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Genetics

HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk

Analysis of the Type 1 Diabetes Genetics Consortium Families

  1. Henry Erlich1,2,
  2. Ana Maria Valdes2,
  3. Janelle Noble2,
  4. Joyce A. Carlson3,
  5. Mike Varney4,
  6. Pat Concannon5,
  7. Josyf C. Mychaleckyj5,
  8. John A. Todd6,
  9. Persia Bonella2,
  10. Anna Lisa Fear2,
  11. Eva Lavant3,
  12. Anthony Louey4,
  13. Priscilla Moonsamy1 and
  14. for the Type 1 Diabetes Genetics Consortium
  1. 1Roche Molecular Systems, Alameda, California
  2. 2Children's Hospital Oakland Research Institute, Oakland, California
  3. 3Clinical Chemistry, University Hospital, Malmö, Sweden
  4. 4Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia
  5. 5Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
  6. 6Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, U.K
  1. Address correspondence and reprint requests to Henry A. Erlich, PhD, Roche Molecular Systems, 1145 Atlantic Ave., Alameda, CA 94501. E-mail: Henry.Erlich{at}Roche.com
Diabetes 2008 Apr; 57(4): 1084-1092. https://doi.org/10.2337/db07-1331
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Article Figures & Tables

Tables

  • TABLE 1

    Descriptive characteristics of the study subjects

    EthnicityOriginFamiliesAffected siblings per familySex (% women)Age at onset
    CaucasianAustralia New Zealand14.6 (94)2.03 ± 0.2951.9310.34 ± 8.08
    Europe49.4 (318)2.01 ± 0.0861.5412.28 ± 4.99
    North America29.9 (193)1.99 ± 0.2045.1810.66 ± 7.19
    Other0.2 (1)2.00 ± 0.0044.358.33 ± 5.93
    Non-CaucasianEast Asian5.9 (38)1.05 ± 0.230.0010.50 ± 7.78
    • Data are % (n) or means ± SD.

  • TABLE 2

    Frequency distribution of DRB1-DQB1 haplotypes in Caucasian probands and in AFBAC

    DRB1DQA1DQB1AFBACProbandTransOR (95% CI)χ2P valueEffect on T1D*
    0101010105019.06.644.60.71 (0.52–0.98)3.960.047
    0101010205040.20.150.00.37 (0.03–4.08)0.700.40
    0102010105011.00.732.50.66 (0.25–1.71)0.740.39
    0103010105010.60.125.00.15 (0.02–1.26)3.990.046
    03010501020112.534.170.93.64 (2.89–4.58)95.332 × 10−22S3
    0401030102010.10.257.11.48 (0.13–16.37)0.100.75
    0401030103013.91.433.60.35 (0.20–0.63)12.784 × 10−4
    0401030103024.528.184.58.39 (5.97–11.80)156.736 × 10−36S2
    0402030103021.03.573.33.63 (1.76–7.49)13.283 × 10−4S4
    0403030103021.20.313.30.27 (0.08–0.84)5.690.017
    0404030103023.25.057.11.59 (1.01–2.49)3.880.049S5
    0404030104020.10.250.01.48 (0.13–16.37)0.100.75
    0405030102010.30.542.11.48 (0.37–5.95)0.310.58
    0405030103020.22.587.311.37 (2.71–47.68)16.884 × 10−5S1
    0407030103011.40.28.00.11 (0.03–0.50)11.686 × 10−4
    0408030103010.40.120.00.18 (0.02–1.65)2.810.094
    0408030103040.30.756.51.98 (0.52–7.49)1.030.31
    07010201020110.13.528.20.32 (0.22–0.46)35.672 × 10−9
    0701020103034.30.13.60.02 (0.00–0.13)48.334 × 10−12P1
    0801030103020.00.271.42.170.14
    0801040104022.43.150.01.25 (0.73–2.14)0.680.41
    0803060103010.30.00.00.003.960.047
    0804040104020.20.250.00.74 (0.10–5.26)0.090.76
    0901030102010.00.2100.01.450.23
    0901030103031.60.845.20.53 (0.23–1.19)2.400.12
    1001010105010.70.326.10.49 (0.14–1.75)1.220.27
    1101050103016.51.217.90.18 (0.10–0.32)39.803 × 10−10
    1102050103010.40.223.10.37 (0.07–2.02)1.400.24
    1103050103011.00.225.00.25 (0.07–0.91)5.060.024
    1104010306030.30.112.50.25 (0.03–2.37)1.690.19
    1104050103012.30.26.30.07 (0.02–0.30)21.883 × 10−6P4
    1201050103011.10.330.30.29 (0.09–0.94)4.680.031
    1301010306035.90.814.80.13 (0.07–0.26)43.594 × 10−11
    1302010206042.62.246.10.87 (0.49–1.52)0.260.61
    1302010206090.30.022.20.003.960.047
    1303050103011.00.110.00.08 (0.01–0.64)9.010.003P5
    1401010105032.10.00.00.02 (0.00–0.32)23.511 × 10−6P2
    1404010105030.10.150.00.74 (0.05–11.85)0.050.83
    1501010205010.20.00.00.002.640.10
    15010102060212.00.43.90.03 (0.01–0.07)127.142 × 10−29P3
    1501010206030.30.00.00.003.960.047
    1502010306010.70.213.30.25 (0.05–1.22)3.370.066
    1601010205022.01.035.70.49 (0.23–1.02)3.670.055
    1602010205020.10.150.00.74 (0.05–11.85)0.050.83
    Total8981,214721.725 × 10−124
    • Data are %.

    • * For haplotypes with a frequency >1% in either probands or control subjects, the five most susceptible (S) and the five most protective (P) haplotypes are indicated. T1D, type 1 diabetes.

  • TABLE 3

    Frequency distribution of DRB1-DQB1 haplotypes in East-Asian families and in AFBAC

    DRB1DQA1DQB1AFBACProbandOR (95% CI)χ2P value
    0301050102012.822.410.08 (2.24–45.45)11.050.0009
    0402030103020.01.33.83 (0.05–310.02)0.410.5216
    0403030103025.62.60.46 (0.08–2.59)0.780.3772
    0405010305034.21.30.31 (0.03–3.02)1.110.2917
    0405030104012.86.62.46 (0.46–13.13)1.130.2879
    0405030104020.05.315.94 (0.28–918.70)3.110.0777
    0406030103021.41.30.95 (0.06–15.42)0.000.9695
    0408030103040.01.33.83 (0.05–310.02)0.410.5216
    0410030103020.01.33.83 (0.05–310.02)0.410.5216
    0410030104021.40.00.23 (0.00–18.98)0.490.4831
    0441030103021.40.00.23 (0.00–18.98)0.490.4831
    0701020102012.81.30.47 (0.04–5.26)0.390.5324
    0701020103032.80.00.12 (0.00–7.48)1.460.2272
    0803010306011.40.00.23 (0.00–18.98)0.490.4831
    0901030103035.611.82.28 (0.67–7.78)1.660.1971
    1101010306012.80.00.12 (0.00–7.48)1.460.2272
    1101050103015.61.30.23 (0.02–2.08)1.970.1607
    1201050103011.40.00.23 (0.00–18.98)0.490.4831
    1202010205020.01.33.83 (0.05–310.02)0.410.5216
    12020601030118.13.90.19 (0.05 0.69)6.810.0091
    1302010206090.01.33.83 (0.05–310.02)0.410.5216
    1404010105031.43.92.92 (0.30–28.72)0.900.3440
    1501010205021.42.61.92 (0.17–21.63)0.280.5956
    1501010206021.40.00.23 (0.00–18.98)0.490.4831
    15020101050113.91.30.08 (0.01–0.66)7.860.0050
    15020102050222.227.61.34 (0.63–2.83)0.430.5106
    Total727644.920.0085
    • Dataare%.

  • TABLE 4

    Relative predispositional effects of seven DR-DQ haplotypes

    HaplotypeAFBACType 1 diabetesAssociation in all samplesAssociation excluding DR3, DR4, and protective haplotypes*
    OR (95% CI)P valueRankOR (95% CI)P valueRank
    DRB1*0801 DQA1*0401 DQB1*04022.453.051.25 (0.73–2.14)0.4112.58 (1.48–4.48)0.00131
    DRB1*1302 DQA1*0102 DQB1*06042.562.230.87 (0.49–1.52)0.6121.72 (0.96–3.07)0.0762
    DRB1*0101 DQA1*0101 DQB1*05019.026.600.71 (0.52–0.98)0.04731.55 (1.08–2.22)0.0293
    DRB1*0901 DQA1*0301 DQB1*03031.560.820.53 (0.23–1.19)0.1241.00 (0.44–2.28)0.734
    DRB1*1601 DQA1*0102 DQB1*05022.000.990.49 (0.23–1.02)0.05550.93 (0.44–1.96)0.665
    DRB1*0401 DQA1*0301 DQB1*03013.901.400.35 (0.20–0.63)4 × 10−460.65 (0.36–1.20)0.176
    DRB1*0701 DQA1*0201 DQB1*020110.103.500.32 (0.22–0.46)2 × 10−970.58 (0.38–0.87)0.0157
    • Data are %.

    • * The protective haplotypes excluded are DRB1*150x DQB1*060x; all DRB1*11, -*12, -*13, and -*14 haplotypes with DQB1*0301; DRB1*140x DQB1*050x; and DRB1*0701 DQB1*0303 haplotypes.

  • TABLE 5

    Amino acid differences between closely related DR-DQ haplotypes that differ in type 1 diabetes risk

    DRB1*1301-DQA1–0103-DQB1*0603 (OR 0.13)vs.DRB1*1302-DQA1*0102-DQB1*0604 (OR 0.87)
        DRB1 Val-86Gly-86
        DQA1 Arg-41Lys-41
        DQB1 Asp-57, Gly-70, Ala-86Val-57, Arg-70, Gly-86
    DRB1*0401-DQA1*0301g-DQB1*0302 (OR 8.39)vs.DQB1*0404-DQA1*0301g-DQB1*0302 (OR 1.59)
        DRB1 Lys-71, Gly-86Arg-71, Val-86
    DRB1*1502-DQA1*0101g-DQB1*0501 (OR 0.08)vs.DRB1*1502-DQA1*0102-DQB1*0502 (OR 1.34)
        DQA1 Glu-34Gln-34
        DQB1 Val-57Ser-57
  • TABLE 6

    DQB1 alleles on DR4 haplotypes in DR4+ patient genotypes

    GenotypeDQB1*0201DQB1*0301DQB1*0302DQB1*0304DQB1*0400Total†
    DR1/DR40.013.181.85.10.099
    DR3/DR40.40.798.50.40.0453
    DR4/DR41.65.689.31.62.0252
    DR4/DR80.02.597.50.00.040
    • Data are %.

    • † Data are n.

  • TABLE 7

    DRB1*04 subtypes (alleles) in DQB1*0302+ patient genotypes

    As a percentage of genotype*0401*0402*0403*0404*0405*0406*0407*0408Total†
    DR1/DR474.45.80.08.15.80.00.05.886
    DR3/DR466.411.80.213.17.60.00.00.9450
    DR4/DR1373.316.00.01.39.30.00.00.075
    DR4/DR477.35.00.410.35.40.00.01.7242
    DR4/DR764.95.40.010.813.50.00.05.437
    DR4/DR879.55.10.010.30.00.05.10.039
    DR4/DR9100.00.00.00.00.00.00.00.08
    DR4/DRX54.33.70.025.97.41.20.07.481
    • Data are %.

    • † Data are n.

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HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk
Henry Erlich, Ana Maria Valdes, Janelle Noble, Joyce A. Carlson, Mike Varney, Pat Concannon, Josyf C. Mychaleckyj, John A. Todd, Persia Bonella, Anna Lisa Fear, Eva Lavant, Anthony Louey, Priscilla Moonsamy
Diabetes Apr 2008, 57 (4) 1084-1092; DOI: 10.2337/db07-1331

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HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk
Henry Erlich, Ana Maria Valdes, Janelle Noble, Joyce A. Carlson, Mike Varney, Pat Concannon, Josyf C. Mychaleckyj, John A. Todd, Persia Bonella, Anna Lisa Fear, Eva Lavant, Anthony Louey, Priscilla Moonsamy
Diabetes Apr 2008, 57 (4) 1084-1092; DOI: 10.2337/db07-1331
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Keywords

AFBAC, affected family-based control
SNP, single nucleotide polymorphism

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