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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 10 3721-3725
Copyright © 1999 by The Endocrine Society

Original Studies

Human Leukocyte Antigen-A24 and -DQA110301 in Japanese Insulin-Dependent Diabetes Mellitus: Independent Contributions to Susceptibility to the Disease and Additive Contributions to Acceleration of ß-Cell Destruction,1

Koji Nakanishi, Tetsuro Kobayashi, Toshio Murase, Taeko Naruse, Yoshisuke Nose and Hidetoshi Inoko

Department of Endocrinology and Metabolism, Toranomon Hospital and Okinaka Memorial Institute for Medical Research (K.N., T.K., T.M.), Tokyo 105-8470, Japan; the Department of Molecular Life Science, Tokai University School of Medicine (T.N., H.I.), Isehara 259-1100; and the Hyogo Red Cross Blood Center (Y.N.), Kobe 651-0062, Japan

Address all correspondence and requests for reprints to: Koji Nakanishi, M.D, Department of Endocrinology and Metabolism, Toranomon Hospital, 2–2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Statistical analysis
 Results
 Discussion
 References
 
The aim of this study is to identify insulin-dependent diabetes mellitus (IDDM)-susceptible HLA antigens in IDDM patients who do not have established risk allele, HLA-DQA1*0301, and analyze relationship of these HLA antigens and the degree of ß-cell destruction.

In 139 Japanese IDDM patients and 158 normal controls, HLA-A, -C, -B, -DR and -DQ antigens were typed. Serum C-peptide immunoreactivity response ({Delta}CPR) to a 100-g oral glucose load <= 0.033 nmol/l was regarded as complete ß-cell destruction.

All 14 patients without HLA-DQA1*0301 had HLA-A24, whereas only 35 of 58 (60.3%) normal controls without HLA-DQA1*0301 and only 72 of 125 (57.6%) IDDM patients with HLA-DQA1*0301 had this antigen (Pc = 0.0256 and Pc = 0.0080, respectively). {Delta}CPR in IDDM patients with both HLA-DQA1*0301 and HLA-A24 (0.097 ± 0.163 nmol/L, mean ± SD, n = 65) were lower than in IDDM patients with HLA-DQA1*0301 only (0.219 ± 0.237 nmol/L, n = 45, P < 0.0001) and in IDDM patients with HLA-A24 only (0.187 ± 0.198 nmol/L, n = 14, P = 0.0395).

These results indicate that both HLA-DQA1*0301 and HLA-A24 contribute susceptibility to IDDM independently and accelerate ß-cell destruction in an additive manner.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Statistical analysis
 Results
 Discussion
 References
 
INSULIN-dependent diabetes mellitus (IDDM) is caused by the autoimmune destruction of pancreatic ß cells (1). Major histocompatibility complex (MHC) class II most strongly contributes to susceptibility to IDDM (2). In trans-racial studies, human leukocyte antigen (HLA)-DQ{alpha}ß heterodimers composed of a DQ{alpha} chain having arginine at residue 52 (e.g. DQA110301 and 10501) and a DQß chain having amino acids other than aspartic acid at residue 57 (e.g. DQB110302 and 10201) confer susceptibility to IDDM and a HLA- DQ{alpha}ß heterodimer encoded by DQA110102 and DQB110602 confers dominant protection to IDDM (3, 4, 5). In Caucasians, HLA-DQB110302 and 10201 are strongly associated with IDDM. However, these alleles are not positively associated with Japanese IDDM. In Japanese, HLA-DQA110301 strongly confers susceptibility to IDDM. Almost (~85%) IDDM patients have HLA-DQ{alpha}ß heterodimers involving DQA110301 (e.g. DQA110301-DQB110401, DQA110301-DQB110303 and DQA110301-DQB110302) (5, 6, 7, 8). This also conversely means about 15% IDDM patients do not have HLA-DQA110301 as a risk allele. It is not clear that what factors contribute to susceptibility to IDDM in such patients. We have previously shown that specific HLA class I antigen, HLA-A24, associates with acute and complete ß-cell destruction in IDDM if it appears together with IDDM-susceptible HLA class II antigens (8, 9, 10). Thus, this antigen is an attractive candidate for IDDM-susceptible allele when HLA-DQA110301 are not present in patients.

In this study, we identified HLA-A24 as IDDM-susceptible HLA antigen independent of established IDDM-susceptible HLA class II allele, HLA-DQA110301, and further evaluated the effect of these 2 IDDM-susceptible HLA antigens on the degree of ß-cell destruction.


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

Subjects were 139 Japanese IDDM patients (66 women and 73 men; mean [± SD] age at the onset of 31.5 ± 13.4 years [range 8–62 years]; mean [± SD] duration after diagnosis of 13.1 ± 9.1 years [range 0–38 years]). Some of these patients have been described previously (8, 9). A diagnosis of IDDM was made according to the guidelines of the National Diabetes Data Group (11). In addition, a daily urinary C-peptide excretion of < 6.6 nmol/day or integrated serum C-peptide immunoreactivity (CPR) value during a 100-g oral glucose tolerance test (OGTT) of < 3.3 nmol/L was used to define IDDM as previously described (12, 13, 14). All patients exhibited ketoacidosis or ketosis at the time of initiation of insulin therapy. Their mean [±SD] body mass index was 19.7 ± 2.3 kg/m2. The mean [±SD] daily dose of insulin was 0.60 ± 0.22 U/kg body weight-1·day-1. One hundred and fifty-eight healthy individuals, who were also Japanese, were enrolled in the study as normal controls. This study was approved by the Toranomon Hospital Committee on Investigations Involving Human Subjects. All subjects gave their informed consent before entering the study.

HLA typing

HLA-A, -C, -B, -DR and -DQ antigens were typed in all subjects. HLA-A,-C, -B, and -DR antigens were typed by a standard microcytotoxicity test (15). HLA-DQ alleles were typed by previously described PCR - restriction fragment length polymorphism (RFLP) method (8). In 47 IDDM patients, HLA-A, -C, -B, -DR and -DQ haplotypes were determined by HLA typing of their family members. In other patients, most probable HLA-DQ haplotypes were established based on known linkage disequilibria (16).

Twenty-nine IDDM patients and 6 normal controls with HLA-A24 were randomly selected and their HLA-A24 alleles were further subtyped by previously described PCR-RFLP method combined with allele group- and sequence-specific amplification (17).

Assessment of residual ß-cell function in IDDM

Residual ß-cell function was assessed by the serum CPR response ({Delta}CPR) during a 100-g OGTT using a sensitive CPR assay as described previously (8, 9, 18). The {Delta}CPR was calculated by subtracting the fasting CPR value from the maximum value during OGTT. {Delta}CPR <= 0.033 nmol/L was regarded as complete loss of ß-cell function as described previously (8, 9, 18).


   Statistical analysis
Top
 Abstract
 Introduction
 Subjects and Methods
 Statistical analysis
Results
 Discussion
 References
 
Fisher’s exact probability test was used for the assessment of the frequencies between the groups. Corrected p values (Pc) were calculated by multiplication by the number of antigens examined at each locus. Mann-Whitney U test was used for unpaired data. The significance of the difference of the means among the 3 groups was evaluated by one-way ANOVA after ascertaining the homogeneity of the variances by the F-test. In case of difference of the variances among the groups, Kruskal-Wallis test was used. Results were expressed as means ± SD.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Statistical analysis
 Results
Discussion
 References
 
Frequencies of HLA antigens in IDDM patients without HLA-DQA110301

Of 139 IDDM patients, 125 (89.9%) patients had HLA-DQA110301, in whom 54 (43.2%) patients had the DQA110301-DQB110401 haplotype, 46 (36.8%) patients had the DQA110301-DQB110303 haplotype and 34 (27.2%) patients had the DQA110301-DQB110302 haplotype. Fourteen (10.1%) patients had not HLA-DQA110301 (Table 1Go). Of 158 normal controls, 58 (36.7%) subjects had not HLA-DQA110301.


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  		Table 1. HLA-A, -C, -B, and -DR phenotypes; DQ genotypes; and A-C-B-DR-DQ haplotypes in 14 IDDM patients who did not have HLA-DQA16 0301

 
Distributions of HLA-DQ haplotypes were not different between IDDM patients without HLA-DQA110301 and normal controls without HLA-DQA110301 (Table 2Go). Frequencies of HLA-DQA1 and -DQB1 alleles were not different between IDDM patients without HLA-DQA110301 and normal controls without HLA-DQA110301, either (data not shown).


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  		Table 2. Frequencies of HLA-DQ haplotypes in IDDM patients without HLA-DQA13 0301 and normal controls without HLA-DQA13 0301

 
All 14 patients without HLA-DQA110301 had HLA-A24 (Table 1Go). On the contrary, only 35 of 58 (60.3%) normal controls without HLA-DQA110301 and only 72 of 125 (57.6%) IDDM patients with HLA-DQA110301 had this antigen (Pc = 0.0256 and Pc = 0.0080, respectively, Table 3Go). Frequencies of HLA-A2, -DR4 and -DQB110401 in IDDM patients without HLA-DQA110301 were lower than in those with HLA-DQA110301, but not different from those in normal controls without HLA-DQA110301 (Table 3Go). Frequency of HLA-DR2 in IDDM patients without HLA-DQA110301 was higher than in those with HLA-DQA110301, but not different from that in normal controls without HLA-DQA110301 (Table 3Go). Frequencies of other HLA-A, -C, -B and -DR phenotypes and DQB1 alleles were not different between above 3 groups (data not shown).


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  		Table 3. Frequencies of HLA antigens that show different distributions among IDDM patients with and without HLA-DQA1*0301 and normal controls without HLA-DQA1*0301

 
Residual ß-cell function and HLA antigen

As previously described (8), frequency of HLA-A24 was markedly higher in IDDM patients without residual ß-cell function (36/42, 85.7%) than in those with residual ß-cell function (45/89, 50.6%, P < 0.0001). No significant differences were noted between those with and without residual ß-cell function in terms of the duration of diabetes (12.5 ± 9.0 years and 14.6 ± 9.2 years, respectively, P = 0.17) and the age at the onset of diabetes (32.0 ± 12.1 years and 31.9 ± 15.3 years, respectively, P = 0.77).

HLA-A24 was subtyped in 16 IDDM patients with residual ß-cell function, 13 those without, and 6 normal controls. In these subjects, all but one patients had A12402. Only one patient in the group of IDDM patients with residual ß-cell function had A12405.

Frequencies of HLA antigens at other than HLA-A locus were analyzed in IDDM patients with HLA-A24 with respect to the presence or absence of residual ß-cell function. In IDDM patients with HLA-A24, 34 of 36 (94.4%) of those without residual ß-cell function had HLA-DQA110301, whereas only 32 of 44 (72.7%) of those with residual ß-cell function had HLA-DQA110301 (P = 0.0163). In these patients who had HLA-DQA110301 in addition to HLA-A24, distributions of DQ haplotypes were not different between those with and without residual ß-cell function. Frequencies of the haplotypes DQA110301-DQB110401, DQA110301-DQB110303 and DQA110301-DQB110302 in those with and without residual ß-cell function were 50.0% (16/32) and 50.0% (17/34) (P > 0.99), 37.5% (12/32) and 41.2% (14/34) (P = 0.81), and 34.4% (11/32) and 21.6% (8/34) (P = 0.42), respectively. Frequencies of HLA-B52, -DR2, -DQA110103 and -DQB110601 were decreased in IDDM patients without residual ß-cell function [5.6% (2/36), 5.6% (2/36), 5.6% (2/36) and 2.8% (1/36), respectively] compared with those who had residual ß-cell function [29.5% (13/44) (P = 0.0084), 29.5% (13/44) (P = 0.0084), 27.3% (12/44) (P = 0.0163), and 18.2% (8/44) (P = 0.0367), respectively].

Presence of HLA-A24 and/or HLA-DQA110301 and the degree of residual ß-cell function

Every IDDM patient possessed HLA-A24 and/or HLA-DQA110301 in this study. The mean values of serum CPR responses were different among IDDM patients with both HLA-DQA110301 and HLA-A24, HLA-DQA110301 only, and HLA-A24 only (P = 0.0002 by Kruskal-Wallis test, Fig. 1Go). Serum CPR responses in IDDM patients with both HLA-DQA110301 and HLA-A24 (0.097 ± 0.163 nmol/L, n = 65) were lower than in those with HLA-DQA110301 only (0.219 ± 0.237 nmol/L, n = 45, P < 0.0001) and were also lower than in those with HLA-A24 only (0.187 ± 0.198 nmol/L, n = 14, P = 0.0395). Serum CPR responses were not different between those with HLA-DQA110301 only and those with HLA-A24 only (P = 0.656). There was no difference among these 3 groups in terms of the duration of diabetes (P = 0.243, patients with both HLA-DQA110301 and HLA-A24, 14.0 ± 9.0 years; patients with only HLA-DQA110301, 11.5 ± 8.7 years; patients with only HLA-A24, 14.9 ± 10.2 years) and the age at the onset of diabetes (P = 0.893, patients with both HLA-DQA110301 and HLA-A24, 31.2 ± 14.8 years; patients with only HLA-DQA110301, 31.1 ± 11.6 years; patients with only HLA-A24, 34.7 ± 14.0 years).



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  		Figure 1. Distributions of serum CPR responses after a 100-g oral glucose load in IDDM patients with both HLA-DQA1*0301 and HLA-A24, those with HLA-DQA1*0301 only, and those with HLA-A24 only. Difference of the mean values (—) among 3 groups was significant (P = 0.0002 by Kruskal-Wallis test).

 
In IDDM patients with both HLA-A24 and HLA-DQA110301, HLA-A, -C, -B, -DR and -DQ haplotypes were determined in 27 patients. A24 and DQA110301 occurred on the same haplotype in 26 of these 27 patients.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Statistical analysis
 Results
 Discussion
References
 
It is established that susceptibility to IDDM is most strongly conferred by HLA-DQ locus. DQ{alpha}ß heterodimers having non-Asp at position 57 of DQß chain and Arg at position 52 of DQ{alpha} chain are positively associated with IDDM (3, 19). In Japanese, DQ molecules involving DQA110301 (Arg at position 52 of DQ{alpha} chain) is most strongly associated with IDDM (5, 6, 7, 8). However, there certainly exists a small fraction of IDDM patients who do not possess such DQ molecules. These patients may have other major IDDM-susceptible genes. If such IDDM-susceptible genes exist, their frequencies should be extremely high in IDDM patients without HLA-DQA110301 compared with normal controls without HLA-DQA110301 and IDDM patients with HLA-DQA110301. Only HLA-A24 corresponded to such a HLA antigen in this study. All (14/14) IDDM patients without HLA-DQA110301 had HLA-A24. On the other hand, the frequency of HLA-A24 in normal controls without HLA-DQA110301 and that in IDDM patients with HLA-DQA110301 were only 60% and 57%, respectively, which correspond to the frequency of HLA-A24 in general Japanese population (8). No other HLA antigens including HLA- A2, -DR4, -DQB110401 and -DR2 showed such a difference among 3 groups.

Thus, HLA-A24 always existed in the case of absence of DQ molecules involving DQA110301 in IDDM patients. This implies that HLA-A24 confers susceptibility to IDDM independently of DQ molecules involving DQA110301. We have previously shown that HLA-A24 associates with complete ß-cell destruction in IDDM patients with IDDM-susceptible HLA class II alleles (8). HLA-A24 are also shown to be associated with earlier onset of IDDM (20). This study suggests that the presence of HLA-A24 not only accelerates ß-cell destruction in IDDM, but also confers susceptibility to IDDM itself. In fact, new IDDM-susceptible locus was mapped adjacent to MHC class I locus in nonobese diabetic mice (21). In the Finnish population, comparison of HLA-A alleles on the same HLA-C, -B, -DR and -DQ haplotypes revealed the association of HLA-A locus with susceptibility to IDDM (22). In addition, HLA-A24 occurred more frequently in islet cell antibody-positive first-degree relatives of IDDM patients who developed IDDM in Australian population (23).

Then, when we suppose that HLA-A24 and -DQA110301 contribute to susceptibility to IDDM independently, what is their joint effect? In spite of strong association of HLA-A24 with complete ß-cell destruction in IDDM, about half of IDDM patients with HLA-A24 still retains residual ß-cell function (8). We have previously shown that HLA-A24 protein is identical (A24.1) in one dimensional isoelectric focusing gel analysis between IDDM patients with residual ß-cell function, those without, and normal controls (8). This finding was confirmed at the DNA level in this study. In IDDM patients and normal controls with HLA-A24, all but one subjects had A12402, which corresponds to A24.1 (24) and is most prevalent allele in the Japanese population (25). Therefore, there is a possibility that factors other than HLA-A24 also modulate the degree of residual ß-cell function in IDDM. Comparison of frequencies of HLA antigens at other than HLA-A locus between HLA-A24-positive IDDM patients with residual ß-cell function and those without revealed that the latter had DQ molecules involving DQA110301 more frequently (94%) than the former (73%). Although there is no difference in the degree of residual ß-cell function between IDDM patients with only HLA-DQA110301 and those with only HLA-A24, IDDM patients who had these two HLA antigens together showed lower residual ß-cell function than those who had only one of these two HLA antigens. Thus, HLA-DQA110301 and HLA-A24 may accelerate ß-cell destruction in an additive manner. However, another possibility that other loci on the A24, DQA110301 haplotype confer the acceleration of ß-cell destruction can not be ruled out in this study because DQA110301 and A24 occurred on the same haplotype in all but one (26/27) patients probably due to linkage disequilibrium in Japanese (16).

HLA-B52, -DR2, -DQA110103, and -DQB110601, which were in linkage disequilibrium in Japanese (26, 27), were also increased in HLA-A24-positive IDDM patients with residual ß-cell function compared with those without residual ß-cell function. This is consistent with our previous study which shows that HLA-DR2 associates with the presence of residual ß-cell function independently of HLA-A24 (9).

The importance of HLA-A locus in the susceptibility to IDDM has been reported in Japanese (8, 9), Finnish (22), and Australian (23) populations. Further trans-racial studies are preferable for confirmation of this finding and better understanding of genetics of IDDM.


   Acknowledgments
 
We thank Michita Satoh for technical assistance.


   Footnotes
 
1 This work was supported in part by the Japanese Ministry of Education, Science, and Culture under Grant 09671086. Part of this work was presented at the 58th Annual Meeting of the American Diabetes Association, Chicago, IL, June 13–16, 1998. Back

Received November 11, 1998.

Revised June 17, 1999.

Accepted June 28, 1999.


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

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