Varney MD, Valdes AM, Carlson JA, Noble JA, Tait BD, Bonella P, Lavant E, Fear AL, Louey A, Moonsamy P, Mychaleckyj JC, Erlich H, for the Type 1 Diabetes Genetics Consortium. HLA DPA1, DPB1 alleles and haplotypes contribute to the risk associated with type 1 diabetes: analysis of the Type 1 Diabetes Genetics Consortium families. Diabetes 2010;59:2055–2062

In a recent re-examination of the data in the article listed above, we have detected an error in the determination by segregation of DPA1-DPB1 haplotypes. The determination of DPA1-DPB1 haplotypes by segregation has been re-calculated and confirmed manually using the latest dataset available from the Type 1 Diabetes Genetics Consortium (T1DGC); the results are shown below.

The initially reported observations of a type 1 diabetes risk associated with DPB1*0301 (DPA1*0103-DPB1*0301) and DPB1*0202 (DPA1*0103-DPB1*0202) and protection with DPB1*0402 (DPA1*0103-DPB1*0402) remain valid; in the new analysis, the associations were significant when comparisons were made directly (unadjusted for linkage disequilibrium), conditional on HLA-(B)-DRB1-DQA1-DQB1 linkage disequilibrium and, except DPB1*0202, in the absence of the primary DR-DQ associations (relative predispositional analyses). However, the initially reported observation of the protective association with DPA1*0103-DPB1*0101 but not DPA1*0201-DPB1*0101 was invalid because, in our revised and corrected haplotype determination, the haplotype DPA1*0103-DPB1*0101 was not observed.

We gratefully acknowledge the contribution of Wolfgang Helmberg in the revised DPA1-DPB1 haplotype segregation.

TABLE 1

Proband and affected family-based control (AFBAC) HLA DPA1, DPB1 allele and DPA1-DPB1 haplotype frequency distribution in 1,718 Caucasian type 1 diabetic families

 AFBAC (%) (n = 2,565) Proband (%) (n = 3,435) Padj Odds ratio 95% CI  AFBAC (%) (n = 2,565) Proband (%) (n = 3,435) Padj Odds ratio 95% CI 
DPA1*            
 0103 82.2 84.0  1.1        
 0104 0.7 1.1  1.6 0.9–2.8       
 0201 13.6 13.2  1.0 0.8–1.2       
 0202 3.1 1.5 4.5E-5 0.5 0.3–0.7       
DPB1*      DPA1*-DPB1*     
 0101 4.7 7.2 1.7E-3 1.6 1.2–2.0 0201-0101 4.0 6.8 5.6E-5 1.8 1.4–2.2 
 0201 13.9 15.3  1.1 0.9–1.3 0103-0201 13.3 15.1  1.2 1.0–1.3 
 0202 0.7 2.8 4.7E-8 4.1 2.5–6.9 0103-0202 0.7 2.8 2.1E-8 4.4 2.6–7.3 
 0301 9.9 16.0 2.4E-9 1.7 1.4–2.1 0103-0301 9.9 16.0 1.9E-9 1.7 1.5–2.0 
 0401 43.8 40.2  0.9  0103-0401 43.1 40.0  0.9 0.8–1.0 
 0402 11.5 5.4 1.3E-15 0.4 0.4–0.5 0103-0402 11.4 5.3 7.8E-16 0.4 0.4–0.5 
 0501 1.6 1.1  0.7 0.5–1.1 0202-0501 1.2 0.6  0.5 0.3–0.8 
 0601 1.6 2.3  1.5 1.0–2.2 0103-0601 1.6 2.3  1.5 1.0–2.2 
 1001 1.5 1.0  0.6 0.4–1.0 0201-1001 1.5 1.0  0.6 0.4–1.0 
 1101 1.9 0.8 5.6E-3 0.4 0.3–0.7 0201-1101 1.9 0.8 5.6E-3 0.4 0.3–0.7 
 1301 2.0 1.6  0.8 0.6–1.2 0201-1301 1.6 1.4  0.8 0.5–1.3 
 1401 1.3 0.8  0.6 0.4–1.0 0201-1401 1.3 0.8  0.6 0.4–1.0 
 1501 0.7 1.5  2.1 1.2–3.6 0104-1501 0.7 1.0  1.5 0.8–2.6 
 1701 1.7 1.0  0.6 0.4–1.0 0201-1701 1.6 1.0  0.6 0.4–1.0 
 AFBAC (%) (n = 2,565) Proband (%) (n = 3,435) Padj Odds ratio 95% CI  AFBAC (%) (n = 2,565) Proband (%) (n = 3,435) Padj Odds ratio 95% CI 
DPA1*            
 0103 82.2 84.0  1.1        
 0104 0.7 1.1  1.6 0.9–2.8       
 0201 13.6 13.2  1.0 0.8–1.2       
 0202 3.1 1.5 4.5E-5 0.5 0.3–0.7       
DPB1*      DPA1*-DPB1*     
 0101 4.7 7.2 1.7E-3 1.6 1.2–2.0 0201-0101 4.0 6.8 5.6E-5 1.8 1.4–2.2 
 0201 13.9 15.3  1.1 0.9–1.3 0103-0201 13.3 15.1  1.2 1.0–1.3 
 0202 0.7 2.8 4.7E-8 4.1 2.5–6.9 0103-0202 0.7 2.8 2.1E-8 4.4 2.6–7.3 
 0301 9.9 16.0 2.4E-9 1.7 1.4–2.1 0103-0301 9.9 16.0 1.9E-9 1.7 1.5–2.0 
 0401 43.8 40.2  0.9  0103-0401 43.1 40.0  0.9 0.8–1.0 
 0402 11.5 5.4 1.3E-15 0.4 0.4–0.5 0103-0402 11.4 5.3 7.8E-16 0.4 0.4–0.5 
 0501 1.6 1.1  0.7 0.5–1.1 0202-0501 1.2 0.6  0.5 0.3–0.8 
 0601 1.6 2.3  1.5 1.0–2.2 0103-0601 1.6 2.3  1.5 1.0–2.2 
 1001 1.5 1.0  0.6 0.4–1.0 0201-1001 1.5 1.0  0.6 0.4–1.0 
 1101 1.9 0.8 5.6E-3 0.4 0.3–0.7 0201-1101 1.9 0.8 5.6E-3 0.4 0.3–0.7 
 1301 2.0 1.6  0.8 0.6–1.2 0201-1301 1.6 1.4  0.8 0.5–1.3 
 1401 1.3 0.8  0.6 0.4–1.0 0201-1401 1.3 0.8  0.6 0.4–1.0 
 1501 0.7 1.5  2.1 1.2–3.6 0104-1501 0.7 1.0  1.5 0.8–2.6 
 1701 1.7 1.0  0.6 0.4–1.0 0201-1701 1.6 1.0  0.6 0.4–1.0 

Only alleles or haplotypes with a frequency >5% in an individual category or >1% where the nominal P value was <0.05 were compared. The nominal P value was adjusted (Padj) for multiple alleles or haplotypes by applying the Bonferroni correction of multiplying the nominal P value by the number of alleles or haplotypes compared. Alleles or haplotypes with a frequency of <1% for both categories are not shown.

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TABLE 2

Expected and observed proband DPA1, DPB1, and DPA1-DPB1 frequencies conditioned on HLA DRB1-DQA1-DQB1 linkage disequilibrium in 1,718 Caucasian type 1 diabetic families

 Proband Fexp (%) Proband Fobs (%) Padj Odds ratio (Fobs/Fexp) 95% CI  Proband Fexp (%) Proband Fobs (%) Padj Odds ratio (Fobs/Fexp) 95% CI 
DPA1*      DPA1*-DPB1*      
 0103 80.8 84.0  1.2 1.1–1.4       
 0104 0.7 1.1  1.6 0.9–2.8       
 0201 15.4 13.3  0.8 0.7–1.0       
 0202 3.1 1.5 5.1E-5 0.5 0.3–0.7       
DPB1*            
 0101 8.9 7.2  0.8 0.7–0.9 0201-0101 8.5 6.8 0.03 0.8 0.7–1.0 
 0201 13.0 15.3  1.2 1.0–1.4 0103-0201 12.6 15.1  1.2 1.1–1.4 
 0202 1.6 2.8 0.02 1.7 1.2–2.5 0103-0202 1.6 2.8 0.02 1.8 1.2–2.5 
 0301 9.3 16.0 1.4E-11 1.9 1.6–2.2 0103-0301 9.3 16.0 1.9E-9 1.8 1.6–2.2 
 0401 41.7 40.2  0.9 0.8–1.0 0103-0401 42.0 40.0  0.9 0.8–1.0 
 0402 10.8 5.4 8.9E-13 0.5 0.4–0.6 0103-0402 10.7 5.3 6.1E-16 0.5 0.4–0.6 
 0501 1.5 1.1  0.8 0.5–1.2 0202-0501 1.2 0.6 0.05 0.5 0.3–0.8 
 0601 1.7 2.3  1.4 1.0–2.0 0103-0601 1.7 2.3  1.4 1.0–2.0 
 1001 1.4 1.0  0.7 0.4–1.1 0201-1001 1.5 1.0  0.7 0.4–1.1 
 1101 1.8 0.8 0.01 0.5 0.3–0.8 0201-1101 1.8 0.8 4.2E-3 0.5 0.3–0.7 
 1301 1.9 1.6  0.9 0.6–1.3 0201-1301 1.6 1.4  0.9 0.6–1.3 
 1401 1.3 0.8  0.6 0.4–1.0 0201-1401 1.3 0.8  0.6 0.4–1.0 
 1501 0.7 1.5 0.03 2.2 1.3–3.7 0104-1501 0.7 1.1  1.6 0.9–2.7 
 1701 1.6 1.0  0.6 0.4–1.0 0201-1701 1.6 1.0  0.6 0.4–1.0 
 Proband Fexp (%) Proband Fobs (%) Padj Odds ratio (Fobs/Fexp) 95% CI  Proband Fexp (%) Proband Fobs (%) Padj Odds ratio (Fobs/Fexp) 95% CI 
DPA1*      DPA1*-DPB1*      
 0103 80.8 84.0  1.2 1.1–1.4       
 0104 0.7 1.1  1.6 0.9–2.8       
 0201 15.4 13.3  0.8 0.7–1.0       
 0202 3.1 1.5 5.1E-5 0.5 0.3–0.7       
DPB1*            
 0101 8.9 7.2  0.8 0.7–0.9 0201-0101 8.5 6.8 0.03 0.8 0.7–1.0 
 0201 13.0 15.3  1.2 1.0–1.4 0103-0201 12.6 15.1  1.2 1.1–1.4 
 0202 1.6 2.8 0.02 1.7 1.2–2.5 0103-0202 1.6 2.8 0.02 1.8 1.2–2.5 
 0301 9.3 16.0 1.4E-11 1.9 1.6–2.2 0103-0301 9.3 16.0 1.9E-9 1.8 1.6–2.2 
 0401 41.7 40.2  0.9 0.8–1.0 0103-0401 42.0 40.0  0.9 0.8–1.0 
 0402 10.8 5.4 8.9E-13 0.5 0.4–0.6 0103-0402 10.7 5.3 6.1E-16 0.5 0.4–0.6 
 0501 1.5 1.1  0.8 0.5–1.2 0202-0501 1.2 0.6 0.05 0.5 0.3–0.8 
 0601 1.7 2.3  1.4 1.0–2.0 0103-0601 1.7 2.3  1.4 1.0–2.0 
 1001 1.4 1.0  0.7 0.4–1.1 0201-1001 1.5 1.0  0.7 0.4–1.1 
 1101 1.8 0.8 0.01 0.5 0.3–0.8 0201-1101 1.8 0.8 4.2E-3 0.5 0.3–0.7 
 1301 1.9 1.6  0.9 0.6–1.3 0201-1301 1.6 1.4  0.9 0.6–1.3 
 1401 1.3 0.8  0.6 0.4–1.0 0201-1401 1.3 0.8  0.6 0.4–1.0 
 1501 0.7 1.5 0.03 2.2 1.3–3.7 0104-1501 0.7 1.1  1.6 0.9–2.7 
 1701 1.6 1.0  0.6 0.4–1.0 0201-1701 1.6 1.0  0.6 0.4–1.0 

Only alleles or haplotypes with a frequency >5% in an individual category or >1% where the nominal P value was <0.05 were compared. The nominal P value was adjusted (Padj) for multiple alleles or haplotypes by applying the Bonferroni correction of multiplying the nominal P value by the number of alleles or haplotypes compared. Alleles or haplotypes with a frequency of <1% for both categories are not shown.

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TABLE 3

Relative predispositional analysis; DPA1, DPB1 allele and DPA1-DPB1 haplotype frequency distribution in 1,718 Caucasian type 1 diabetic families following the removal of the high-risk and protective DRB1-DQA1-DQB1 haplotypes

 AFBAC (%) (n = 1,666) Proband (%) (n = 884) Padj Odds ratio 95% CI  AFBAC (%) (n = 1,666) Proband (%) (n = 884) Padj Odds ratio 95% CI 
DPA1*      DPA1*-DPB1*      
 0103 82.4 84.3  1.1 1.0–1.2       
 0104 0.7 2.3 2.8E-3 3.2 1.6–6.6       
 0201 12.8 10.4  0.8 0.6–1.0       
 0202 3.5 2.6  0.7 0.5–1.2       
DPB1*            
 0101 2.2 1.8  0.8 0.5–1.5 0201-0101 1.2 1.2  1.0 0.5–2.2 
 0201 16.1 15.3  0.9 0.8–1.2 0103-0201 15.6 15.2  1.0 0.8–1.2 
 0301 10.9 19.2 3.9E-7 1.9 1.5–2.4 0103-0301 10.8 19.2 2.3E-7 2.0 1.6–2.5 
 0401 39.3 38.9  1.0 0.8–1.2 0103-0401 38.4 38.5  1.0 0.8–1.2 
 0402 14.7 6.6 6.8E-8 0.4 0.3–0.6 0103-0402 14.5 6.3 4.2E-8 0.4 0.3–0.5 
 0501 1.4 1.4  1.0 0.5–2.0 0202-0501 1.0 0.8  0.8 0.3–1.9 
 0601 1.2 1.8  1.5 0.8–2.9 0103-0601 1.2 1.8  1.5 0.8–2.9 
 1001 1.7 1.2  0.7 0.4–1.4 0201-1001 1.7 1.2  0.7 0.4–1.4 
 1101 2.8 1.8  0.7 0.4–1.2 0201-1101 2.8 1.8  0.7 0.4–1.2 
 1301 1.9 2.4  1.2 0.7–2.2 0201-1301 1.5 1.8  1.2 0.6–2.3 
 1501 0.8 2.9 1.3E-4 3.9 2.0–7.5 0104-1501 0.7 2.3 4.7E-3 3.2 1.6–6.6 
 1701 2.3 2.5  1.1 0.6–1.8 0201-1701 2.3 2.5  1.1 0.6–1.9 
 AFBAC (%) (n = 1,666) Proband (%) (n = 884) Padj Odds ratio 95% CI  AFBAC (%) (n = 1,666) Proband (%) (n = 884) Padj Odds ratio 95% CI 
DPA1*      DPA1*-DPB1*      
 0103 82.4 84.3  1.1 1.0–1.2       
 0104 0.7 2.3 2.8E-3 3.2 1.6–6.6       
 0201 12.8 10.4  0.8 0.6–1.0       
 0202 3.5 2.6  0.7 0.5–1.2       
DPB1*            
 0101 2.2 1.8  0.8 0.5–1.5 0201-0101 1.2 1.2  1.0 0.5–2.2 
 0201 16.1 15.3  0.9 0.8–1.2 0103-0201 15.6 15.2  1.0 0.8–1.2 
 0301 10.9 19.2 3.9E-7 1.9 1.5–2.4 0103-0301 10.8 19.2 2.3E-7 2.0 1.6–2.5 
 0401 39.3 38.9  1.0 0.8–1.2 0103-0401 38.4 38.5  1.0 0.8–1.2 
 0402 14.7 6.6 6.8E-8 0.4 0.3–0.6 0103-0402 14.5 6.3 4.2E-8 0.4 0.3–0.5 
 0501 1.4 1.4  1.0 0.5–2.0 0202-0501 1.0 0.8  0.8 0.3–1.9 
 0601 1.2 1.8  1.5 0.8–2.9 0103-0601 1.2 1.8  1.5 0.8–2.9 
 1001 1.7 1.2  0.7 0.4–1.4 0201-1001 1.7 1.2  0.7 0.4–1.4 
 1101 2.8 1.8  0.7 0.4–1.2 0201-1101 2.8 1.8  0.7 0.4–1.2 
 1301 1.9 2.4  1.2 0.7–2.2 0201-1301 1.5 1.8  1.2 0.6–2.3 
 1501 0.8 2.9 1.3E-4 3.9 2.0–7.5 0104-1501 0.7 2.3 4.7E-3 3.2 1.6–6.6 
 1701 2.3 2.5  1.1 0.6–1.8 0201-1701 2.3 2.5  1.1 0.6–1.9 

The relative predispositional analysis removed the following high-risk and protective DRB1-DQA1-DQB1 haplotypes: 0301-0501-0201, 0401-0301-0302, 0402-0301-0302, 0404-0301-0302, 0405-0301-0302, 0701-0201-0303, 1401-0101-0503, and 1501-0102-0602; the distribution of the remaining DPA1, DPB1, and DPA1-DPB1 alleles and haplotypes was compared. Only alleles or haplotypes with a frequency >5% in an individual category or >1% where the nominal P value was <0.05 were compared. The nominal P value was adjusted (Padj) for multiple alleles or haplotypes by applying the Bonferroni correction of multiplying the nominal P value by the number of alleles or haplotypes compared. Alleles or haplotypes with a frequency of <1% for both categories are not shown.

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TABLE 4

DPA1-DPB1 haplotype distribution in probands and AFBACs calculated for DRB1*0301 haplotypes

 0301-0501-0201 A1-B8-DR3 A30-B18-DR3 DR3 positive, A1-B8-DR3 and A30-B18-DR3 negative 
DPA1-DPB1 AFBAC (%) (n = 284) Proband (%) (n = 1,177) AFBAC (%) (n = 137) Proband (%) (n = 421) AFBAC (%) (n = 16) Proband (%) (n = 95) AFBAC (%) (n = 131) Proband (%) (n = 421) 
0201-0101 26.11 17.71 33.6 24.5   21.4 16.4 
0103-0201 9.9 12.7 7.3 13.8 6.3 2.1 13.0 15.2 
0103-0202 4.6 7.9   43.8 45.3 4.6 6.2 
0103-0301 8.52 16.52 5.14 12.84 18.8 25.3 10.7 15.9 
0103-0401 34.2 32.2 36.5 34.2 18.8 17.9 33.6 33.0 
0103-0402 7.73 3.73 10.24 4.54   6.1 3.8 
0201-1001     12.5 2.1   
 0301-0501-0201 A1-B8-DR3 A30-B18-DR3 DR3 positive, A1-B8-DR3 and A30-B18-DR3 negative 
DPA1-DPB1 AFBAC (%) (n = 284) Proband (%) (n = 1,177) AFBAC (%) (n = 137) Proband (%) (n = 421) AFBAC (%) (n = 16) Proband (%) (n = 95) AFBAC (%) (n = 131) Proband (%) (n = 421) 
0201-0101 26.11 17.71 33.6 24.5   21.4 16.4 
0103-0201 9.9 12.7 7.3 13.8 6.3 2.1 13.0 15.2 
0103-0202 4.6 7.9   43.8 45.3 4.6 6.2 
0103-0301 8.52 16.52 5.14 12.84 18.8 25.3 10.7 15.9 
0103-0401 34.2 32.2 36.5 34.2 18.8 17.9 33.6 33.0 
0103-0402 7.73 3.73 10.24 4.54   6.1 3.8 
0201-1001     12.5 2.1   

The distribution of DPA1-DPB1 haplotypes was compared for different DRB1*0301 haplotypes. DR3 (DRB1*0301-DQA1*0501-DQB1*0201)–positive haplotypes were subdivided into the presence or absence of the extended A*0101-B*0801-C*0701-DRB1*0301-DQA1*0501-DQB1*0201– and A*3002-B*1801-C*0501-DRB1*0301-DQA1*0501-DQB1*0201–positive haplotypes. Haplotypes with a frequency of <5% for an individual category are not shown, and categories with a significant differences (Padj < 0.05) are shown in boldface type. DPA1*0201-DPB1*0101 haplotypes were not found on the A*30-B*18 subset of DR3 haplotypes, and DPA1*0103-DPB1*0202 haplotypes were not found on the A*01-B*08 subset.

1

Padj = 0.02, odds ratio 0.6 (95% CI 0.5–0.8);

2

Padj = 0.01, odds ratio 2.1 (95% CI 1.4–3.3);

3

Padj = 0.02, odds ratio 0.5 (95% CI 0.3–0.8); and

4

Pnominal = 0.02.

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FIG. 1.
FIG. 1. Expected and observed proband DPA1-DPB1 haplotype frequencies conditioned on HLA-B-DRB1-DQA1-DQB1 linkage disequilibrium. Alleles or haplotypes with a frequency of <5% for an individual category with a nonsignificant comparison or <1% where P < 0.05 are not shown. Nominal P values were adjusted for the number of haplotypes observed.
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Expected and observed proband DPA1-DPB1 haplotype frequencies conditioned on HLA-B-DRB1-DQA1-DQB1 linkage disequilibrium. Alleles or haplotypes with a frequency of <5% for an individual category with a nonsignificant comparison or <1% where P < 0.05 are not shown. Nominal P values were adjusted for the number of haplotypes observed.

FIG. 1.
FIG. 1. Expected and observed proband DPA1-DPB1 haplotype frequencies conditioned on HLA-B-DRB1-DQA1-DQB1 linkage disequilibrium. Alleles or haplotypes with a frequency of <5% for an individual category with a nonsignificant comparison or <1% where P < 0.05 are not shown. Nominal P values were adjusted for the number of haplotypes observed.
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Expected and observed proband DPA1-DPB1 haplotype frequencies conditioned on HLA-B-DRB1-DQA1-DQB1 linkage disequilibrium. Alleles or haplotypes with a frequency of <5% for an individual category with a nonsignificant comparison or <1% where P < 0.05 are not shown. Nominal P values were adjusted for the number of haplotypes observed.

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© 2011 by the American Diabetes Association.
2011