRB1*15:01, DRB1*15:02 | — | ||
DQß70 | Arg | — | S | (S) DQB1*03:02, DQB1*03:03 | |
Glu | S | (S) DQB1*04:01 | — | ||
Gly | P | (P) DQB1*05:03, DQB1*06:02 | P | (P) DQB1*06:02 | |
DQß85 | Leu | S | (S) DQB1*03:03, DQB1*04:01 | S | (S) DQB1*03:02, DQB1*03:03 |
Val | P | (P) DQB1*03:01 | P | (P) DQB1*06:02 |
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Katahira, M.; Tsunekawa, T.; Mizoguchi, A.; Yamaguchi, M.; Tsuru, K.; Takashima, H.; Terada, R. Critical Amino Acid Variants in HLA-DRB1 and -DQB1 Allotypes in the Development of Classical Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Japanese Population. Curr. Issues Mol. Biol. 2021, 43, 107-115. https://doi.org/10.3390/cimb43010009
Katahira M, Tsunekawa T, Mizoguchi A, Yamaguchi M, Tsuru K, Takashima H, Terada R. Critical Amino Acid Variants in HLA-DRB1 and -DQB1 Allotypes in the Development of Classical Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Japanese Population. Current Issues in Molecular Biology. 2021; 43(1):107-115. https://doi.org/10.3390/cimb43010009
Chicago/Turabian StyleKatahira, Masahito, Taku Tsunekawa, Akira Mizoguchi, Mariko Yamaguchi, Kahori Tsuru, Hiromi Takashima, and Ryoma Terada. 2021. "Critical Amino Acid Variants in HLA-DRB1 and -DQB1 Allotypes in the Development of Classical Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Japanese Population" Current Issues in Molecular Biology 43, no. 1: 107-115. https://doi.org/10.3390/cimb43010009
APA StyleKatahira, M., Tsunekawa, T., Mizoguchi, A., Yamaguchi, M., Tsuru, K., Takashima, H., & Terada, R. (2021). Critical Amino Acid Variants in HLA-DRB1 and -DQB1 Allotypes in the Development of Classical Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Japanese Population. Current Issues in Molecular Biology, 43(1), 107-115. https://doi.org/10.3390/cimb43010009