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Contribution of Selective HLA-DRB1/DQB1 Alleles and Haplotypes to the Genetic Susceptibility of Type 1 Diabetes among Lebanese and Bahraini Arabs

College of Medicine and Medical Sciences (F.A.A.-J., A.A.-A., W.Y.A.), Arabian Gulf University, Department of Pediatrics (F.A.A.-J., A.A.-A., K.A.-O.), Salmaniya Medical Complex, Manama, Bahrain; St. Georges University Hospital (S.F.W.-G., N.I.-H., P.N.), Beirut, Lebanon; Joslin Diabetes Center-Bahrain (M.R.A.), Manama, Bahrain; and Nelson R. Mandela School of Medicine (A.A.M.), University of Natal, 4013 Durban, South Africa

Address all correspondence and requests for reprints to: Wassim Y. Almawi, Ph.D., Al-Jawhara Center for Molecular Medicine, Genetics, and Inherited Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, P.O. Box 22979, Manama, Bahrain. E-mail: wyalmawi{at}yahoo.co.uk.

	Abstract

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Context: Human leukocyte antigen (HLA) class II genes contribute to the genetic susceptibility of type 1 diabetes (T1D), and both susceptible and protective alleles were implicated with its pathogenesis, which varies among various ethnic/racial groups.

Objective: This study investigated the heterogeneity in HLA class II haplotypes distribution among Bahraini and Lebanese T1D patients.

Design: This was a cross-sectional retrospective study.

Setting: The study was conducted at primary care private and public health centers.

Patients and Other Participants: Subjects comprised 126 T1D patients and 126 healthy controls from Bahrain and 78 Lebanese T1D patients and 111 control subjects.

Intervention(s): There were no interventions.

Results: Although Lebanese and Bahraini patients share DRB1*030101, DQB1*0201 as susceptible and DRB1*100101 and DQB1*030101 as protective alleles, DRB1*040101 was an additional susceptible allele in Bahraini patients, and DRB1*130701 and DQB1*050101 were additional susceptible and protective alleles in Lebanese, respectively. DRB1*030101-DQB1*0201 was susceptible, whereas DRB1*070101-DQB1*0201 and DRB1*110101-DQB1*030101 were protective haplotypes in Bahraini and Lebanese. DRB1*040101-DQB1*0302 and DRB1*040101-DQB1*050101 displayed different associations: they were protective in Lebanese but susceptible or neutral among Bahrainis. Whereas the frequency of homozygous DRB1*03011-DQB1*0201 was higher in Bahraini and to a lesser extent Lebanese patients, homozygous DRB1*110101-DQB1*030101 was significantly more frequent in Lebanese but not Bahraini controls, whereas DRB1*030101-DQB1*0201/DRB1*040101-DQB1*0201 was the major genotype among Bahraini patients but not Lebanese subjects in whom it was present at very low frequencies.

Conclusion: In view of these differences between Bahraini and Lebanese, this demonstrates that the contribution of HLA class II to the genetic susceptibility to T1D must be evaluated with regard to specific HLA haplotypes and also ethnic origin and racial background.

	Introduction

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TYPE 1 (INSULIN-DEPENDENT) diabetes (T1D) is an autoimmune disease characterized by insulin insufficiency resulting from autoimmune destruction of insulin-secreting ß-cells of the pancreas (1). Although the exact trigger is not completely understood, susceptibility to T1D is determined by combination of environmental and genetic factors (2). Many susceptibility loci were described, including the human leukocyte antigen (HLA) and insulin gene regions (1, 3). Previous studies demonstrated that HLA class II genes have the greatest genetic effect on T1D susceptibility, and both susceptible and protective alleles at the DRB1, DQA1, and DQB1 loci were implicated with disease pathogenesis (4, 5). Strong association of HLA-DR3 and -DR4, and HLA-DQA1 and -DQB1 alleles (6) and negative association of HLA-DR2 and DQB1*0602 alleles were previously reported in T1D patients (7). It also became evident that the disease association (positive, neutral, or negative) of a particular DRB1 and DQA1/DQB1 allele varies among various ethnic and racial groups (8).

The variation in association of HLA class II genes with T1D was highlighted by the findings that DRB1*0301-DQB1*0201 and DRB1*040101-DQB1*0302 haplotypes, particularly in the heterozygous state, conferred T1D susceptibility (9), whereas DRB1*15-DQB1*0602 haplotype was generally protective of T1D in Caucasians. In contrast, DR3- and DR4-containing haplotypes are not associated with T1D in Southeast Asian communities, including Japan and Korea (4, 10). Instead, other haplotypes such as DRB1*0405-DQB1*0302 and DRB1*0802-DQB1*0302, not as common among Caucasians, confer disease susceptibility in these communities (4). Among Caucasians, the presence of DRB1*0301-DQB1*0201 and DRB1*040101-DQB1*0302 haplotypes are linked with high incidence of T1D, whereas lower disease is associated with low frequency of these haplotypes (4, 9), which may be explained by the selective distribution of susceptible (and protective) HLA DR/DQ alleles (4, 11).

We previously reported on the distribution of HLA class II alleles and haplotypes among T1D patients from Bahrain (12), a country with a very high incidence of diabetes (13). In view of the heterogeneity of Arabs, who have distinct ethnic backgrounds and geographical/racial origins (North Africans, Arabian peninsula, Eastern Mediterranean) (14), the present study was aimed at addressing the association of HLA-DRB1 and -DQB1 haplotypes with T1D in Bahraini and Lebanese Arabs. In particular, we sought to determine the prevalence of DRB1-DQB1 haplotype genotypic combination in search of specific T1D susceptible and protective haplotypes and genotypes.

	Subjects and Methods

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Subjects

Bahraini study subjects comprised 126 unrelated T1D patients (60 males and 68 females, mean age 13.3 ± 9.4 yr). T1D diagnosis was according to clinical features and laboratory findings. All T1D patients were receiving insulin for controlling hyperglycemia, were not obese (body mass index 22.08 ± 7.5 kg/m²), were free of any concomitant complication, and were not receiving additional treatment at the time of blood collection. Patients with other forms of diabetes (type 2, latent autoimmune diabetes of adults, maturity-onset diabetes of the young, etc.) were not included in the study. Controls consisted of university students and healthy children and comprised 63 males and 63 females (mean age 28.8 ± 15.1 yr). Control subjects had normal fasting/random glucose levels and no family history of T1D or other autoimmune diseases. All were Bahraini Arabs, and non-Arab Bahrainis or recently naturalized Bahrainis were excluded. Lebanese subjects comprised 78 T1D patients (29 males and 49 females, mean age 20.7 ± 11.5 yr). The criteria for the diagnosis of T1D were the same as those adopted for Bahraini patients. Lebanese controls consisted of 51 males and 60 females (mean age 28.8 ± 11.4 yr). None of the participants (patients and controls) was a smoker, consumed alcohol, or was on any drug/medication (including substance of abuse), and all were asked to sign a consent form according to the study protocol, and all institutional ethics requirements were met.

HLA-DRB1 and -DQB1 genotyping

Total genomic DNA was extracted from EDTA-anticoagulated venous blood by the phenol-chloroform method. HLA-DRB1 and -DQB1 gene alleles were analyzed using the PCR-sequence-specific priming (SSP) technique, using the SSP2L HLA class II (DRB/DQB) genotyping kit according to manufacturer’s specifications (One Lambda, Thousand Oaks, CA). PCR products were analyzed on 2.5% (wt/vol) agarose gel stained with ethidium bromide (0.5 µg/ml).

Data analysis

Allele frequencies were determined as described (15) using the HLAStat 2000 software (courtesy of Dr. M. Busson, Hôpital St. Louis, Paris, France), which also computed the P values (Fisher’s exact probability test) and odds ratios (ORs). The frequencies of the most frequent haplotypes were determined by the maximum likelihood method, using the Arlequin (version 2.000) population genetics data analysis software (16). P values were corrected for the number of different alleles tested (Pc) using the Bonferroni inequality method (17), and significance was determined at P < 0.05. Additional statistical was performed with SPSS version 13.0 for Windows statistical package (SPSS Inc., Chicago, IL).

	Results

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HLA-DRB1 and HLA-DQB1 allele frequencies among Lebanese subjects

Significant DRB1 allelic differences were seen between Lebanese T1D patients and controls, seven of 31 loci being significantly different (P < 0.05). When the Bonferroni correction was applied, differences were significant for only three, which comprised DRB1*030101 (Pc < 0.033) and DRB1*130701 (Pc = 0.008), which were higher among patients, and DRB1*110101 (Pc = 0.002), which was higher in control subjects (Table 1). Similarly, significant DQB1 allelic differences were seen at the DQB1 locus, three of eight loci being significantly different, even after the Bonferroni correction. These comprised DQB1*0201 (Pc < 0.001), which was higher among patients (Table 2), and DQB1*030101 (Pc < 0.001) and DQB1*050101 (Pc = 0.006), which were higher among control subjects (Table 1).

Similarly, significant DRB1 allelic differences were seen in Bahraini subjects, eight of 31 loci being significantly different (P < 0.05). With the application of the Bonferroni correction, significant differences were significant for three, which comprised DRB1*030101 (Pc < 0.001) and DRB1*040101 (Pc < 0.001), which were higher among T1D patients, and DRB1*110101 (Pc = 0.001), which was higher in control subjects (Table 2). Significant DQB1 allelic differences were also seen at the DQB1 locus; five of eight loci were significantly different. After the Bonferroni correction, only four were significant; these comprised DQB1*0201 (Pc < 0.001) and DQB1*0302 (Pc < 0.001), which were higher among patients, and DQB1*030101 (Pc = 0.003) and DQB1*050101 (Pc < 0.001), which were higher among control subjects (Table 2).

Frequencies of DRB1-DQB1 haplotypes

In Lebanese, the frequencies of DRB1*030101-DQB1*0201 (P < 0.001) and DRB1*130701-DQB1*0302 (P = 0.002) were higher, whereas the frequencies of DRB1*010101-DQB1*050101 (P < 0.001), DRB1*040101-DQB1*0302 (P < 0.001), DRB1*040101-DQB1*050101 (P < 0.001), DRB1*070101-DQB1*0201 (P = 0.028), DRB1*110101-DQB1*030101 (P < 0.001), DRB1*100101-DQB1*060101 (P = 0.002), and DRB1*150101-DQB1*060101 (P = 0.011) were lower in T1D patients than control subjects (Table 3). Among Bahraini subjects, the frequencies of DRB1*030101-DQB1*0201 (P < 0.001), DRB1*040101-DQB1*0302 (P < 0.001), and DRB1*160101-DQB1*0201 (P < 0.001) were higher, whereas the frequencies of DRB1*070101-DQB1*0201 (P < 0.001), DRB1*100101-DQB1*050101 (P = 0.002), and DRB1*110101-DQB1*030101 (P < 0.007) were lower in T1D patients compared with control subjects (Table 4).

Significant DRB1-DQB1 genotype differences were seen between Lebanese T1D patients and controls, 10 of 14 genotypes being significantly different (P < 0.05). When the adjusted P values were applied, differences were significant for only three, which comprised DRB1*030101-DQB1*0201/DRB1*030201-DQB1*0302 (Pc = 0.04,) which was higher, and DRB1*040101-DQB1*030101/DRB1*110101-DQB1*0302 (Pc < 0.01) and DRB1*110101-DQB1*030101/DRB1*140101-DQB1*050101 (Pc = 0.04), which were lower among patients (Table 5). Similarly, significant genotype differences were seen between Bahraini patients and controls; six of 14 genotypes were significantly different (Table 6). After adjusting P values, differences were significant for only three, which comprised DRB1*030101-DQB1*0201/DRB1*030101-DQB1*0201 (Pc = 0.014) and DRB1*030101-DQB1*0201/DRB1*040101-DQB1*0201 (Pc < 0.01), which were higher, and DRB1*110101-DQB1*030101/DRB1*160101-DQB1*050101 (Pc = 0.014), which was lower among patients (Table 6).

	Discussion

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In both Lebanese and Bahraini, DRB1*030101-DQB1*0201 was strongly associated with and DRB1*070101-DQB1*0201 and DRB1*110101-DQB1*030101 were protective of T1D, further supporting the notion that DRB1*030101-DQB1*0201 on its own is a major T1D susceptibility haplotype among Caucasians (18, 19, 20). The strong susceptibility conferred by the DR4-containing haplotypes, in particular DRB1*040101-DQB1*0302 in Bahraini patients, was also reminiscent of previous studies that showed that DRB1*0301-DQB1*0201 and DRB1*04-DQB1*0302 haplotypes were strongly associated with T1D in Caucasians (19, 21), with heterozygous DRB1*0301-DQB1*0201/DRB1*04-DQB1*0302 in particular conferring strong disease susceptibility. It was noteworthy that DRB1*1307-DQB1*0302, a rare haplotype in Caucasian populations, conferred disease susceptibility among Lebanese patients and was not associated in the Bahraini counterparts.

Whereas DRB1*040101 haplotypes were not only not associated with T1D among Lebanese T1D, these haplotypes appeared to be protective of T1D among Lebanese, a finding also reported in Czech (22) and Israeli Jews and Arabs (23). This was principally due to the high prevalence of DRB1*04 among healthy Lebanese, as shown by us (14) and others (24, 25), and is also frequent in the healthy populations of Mediterranean countries (23, 26). When genotypes were analyzed among Lebanese, DRB1*040101-DQB1*0302 displayed mixed effect: it conferred susceptibility when combined with DRB1*030101-DQB1*0302 but was negatively associated with T1D when combined with DRB1*110101 haplotypes. Whereas an additive effect of DRB1*04011 to DQB1*0302 (27) and an interaction between DR3 and DR4 haplotypes in conferring disease susceptibility remain possible, it appears more likely that DR4 did not play a significant role because homozygous DRB1*040101-DQ1*0302 was not associated with any appreciable effects and because homozygous DR4 genotype (DRB1*040101-DQB1*0302/DRB1*040101-DQB1*0302) was not significantly associated with T1D. Thus, it would appear more likely that the strong DR3 haplotype was responsible for disease susceptibility in the DR3-DR4 genotypic combination.

Similar to DRB1 alleles, differential distribution of DQB1 alleles was seen in Lebanese and Bahraini patients, exemplified by the strong association of (susceptible) DQB1*0201 and (protective) DQB1*050101 with T1D in both communities and the T1D association of DQB1*0302 in Bahraini but not Lebanese patients. Heterogeneity in the association of DQB1*0302 with T1D was also demonstrated in Europe, with a gradient-like nature in which it was linked with T1D in Northern European countries including Finland (28), Czech Republic (29), and Romania (9, 30) but loses its T1D susceptible nature in Southern European/Mediterranean countries such as Greece (28, 31) and Albania (31), who, on the contrary, had DQB1*0201 as the major DQB1 susceptible allele, similar to what was shown here for Lebanese patients. It remains to be seen whether the lack of association of DQB1*0302 with T1D in Lebanon and other Mediterranean countries is directly linked with the generalized lower incidence of T1D, as was suggested (28, 30). It is also possible that the lack of association between DQB1*0302 and T1D in Lebanese, and its apparent strong association among Bahrainis, may be due to the presence of DQB1*0302 haplotypes with protective or susceptible DRB1 alleles, respectively. Previous studies in Caucasian (9, 32) and non-Caucasian (4, 10) populations support this hypothesis.

Insofar as HLA class II DR and DQ molecules bind and present, as a complex, processed antigen fragments to T cells, the presence of disease-associated HLA class II haplotype dictates to a large extent selection for the presentation of ß-cell-specific peptides that are capable of activating autoreactive T cells and later for the expansion of these autoreactive T-cell clones (33, 34). Accordingly, the strong association of DRB1*030101-DQB1*0201 and negative association of DRB1*110101-DQB1*030101 with T1D is likely due to differences in affinity to autoantigenic fragments presented by each haplotype, as was suggested (35), in which molecules encoded by DRB1*030101-DQB1*0302 haplotype have higher affinity to a diabetogenic peptide than those encoded by other haplotypes, which bind to and present the peptide to autoreactive T cells, and molecules encoded by DRB1*110101-DQB1*030101 haplotype have lower affinity for select ß-cell autoantigens (GAD-65), thereby conferring lower disease susceptibility. Whereas this may explain the basis of the disease susceptibility of DR3 haplotypes and the protective nature of DR11 haplotypes in both study communities, it remains to be seen as to the pathogenic nature of DR4 haplotypes because they exert a susceptible role among Bahrainis, whereas they are largely protective among Lebanese.

In summary, the present study indicated that the contribution of HLA haplotypes to the genetic susceptibility to T1D differs among Bahraini and Lebanese Arabs, with DRB1*03011-DQB1*0201 and DRB1*110101-DQB1*030101 haplotypes conferring disease susceptibility and protection, respectively, in both communities, with the most notable difference in class II usage being the DRB1*040101DQB1*0302, which was a susceptible haplotype only in Bahraini T1D patients. Furthermore, our results highlight the significance of analyzing genotypic combination as opposed to single alleles and haplotype analysis in determining T1D genetic susceptibility because an individual haplotype may influence the pathogenic nature of the other haplotype within a particular genotype combination. A larger study that addresses the class II genotype and also class I genotype distribution among T1D will be needed to fully elucidate the contribution of HLA haplotypes and genotypes to the genetic susceptibility of T1D.

	Footnotes

 
First Published Online June 28, 2005

Abbreviations: HLA, Human leukocyte antigen; OR, odds ratio; Pc, P values corrected for the number of different alleles tested; SSP, sequence-specific priming; T1D, type 1 diabetes.

Received May 24, 2005.

Accepted June 22, 2005.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) All Versions of this Article: 90/9/5104    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart 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 Al-Jenaidi, F. A. Articles by Almawi, W. Y. Search for Related Content PubMed PubMed Citation Articles by Al-Jenaidi, F. A. Articles by Almawi, W. Y. Related Collections Diabetes and Insulin Pediatric Endocrinology