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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3793-3797
Copyright © 2000 by The Endocrine Society

Original Studies

DR- and DQ-Associated Protection from Type 1A Diabetes: Comparison of DRB111401 and DQA1,10102-DQB1,10602,1

M. J. Redondo, E. Kawasaki, C. L. Mulgrew, J. A. Noble, H. A. Erlich, B. M. Freed, B. A. Lie, E. Thorsby, G. S. Eisenbarth, D. E. Undlien and K. S. Ronningen

Barbara Davis Center for Childhood Diabetes (M.J.R., E.K., C.L.M., G.S.E.) and Department of Medicine (B.M.F.), University of Colorado Health Sciences Center, Denver, Colorado 80262; Children’s Hospital Oakland Research Institute (J.A.N., H.A.E.), Oakland, California 94609; Department of Human Genetics, Inc. (J.A.N., H.A.E.), Roche Molecular Systems, Alameda, California 94501; Institute of Immunology (B.A.L., E.T., D.E.U.), The National Hospital, University of Oslo, 0027 Oslo, Norway; and Section of Epidemiology (K.S.R.), National Institute of Public Health, N-0403 Oslo, Norway

Address correspondence and requests for reprints to: George S. Eisenbarth, M.D., Ph.D., Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 4200 East 9th Avenue, B-140, Denver, Colorado 80262. E-mail: george.eisenbarth{at}UCHSC.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The transmission disequilibrium test was used to analyze haplotypes for association and linkage to diabetes within families from the Human Biological Data Interchange type 1 diabetes repository (n = 1371 subjects) and from the Norwegian Type 1 Diabetes Simplex Families study (n = 2441 subjects). DQA1*0102-DQB1*0602 was transmitted to 2 of 313 (0.6%) affected offspring (P < 0.001, vs. the expected 50% transmission). Protection was associated with the DQ alleles rather than DRB1*1501 in linkage disequilibrium with DQA1*0102-DQB1*0602: rare DRB1*1501 haplotypes without DQA1*0102-DQB1*0602 were transmitted to 5 of 11 affected offspring, whereas DQA1*0102-DQB1*0602 was transmitted to 2 of 313 affected offspring (P < 0.0001). Rare DQA1*0102-DQB1*0602 haplotypes without DRB1*1501 were never transmitted to affected offspring (n = 6).

The DQA1*0101-DQB1*0503 haplotype was transmitted to 2 of 42 (4.8%) affected offspring (P < 0.001, vs. 50% expected transmission). Although DRB1*1401 is in linkage disequilibrium with DQB1*0503, neither of the two affected children who carried DQA1*0101-DQB1*0503 had DRB1*1401. However, all 13 nonaffected children who inherited DQA1*0101-DQB1*0503 had DRB1*1401. In a case-control comparison of patients from the Barbara Davis Center, DQA1*0101-DQB1*0503 was found in 5 of 110 (4.5%) controls compared with 3 of 728 (0.4%) patients (P < 0.005). Of the three patients with DQB1*0503, only one had DRB1*1401. Our data suggest that both DR and DQ molecules (the DRB1*1401 and DQA1*0102-DQB1*0602 alleles) can provide protection from type 1A diabetes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TYPE 1A DIABETES has recently been defined as immune-mediated diabetes mellitus (1). Genes in the major histocompatibility complex, in particular class II genes, are the major determinants of genetic predisposition and resistance. The human lymphocyte antigen (HLA) haplotype with DRB111501 and DQA110102-DQB110602 is associated with protection from type 1A diabetes; approximately 20% of Americans and Europeans have DQA110102-DQB110602, whereas less than 1% of children with type 1A diabetes carry these alleles. The protection provided by DQA110102-DQB110602 seems to be dominant over the risk conferred by other haplotypes, such as DQA110301-DQB110302 or DQA110501-DQB110201 (2). Identification of additional protective HLA haplotypes would facilitate molecular studies on the mechanisms that lead to "protection" from type 1A diabetes. In the current study, we analyzed DRB111401-DQA110101-DQB110503, a rare haplotype that earlier reports have suggested to be protective for type 1A diabetes (3, 4, 5, 6). We also analyzed the well known protective haplotype DRB111501-DQA110102-DQB110602. Both DR and DQ molecules (I-E and I-A) can protect from autoimmune diabetes in the NOD mouse (7). Thus, we investigated whether protection conferred by certain haplotypes is associated with the DR or DQ molecules. For these studies, large populations are required to assess the effect of uncommon protective HLA alleles and haplotypes. Combining families from the Norwegian Type 1 Diabetes Simplex Families (NODIAB) study, the Human Biological Data Interchange (HBDI), and the Barbara Davis Center have allowed us to begin to address the question posed above.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The HBDI created a repository for DNA and cell lines derived from 276 families with type 1A diabetes. The HBDI collection was established, in part, for the purpose of mapping non-HLA genes associated with type 1A diabetes by linkage analysis. Of the HBDI families, 95.5% were multiplex (with two affected siblings), 96% with unaffected parents, and 99.5% of Caucasian origin. The NODIAB study included 526 Norwegian families with at least one affected child diagnosed before age 15. In this study, 97.7% of the families were simplex. The data set from the Barbara Davis Center included 728 patients with type 1A diabetes and 110 unrelated controls. All patients with type 1A diabetes were positive for autoantibodies reacting with at least one of the three following molecules: GAD65, ICA512/IA-2, or insulin (insulin autoantibodies were only analyzed if the sample was drawn within 1 week of insulin therapy). The control subjects were healthy individuals without first-degree relatives with type 1A diabetes. Patients and families gave informed consent for study participation.

HLA typing

For the HBDI data set and for the individuals from the Barbara Davis Center, DQB1 typing was performed by the PCR/single-strand oligonucleotide probe method as described previously (8), and DQA1 typing by the PCR/reverse dot-blot method. DRB1 typing was performed in B.M.F.’s laboratory by PCR-single-strand probe of exon 2, followed by DNA sequencing. For the NODIAB samples, DQA1 typing was performed with an allele-specific PCR assay, and DQB1 typing with PCR and sequence-specific probes (9). Patients and families gave informed consent for study participation.

Statistical analysis

The transmission disequilibrium test (TDT) (10) was used to analyze the difference between the frequency of transmission of an allele from parents to their affected offspring and the expected frequency of transmission (50%) under the hypothesis of no linkage. Only parents heterozygous for the allele of study were included in the analysis. The {chi}2 and Fisher’s exact tests were used for case-control analysis.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Transmission frequencies for the DQA110101-DQB110503 and the DQA110102-DQB110602 haplotypes in the HBDI repository and the NODIAB study are shown in Fig. 1Go. In the combined series, DQA110101-DQB110503 was transmitted from heterozygous parents to 4.8% (2 of 42) of affected offspring (P < 0.0001 compared with the 50% expected transmission). Transmission of this haplotype to nonaffected offspring was 68.4% (13 of 19) (P < 0.0001 compared with transmission to affected offspring). In a similar manner, DQA110102-DQB110602 was transmitted to 0.6% (2 of 313) of affected offspring (P < 0.0001) and 55.9% (160 of 286) of unaffected offspring (P < 0.0001). Tables 1Go and 2Go show characteristics of patients with type 1A diabetes and DQA110101-DQB110503 or DQA110102-DQB110602. All eight patients who were tested for autoantibodies, three with DQA110101-DQB110503 and five with DQA110102-DQB110602, were autoantibody positive. Four of five patients with DQA110101-DQB110503 had a high-risk haplotype such as DQA110301-DQB110302 or DQA110501-DQB110201. Six of seven patients with DQA110102-DQB110602 had a high-risk haplotype.



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  		Figure 1. Transmission analysis of DQA1*0101-DQB1*0503 (A) and DQA1*0102-DQB1*0602 (B). Transmission to affected offspring was compared with the expected 50% transmission. Transmission to unaffected offspring was compared with transmission to affected offspring. Numbers at the bottom are the total number of subjects. a, P < 0.0005; b, P < 0.002; c, P < 0.0001; d, P < 0.001; e, P < 0.002. HBDI, Human Biological Data Interchange; NODIAB, Norwegian Type 1 Diabetes Simplex Families.

 

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  		Table 1. Characteristics of the rare patients with type 1A diabetes and HLA-DQA14 0101-DQB14 0503

 

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  		Table 2. Characteristics of the rare patients with type 1A diabetes and DQA14 0102-DQB14 0602

 
In a case-control study of patients and controls from the Barbara Davis Center, DQA110101-DQB110503 was found in 5 of 110 (4.5%) controls compared with 3 of 728 (0.4%) patients with type 1A diabetes (P < 0.005) (Fig. 2AGo). The haplotype DQA110102-DQB110602 was found in 5 of 728 patients (0.7%) with type 1A diabetes and in 20 of 110 control subjects (18.2%) (P < 0.0001).



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  		Figure 2. A, Percentage of patients with type 1A diabetes and control subjects positive for DQA1*0101-DQB1*0503, in the Barbara Davis Center data set (P < 0.005). Numbers on top are the total number of subjects. B, Percentage of DQA1*0101-DQB1*0503 haplotypes with DRB1*1401 for "non-DM" haplotypes (haplotypes present in a parent but not transmitted to a child with diabetes, from the NODIAB and the HBDI series), controls (from the Barbara Davis Center series), and "type 1 DM" haplotypes" (haplotypes found in patients with type 1A diabetes, in the HBDI and the Barbara Davis Center series). Non-DM haplotypes vs. type 1 DM, P < 0.002. Controls vs. type 1 DM, P < 0.05. Numbers on top are the total number of haplotypes.

 
The DRB111401 allele is in linkage disequilibrium with DQA110101-DQB110503 (11). There were 24 families in whom DQA110101-DQB110503 was not transmitted to a child with diabetes, with 12 haplotypes from the HBDI series and 12 haplotypes from the NODIAB families. All 24 such "non-type 1A diabetes" haplotypes had the allele DRB111401. In the Barbara Davis Center series, of four controls positive for DQA110101-DQB110503 who had DRB1 typing, all had DRB111401. In contrast, of five patients with type 1A diabetes with the haplotype DQA110101-DQB110503 (two patients from the HBDI series and three from the Barbara Davis Center series), only one had DRB111401 (Fig. 2BGo). The remaining four patients with DQA110101-DQB110503 had DRB110103, 0101, or 1404 (the latter was found in two patients) (Table 1Go).

The DRB111401 allele was not transmitted to any affected children, of 37 children who could have received this allele (25 children for the HBDI study and 12 children from the NODIAB study; P < 0.0001, compared to the expected 50% transmission). On the other hand, this allele was transmitted to 68.4% (13 of 19; 5 of 7 children from the HBDI and 8 of 12 from the NODIAB study) of unaffected children (P < 0.0001, compared to transmission with affected children). The DRB111401 allele was not found with a DQ haplotype other than DQA110101-DQB110503 in the HBDI families.

The DRB111501 allele is in linkage disequilibrium with the DQA110102-DQB110602 haplotype (11, 12, 13). However, it was present in the HBDI series without this haplotype in five families. These haplotypes had DQA110102-DQB110502 (found in two families), DQA110102-DQB110603 (found in two families), and DQA110401-DQB110402. In these five families, the DRB111501 allele was transmitted to 5 of 11 affected offspring and 11 of 15 nonaffected offspring. This transmission of DRB111501 to 5 of 11 affected children is significantly different from transmission of the DRB111501-DQA110102-DQB110602 haplotype (2 of 147, P < 0.0001). In comparison, rare DQA110102-DQB110602 haplotypes with a DRB1 allele other than DRB111501 were not transmitted to any of the six affected children who could have inherited it. The DRB1 alleles found in these haplotypes were DRB111101 (found in two families) and DRB111401.

Of note, there were nine offspring (four children from the HBDI and five from NODIAB) who were heterozygous for a high-risk haplotype (DQA110301-DQB110302 or DQA110501-DQB110201) and DRB111401-DQA110101-DQB110503. None of these subjects developed type 1A diabetes.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Large study populations are required to assess the effect of uncommon haplotypes, such as DQA110101-DQB110503, on disease. This haplotype was present in 3.6% (11 of 240) of haplotypes of the Centre d’Etude du Polymorphisme Humain families, drawn from the general population of Utah and France (14, 15). The haplotype DRB111401-DQB110503 was present in 1.6% of haplotypes in North America (16). In the current study, the TDT was used to analyze association and linkage between diabetes and HLA haplotypes in two family-based data sets, the HBDI and the NODIAB series. An additional series from the Barbara Davis Center was used for a case-control analysis. Artifacts of population structure, such as admixture or stratification, can result in spurious association. The TDT analyzes linkage and association within families and is able to distinguish true from spurious associations (10, 17).

In the current study, transmission of DQA110101-DQB110503 from heterozygous parents to children with type 1A diabetes was significantly lower than the expected 50% under the hypothesis of no linkage, in two independent family-based studies, the HBDI and the NODIAB series (P < 0.0005 and P < 0.02, respectively). Transmission to affected and unaffected children was also significantly different (P < 0.001 and P < 0.002, respectively), ruling out a false positive result of linkage caused by preferential transmission in the meiotic process ("segregation distortion").

In the case-control analysis from the Barbara Davis Center, DQA110101-DQB110503 was present in 4.5% (5 of 110) of controls and 0.4% (3 of 728) of patients with type 1A diabetes. These findings are consistent with those reported by the 12th HLA Workshop (3) where the DQB110503 allele was found in 5.8% (149 of 2550) of Caucasian controls and 0.6% (15 of 2438) of patients with type 1A diabetes. Also, a study of Norwegian and Swedish individuals reported the haplotype frequencies of the DQA110101-DQB110503 haplotype to be, respectively, 5.2% (12 of 320) and 5.1% (10 of 196) of controls and 1.3% (1 of 76) and 0% (0 of 80) of patients with type 1A diabetes (6). This study excluded DR3 and DQB110302 subjects from the analysis. Two additional studies (4, 5) also found that the relative risk of diabetes was decreased for DR14-DQA110101-DQB110503. The strong protective effect of DQA110102-DQB110602 and DQA110101-DQB110503 has been most recently reported by Lie et al. (18).

The DQA110101-DQB110503 haplotype is in linkage disequilibrium with DRB111401 (11). In the Centre d’Etude du Polymorphisme Humain families (14), obtained from the general population from Utah and France, 91% (10 of 11) of DQA110101-DQB110503 haplotypes had DRB111401, consistent with the frequency found in the current study for controls. A Norwegian study did not find a patient with the DRB111401 allele among 87 patients with type 1A diabetes, whereas it was present in 12 of 181 (7%) controls (11). In the current study, only one of five patients with type 1A diabetes and the DQA110101-DQB110503 haplotype had DRB111401 compared with 100% (24 of 24, P < 0.002) "non-type 1 diabetes haplotypes" and 100% (4 of 4, P < 0.05) in control subjects from the Barbara Davis Center. This finding suggests that the protection conferred by DRB111401-DQA110101-DQB110503 haplotypes is mediated by DRB111401 itself or combined with DQA110103-DQB110503, rather than by DQA110103-DQB110503. The DRB111401 allele was never found with a DQ haplotype other than DQA110101-DQB110503 in the HBDI material, consistent with a previous study from Norway (12). Interestingly, in a study of Mexican American patients, the DRB111402-DQA110501-DQB110301 was found to be protective for diabetes (19).

As expected, both transmission analysis and a case-control comparison of the well known protective haplotype DQA110102-DQB110602 gave evidence for dramatic protection from disease. In North America, 71.9% of DQB110602 alleles are associated with DRB111501; the remaining 28% are scattered among other DRB1 alleles. The linkage disequilibrium is stronger in Europe (94.8%). DRB111501 is associated with DQB110602 68.6% of the time (16). In the current study, rare combinations of DRB111501 with DQ molecules other than DQA110102-DQB110602 (20) were transmitted to 5 of 11 affected children, whereas DQA110102-DQB110602 haplotypes with a DRB1 allele other than DRB111501 were transmitted to 0 of 6 affected children. These findings suggest that the protection associated to the DQA110102-DQB110602 haplotype is not afforded by the DRB111501 allele because DRB111501 without DQA110102-DQB110602 is not associated with protection. Other studies have also suggested that protection is more strongly associated to the DQ molecule than to DR2 in this haplotype (13, 21, 22, 23).

In the combined series none of the nine offspring who inherited DRB111401-DQA110101-DQB110503 and a high-risk DR3 or DR4 haplotype had diabetes. Thus, protection conferred by the DRB111401-DQA110101-DQB110503 haplotype seems to be dominant over the susceptibility encoded by high-risk haplotypes, such as DQA110301-DQB110302 or DQA110501-DQB110201. Additional series of patients will need to be studied to confirm this hypothesis of dominant protection.

In conclusion, we have analyzed DQA110102-DQB110602 and DQA110101-DQB110503 haplotypes for linkage to diabetes in two independent family-based data sets, along with a case-control study. Our data confirm the well recognized protective effect of DQA110102-DQB110602 and suggest a protective effect also for the uncommon haplotype DRB111401-DQA110101-DQB110503. In addition, our findings indicate that protection provided by the DQA110101-DQB110503 haplotype is probably mediated by the DRB111401 allele, in linkage disequilibrium with DQA110101-DQB110503.


   Acknowledgments
 
We thank Hanne E. Akselsen, Sunanda Babu, and Tianbao Wang for technical assistance.


   Footnotes
 
1 Supported by NIH Grants DK-32083-16 and DK-46626, the American Diabetes Foundation, the Children’s Diabetes Foundation, the Norwegian Diabetes Association, the Novo Nordisk Foundation, and the Juvenile Diabetes Foundation (Grant 1-1998-52). M.J.R. was supported by the Fondo de Investigación Sanitaria (F.I.S. 98/9211), and J.A.N. was supported by a Career Development Award from the American Diabetes Association. Back

Received January 13, 2000.

Revised July 7, 2000.

Accepted July 14, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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  9. Helland A, Olsen AO, Gjoen K, et al. 1998 An increased risk of cervical intra-epithelial neoplasia grade II-III among human papillomavirus positive patients with the HLA-DQA1*0102- DQB1*0602 haplotype: a population-based case-control study of Norwegian women. Int J Cancer. 76:19–24.[CrossRef][Medline]
  10. Spielman RS, McGinnis RE, Ewens WJ. 1996 Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 52:506–516.
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  13. Ronningen KS, Spurkland A, Tait BD, et al. 1992 HLA class II associations in insulin-dependent diabetes mellitus among blacks, Caucasiods, and Japanese. In: Tsuji K, Aizawa M, Sasazuki T, eds. HLA 1991. Proceedings of the Eleventh International Histocompatibility Workshop and Conference. Oxford: Oxford University Press; 713–722.
  14. Carrington M, Stephens JC, Klitz W, Begovich AB, Erlich HA, Mann D. 1994 Major histocompatibility complex class II haplotypes and linkage disequilibrium values observed in the CEPH families. Hum Immunol. 41:234–240.[CrossRef][Medline]
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  19. Erlich HA, Zeidler A, Chang J, et al. 1993 HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families. Nat Genet. 3:358–364.[CrossRef][Medline]
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