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Common Susceptibility and Transmission Pattern of Human Leukocyte Antigen DRB1-DQB1 Haplotypes to Korean and Caucasian Patients with Type 1 Diabetes¹

Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center (Y.P., S.B., G.S.E.), Denver, Colorado 80262; Department of Pathology, Immunology, and Laboratory Medicine and Center for Mammalian Genetics, University of Florida College of Medicine (J.-X.S., C.-Y.W.), Gainesville, Florida 32610; Department of Internal Medicine, Hanyang and Seoul National University College of Medicine (Y.P., H.L.), 471-020 Seoul, Korea; Department of Human Genetics, Roche Molecular Systems, Inc. (H.A.E., J.A.N.), Alameda, California 94501; and Children’s Hospital Oakland Research Institute (H.A.E., J.A.N.), Oakland, California 94609

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

	Abstract

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The incidence of type 1 diabetes in Korea is less than 1/10th of that in the United States, and it has been suggested that human leukocyte antigen (HLA) alleles of Asian patients associated with diabetes differ from those of Caucasians. In this study we analyzed the common susceptibility and transmission pattern of a series of HLA DRB1-DQB1 haplotypes to Korean and Caucasian patients with type 1 diabetes. We performed HLA DR and DQ typing of 158 type 1 diabetic patients in a case control study, 140 nondiabetic subjects from the same geographical area, 49 simplex families from Seoul, and 283 families from the Human Biological Data Interchange. Although the haplotype frequencies in the two populations are quite different, when identical haplotypes are compared, their odds ratios are nearly the same. For all parental haplotypes, the transmission to diabetic offspring was similar for Korean and Caucasian families (r = 0.8; P < 10^-4). Allowing for ethnic differences in allelic associations due to different frequencies of DRB1 and DQB1 haplotypes (linkage disequilibrium), these data show, not only by case-control comparison but also by transmission analyses of the haplotypes, that the susceptibility effects of DRB1-DQB1 haplotypes are consistent in Koreans and Caucasians. Thus, the influence of class II susceptibility and resistance alleles appears to transcend ethnic and geographic diversity of type 1 diabetes.

	Introduction

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TYPE 1 DIABETES mellitus is an immune-mediated disease resulting from the destruction of ß-cells in the pancreas (1). The precise etiology of type 1 diabetes is not yet well understood; however, both genetic and environmental factors are implicated. Recent mapping studies have indicated that a large number of genes contribute to genetic susceptibility of type 1 diabetes, of which genes in the human leukocyte antigen (HLA) class II region are the most prominent (2, 3, 4). In most Caucasian populations, the HLA region may explain up to 50% of the total familial aggregation of the disease (4, 5, 6); however, it has been suggested that the contribution of HLA to type 1 diabetes in some Asian populations is less important (6, 7).

Several studies have clearly demonstrated that both DQ and DR alleles influence type 1 diabetes susceptibility (8, 9, 10, 11, 12, 13, 14, 15). It has now become evident that there are both susceptible and protective alleles at DRB1, DQA1, and DQB1 loci (5, 6, 7). We hypothesized that the association (positive, neutral, or negative) of a particular allele at a given locus (DRB1, DQA1, and DQB1) may be different in various ethnic groups, but the effects of specific haplotypes on type 1 diabetes susceptibility would be consistent in all populations.

The incidence rate of type 1 diabetes varies considerably across the world (16, 17). In Caucasian populations, including those in Northern Europe, type 1 diabetes incidence rates are high, with rates in excess of 20 cases/yr/100,000 individuals. In contrast, countries in Asia, including Korea, have extremely low type 1 diabetes incidence rates, less than 1 case/yr/100,000 individuals. This low incidence rate in the Asian population may be related to the population frequency distribution of susceptible HLA DR/DQ genes. It is apparent that population frequencies of DR/DQ alleles and haplotypes vary dramatically between ethnic groups (6, 7, 13, 14, 15). Because of this, some highly susceptible DR or DQ alleles that are relatively uncommon in a population may be mistakenly considered neutral in population association studies. The HLA DRB1-DQA1-DQB1 haplotype distribution and its transmission pattern in patients with type 1 diabetes or in the general population in Asia have not been well described. To assess the effect of HLA DR and DQ genes on type 1 diabetes, we performed HLA DR and HLA DQ molecular typing in 158 randomly selected cases from the Seoul Registry (17) and compared those with data from 140 healthy controls. To investigate whether the HLA susceptibility reflected in transmission frequencies within families is correlated among countries with very different type 1 diabetes incidence rates, we also analyzed the transmission of a series of HLA DRB1 and DQB1 haplotypes to diabetic offspring from nondiabetic parents in the family-based samples from Korea (n = 86 parents) and the United States in the Human Biological Data Interchange (HBDI) repository (n = 491 parents).

	Subjects and Methods

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Subjects

The samples used in this study included 3 groups: a Korean case-control study population, a Korean family study, and a Caucasian family study. First, for the case-control study, 158 type 1 diabetic patients were randomly selected from the Korean Seoul Registry (17). The criteria for classification of type 1 diabetes was determined by the report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (18). Their mean age was 13 yr (range, 3–22 yr). One hundred and forty nondiabetic control subjects, with no family history of diabetes, were selected from the same geographical area. Their mean age was 34 yr (range, 14–46 yr). The epidemiological procedures developed for selecting type 1 patients and nondiabetic control subjects are those employed for the WHO Multinational Diamond Molecular Epidemiology Study (19). In addition, a second group of 49 simplex families with type 1 diabetes was recruited from the Seoul Registry in Korea. A third group consisted of 283 families provided by the HBDI. These families were multiplex (>1 affected child), except for 14 families (4.9%) with 1 child/family with diabetes. Among 98 parents of Korean Seoul registry and among 566 parents of HBDI, 12 and 75 were homozygous for DRB1-DQA1-DQB1 haplotypes, respectively, and transmission of haplotypes from these parents to affected offspring could not be analyzed. All of the study participants or their parents gave informed consent to participate in the study according to the protocol of each study.

HLA genotyping

Peripheral blood lymphocytes from all participants were used for the molecular typing of HLA DRB1 and HLA DQ A and B chain gene alleles. For the Korean samples, HLA DQA1/DQB1 was genotyped using the PCR-sequence-specific oligonucleotide techniques according to previous reports (20). HLA DRB1 typing of the Korean samples was performed at the University of Florida (Gainesville, FL) using sequence-specific priming techniques as previously described (7, 15). HLA class II typing for DRB1, DQA1, and DQB1 was performed on samples of HBDI using PCR/SSOP methods previously described (5). The nomenclature used to define the HLA DR and DQ alleles was that of the Official Nomenclature for Factors of the HLA System, 1996 (21).

Data analysis

Initially, we calculated the odds ratio (OR) using the Woolf formula (22) to assess the susceptibility effect of HLA DRB1-DQA1-DQB1 haplotypes. Data from family-based samples allowed unambiguous assignment of alleles to three-locus haplotypes (DRB1-DQA1-DQB1) in all families. The haplotype frequencies were obtained by the method of gene counting. The affected family-based control population of HLA haplotypes never transmitted to the affected sibling pair was determined (23). This control population provides an unbiased estimate of the overall population (control) HLA haplotype frequencies. Differences in the HLA haplotype distributions between cases and controls were determined using the ² test with Yates’ correction (two-tailed). When the expected frequency for one of the haplotypes was less than 5, Fisher’s exact test was used. The Bonferroni correction for multiple comparisons was applied, and both of the P values before the correction (P_NC) and after the correction (P_C) are shown.

The transmission disequilibrium test (TDT) was used to assess the transmission of DRB1-DQA1-DQB1 haplotypes to children with type 1 diabetes as described by Spielman et al. (24) Comparison of the transmission frequencies of different haplotypes to affected children from heterozygous parents between two populations were tested for differences using a ² test. Linear regression analysis was applied to calculate the correlation of transmission frequencies between Koreans and Caucasians.

	Results

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Association of type 1 diabetes with HLA haplotypes in Koreans

As the DR alleles and the DQ alleles showed strong linkage disequilibrium (LD) in our 49 Korean families and other Asian populations, we deduced DR-DQ haplotypes for all patients and controls (Table 1) (7). Comparisons of haplotype frequencies between patient and control groups revealed the following: two haplotypes (DRB1¹03-DQA1¹0501-DQB1¹0201 and DRB1¹0401-DQA1¹0301-DQB1¹0302) had increased frequencies in diabetic patients; three other haplotypes (DRB1¹15-DQA1¹0103-DQB1¹0601, DRB1¹15-DQA1¹0102-DQB1¹0602, and DRB1¹12-DQA1¹0501-DQB1¹0301) had lower frequencies in patients. No other haplotypes showed significant differences between patients and controls.

When we listed the haplotype frequencies in Caucasian and Korean controls and compared these control frequencies to patient frequencies for the same haplotypes, the haplotype frequencies in the two populations were quite different, because LD patterns and allele frequencies were different for the two populations. Although the haplotype frequencies in the two populations were quite different, when identical haplotypes were compared, their risk (OR) was nearly the same (Fig. 1).

View larger version (28K): [in this window] [in a new window]   Figure 1. List of ORs of the respective comparable HLA DRB1-DQB1 haplotypes in Caucasians and Koreans according to the decreasing order of transmission frequencies in Caucasians. Comparable HLA DRB1-DQB1 haplotypes denote all haplotypes that were identical at DRB1 and DQB1. Those haplotypes that only appear in one of the two populations were not shown. The HBDI and Korean haplotype frequencies were calculated from 283 multiplex and 49 simplex families, respectively.

We analyzed the transmission of a series of HLA DRB1, DQA1, and DQB1 haplotypes to diabetic offspring from nondiabetic parents in the United States (HBDI repository, n = 491 parents) and Korea (n = 86 parents). The protective DRB1¹15-DQA1¹0102-DQB1¹0602 and DRB1¹11-DQA1¹0501-DQB1¹0301 haplotypes were transmitted to only 2 of 142 (1.4%) and 13 of 95 (10.0%) respective children with diabetes in Caucasians and to only 1 of 6 (16.7%) and 1 of 10 (10%) diabetic Korean children. The frequencies of transmission of the susceptible DRB1¹0401-DQA1¹0301-DQB1¹0302, DRB1¹0405-DQA1¹0301-DQB1¹0302, and DRB1¹0301-DQA1¹0501-DQB1¹02haplotypes from parents heterozygous for these haplotypes to diabetic offspring were 274 of 340 (80.6%), 24 of 33 (72.7%), and 303 of 400 (75.7%) for Caucasians, respectively, and 1 of 1 (100%), 4 of 4 (100%), and 14 of 14 (100%) for Koreans. The frequencies of transmission of the moderate risk DRB1¹09-DQA1¹0301-DQB1¹0303, DRB1¹01-DQA1¹0101-DQB1¹0501, and DRB1¹13-DQA1¹0102-DQB1¹0604 haplotypes from parents heterozygous for these haplotypes to diabetic offspring were 10 of 23 (43.5%), 73 of 177 (41.2%), and 32 of 88 (36.4%) for Caucasians, respectively, and 13 of 22 (59.1%), 5 of 9 (55.6%), and 7 of 16 (43.7%) for Koreans. For all parental DR/DQ haplotypes found to be the same in Caucasians and Korean families, the transmission frequencies were highly correlated (r = 0.8; P < 10^-4).

	Discussion

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In this study we analyzed the associations of type 1 diabetes with individual DR-DQ haplotypes in Koreans and Caucasians. Analyses of haplotypes are likely to be more informative than analyses of individual alleles for understanding the complex association of HLA and type 1 diabetes. Given the strong LD observed for alleles at the DRB1, DQA1, and DQB1 loci, it has proven difficult to identify which allele on a disease-associated haplotype may be responsible for the genetic predisposition (5, 6). One valuable approach has been to examine the pattern of HLA DR-DQ haplotype disease association in different ethnic groups with differing class II allele frequencies and LD patterns. We assessed the susceptibility effect of the DR-DQ haplotypes in Korean patients and families with affected children with type 1 diabetes using two different methods: one involves a case-control comparison and the other a comparison of transmission frequencies within families. We also assessed the susceptibility influence of the DR-DQ haplotypes from the Caucasian type 1 diabetes families. For the case-control study, we computed ORs for DR-DQ haplotypes in patients with diabetes compared with control (or affected family-based controls) haplotypes. Although the haplotype frequencies in the two populations are quite different, when identical haplotypes are compared their ORs are nearly the same. For all DR/DQ haplotypes found to be the same in Caucasians and Korean families, the transmission frequencies were highly correlated. It would also be helpful to study a similar comparison of the results from Koreans with those from other populations with differing allelic frequency and type 1 diabetes incidence.

The type 1 Korean diabetes cases were selected from population-based incidence registries (17), and controls were selected randomly according to a standardized international protocol (19), permitting precise estimates of population gene frequency. The genotype distribution for the control population was tested for Hardy-Weinberg equilibrium and was not different from that expected. Moreover, we could determine HLA haplotypes unambiguously because we had family information. As expected, this analysis is consistent with prior studies in Japan (14) and China (15).

The associations between type 1 diabetes and DQB1 alleles in Koreans are very similar to those observed in other Asian populations (14, 15). However, major differences were seen between the Asian populations and Caucasians. The most significant difference is the neutral or weakly positive associations of DQB1¹0302 and DQB1¹0401 in the Korean population (OR, 2.1 and 1.1, respectively). These differences can be explained by a different LD pattern in Koreans (6, 7). All DQB1¹0302 haplotypes with susceptible DRB1 alleles (DRB1¹ 0401, 0402, 0405, or 0404) confer increased risk to type 1 diabetes. When DQB1¹0302 is associated with the DR8 allele (20% of the DQB1¹0302 haplotypes), the haplotype also confers increased risk. However, the majority of the DQB1¹0302 haplotypes (65%) are associated with protective DR4 subtypes (DRB1¹0403, ¹0406, or ¹0408) in the general population in Korea. This LD between DQB1¹0302 and protective DR4 subtypes has also been observed in Chinese and Japanese (14, 15) and is believed to be responsible for the weakly positive association between DQB1¹0302 and type 1 diabetes observed in Asian populations, indicating that specific combinations of DRB1 and DQB1 alleles determine disease risk. From the data reported here, it is apparent that population frequencies of DR and DQ alleles and haplotypes vary dramatically between ethnic groups. Because of this, some highly diabetogenic DR or DQ alleles that are relatively uncommon in a population may be mistakenly considered neutral in population association studies. Only haplotype analyses can reveal the effects of DR and DQ alleles simultaneously. Although the nature of association for a particular allele may be very different in various ethnic groups, its effect on type 1 diabetes susceptibility is probably consistent in all populations.

Case-control analyses of Korean subjects revealed two haplotypes that were positively associated (DRB1¹0401-DQB1¹0302 and DRB1¹0301-DQB1¹0201) and three haplotypes that were negatively associated (DRB1¹15-DQB1¹0602, DRB1¹15-DQB1¹0601, and DRB1¹12-DQB1¹0301) with the disease. Although statistical significance disappeared after Bonferroni correction, DRB1¹0405-DQB1¹0302, DRB1¹0407-DQB1¹0302, and DRB1¹09-DQB1¹0303 were positively associated with the disease, whereas DRB1¹0404-DQB1¹0401, DRB1¹14-DQB1¹0503, DRB1¹08-DQB1¹0601, and DRB1¹10-DQB1¹0501 were negatively associated with the disease. These findings are consistent with other reports (5, 6, 7, 13, 14, 15). Although ORs cannot be directly compared between two populations because each was calculated using a different baseline, there is an extreme similarity in the decreasing order of the ORs of the different individual DRB1-DQB1 haplotypes between Caucasians and Koreans. Identical haplotypes show similar ORs in both populations. However, we should consider that the small Korean dataset, in contrast to the large Caucasian dataset of HBDI, may lead to the possibility of overstating the conclusions. Moreover, because of the extensive polymorphism of the human HLA class II alleles, the datasets contain many different, but relatively infrequent, haplotypes. Because of these, we can conclude that with the limitations imposed by the sizes of the datasets, the susceptibility effects of DRB1-DQA1-DQB1 haplotypes are surprisingly similar in ethnic populations that dramatically differ in the incidence of type 1 diabetes.

We also analyzed the transmission of a series of HLA DRB1 and DQB1 haplotypes to diabetic offspring from nondiabetic parents in the United States (HBDI repository) and Korea. The frequencies of transmission of the same haplotypes from parents heterozygous for these haplotypes to diabetic offspring were also similar between Koreans and Caucasians. These analyses confirmed that the susceptibility effects of all DR-DQ haplotypes are consistent in Koreans and Caucasians. However, each of the TDT analyses was based on two completely different groups of families that were not comparable. The comparison between Caucasians and Koreans is only valid if we find significant TDT differences within the Korean group. Moreover, the Korean families were simplex, whereas the HBDI data were from the highly enriched multiplex families. The TDT was used to assess the transmission of DR-DQ haplotypes to children with type 1 diabetes, as described by Spielman et al. (24). This method compares the number of times a given haplotypes is transmitted from heterozygous parents to diabetic offspring with the 50% random expectation and can be applied to multiplex as well as simplex families.

Generally, HLA typing analysis of family material has several advantages over typing of individual samples. The typing data produced are usually more accurate, individual alleles can be assigned unambiguously to haplotypes, and analysis of parental transmission patterns is possible. The large number of families in our HBDI study has enabled a detailed analysis of the contribution of the HLA region to type 1 diabetes susceptibility in Caucasians for those alleles and haplotypes present with reasonable frequency. In our small series of Korean families, the true susceptibility effect of the haplotype cannot be determined with enough statistical power to show significance. However, the high correlation of nearly all haplotypes between Caucasians and Koreans using transmission analysis as well as OR comparisons suggests that our data probably represent a reasonable sampling of type 1 diabetes families in Korea.

From these data, we suggest that the ethnic differences in allelic associations with type 1 diabetes might be explained by different LD patterns of DR and DQ genes, which result in a different counterbalancing effect between DR/DQ molecules. The transmission analyses of the haplotypes confirmed that the susceptibility effects of DRB1-DQB1 haplotypes are consistent in Koreans and other populations. Although differences in the population frequency distribution and LD patterns of HLA DRB1 and DQB1 alleles are noted, the transmission frequency of each individual haplotype is nearly identical between Caucasians and Koreans. Our findings indicate consistency of HLA haplotype transmission between populations with very different diabetes incidence rates. From these data, we conclude that the influence of HLA haplotypes for determining susceptibility to type 1 diabetes may be universal.

	Acknowledgments

 
We extend thanks to the Seoul IDDM registry for supplying Korean families.

	Footnotes

 
¹ This work was supported by a grant from the Korea Health 21 Research and Development Project, Ministry of Health and Welfare, Republic of Korea (HMP-00-B-21200-0039; to Y.P.); NIH Grants DK-32083 (to G.S.E.), DK-50220 and DK-53103 (to J.-X. S.), and DK-46626 (to H.A.E.); and ADA Career Development Award (to J.A.N.).

Received May 15, 2000.

Revised August 10, 2000.

Accepted August 25, 2000.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Park, Y. Articles by Eisenbarth, G. S. Search for Related Content PubMed PubMed Citation Articles by Park, Y. Articles by Eisenbarth, G. S.