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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 43  |  Issue : 2  |  Page : 66-71

The frequency of HLA DRB1-DQB1 alleles in autoimmune type 1 diabetes with or without autoimmune thyroid disease


1 Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Clincal Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission01-Mar-2015
Date of Acceptance12-Mar-2015
Date of Web Publication3-Jun-2015

Correspondence Address:
Enaam S AbdEL-Bar
Department of Clincal Pathology, Faculty of Medicine, Tanta University, Tanta 31716
Egypt
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DOI: 10.4103/1110-1415.158055

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  Abstract 

Introduction
A common genetic susceptibility has long been reported between type 1 diabetes (T1D) and autoimmune thyroid disease (AITD). The HLA region became the first candidate to be studied for this association. The aim of this study was to identify the frequency of HLA DRB1-DQB1 alleles in T1D with or without AITD to clarify the susceptibility and the resistance of the two diseases.
Participants and methods
The study included 75 unrelated patients with T1D. About 50 T1D patients had no AITD (30 male and 20 female), 25 T1D patients had AITD (eight male and 17 female), and 40 healthy individuals served as the control group (17 male and 23 female) with mean ages of 40.6 ± 2.0, 40.5 ± 3.9, and 39 ± 4.3 years, respectively. The following investigations were performed on all participants: the thyroid profile (free T4, FT3, and thyroid-stimulating hormone), thyroid peroxidase antibodies (anti-TPO), and thyroglobulin antibodies (anti-TG). Autoantibodies against glutamic acid decarboxylase (anti-GAD) were determined. HLA-DRB1 and HLA-DQB1 alleles were determined by PCR-SSOP methods.
Results
HLA class II alleles showed an increased frequency of DRB1*0101, DRB1*0301, DRB1*0402, DRB1*0403, and total DR*04 alleles with DQB1*0201 and DQB1*0302 alleles both in T1D patients with AITD and in T1D patients without AITD in comparison with the control group. The frequency of the DRB1*0401 allele was significantly higher only in T1D patients without AITD in comparison with the control group. The frequency of the DQB1*0301 allele was significantly higher only in T1D patients with AITD in comparison with the control group. However, frequencies of DRB1*1001, DRB1*1101, and DRB1*1501 with DQB1*0404, DQB1*0601, DQB1*0602, and DQB1*0603 alleles were significantly lower both in T1D patients with AITD and in T1D patients without AITD in comparison with the control group.
Conclusion
Thus, DRB1*04, DRB1*0301, and DRB1*0101 and DQB1*0201 and DQB1*0302 confer susceptibility to both diseases. The frequency of DQB1*0301 confers susceptibility only to T1D patients with AITD, whereas DRB1*1001, DRB1*1101, and DRB1*1501 and DQB1*0404, DQB1*0601, DQB1*0602, and DQB1*0603 alleles confer protection.

Keywords: autoimmunity, HLA-DQ type, thyroid disease, type 1 diabetes


How to cite this article:
El-Ahwal L, AbdEL-Bar ES. The frequency of HLA DRB1-DQB1 alleles in autoimmune type 1 diabetes with or without autoimmune thyroid disease. Tanta Med J 2015;43:66-71

How to cite this URL:
El-Ahwal L, AbdEL-Bar ES. The frequency of HLA DRB1-DQB1 alleles in autoimmune type 1 diabetes with or without autoimmune thyroid disease. Tanta Med J [serial online] 2015 [cited 2018 May 26];43:66-71. Available from: http://www.tdj.eg.net/text.asp?2015/43/2/66/158055


  Introduction Top


It is believed that most cases of type 1 diabetes (T1D) result from a T-cell-dependent selective destruction of insulin-producing pancreatic B cells and subsequent irreversible insulin deficiency. T1D is caused by predisposing genetic factors in the presence of permissive environment [1] . The most important genes contributing to disease susceptibility are located in the HLA-DQ locus on the short arm of chromosome 6 [2] .

Diabetes prevalence in some Eastern Mediterranean countries is among the highest in the world. On the whole, approximately half of the countries have published incidence rates, and the highest rates are reported in Egypt, Kuwait, Lebanon, Oman, and Qatar, where the incidence of T1D is reported to be 8-10 per 100 000 population per year in children aged below 15 years, whereas in Pakistan, it is only one per 100 000 [3] .

In patients with T1D, other autoimmune diseases such as autoimmune thyroid [Hashimoto's thyroiditis (HT) or Graves' disease(GD)], celiac, and Addison's disease can be present [4] . Their similar pathogenesis and their tendency to occur together suggest that the etiology of T1D and other autoimmune diseases may involve common genetic factors [5] . Much of the familial risk for developing T1D and associated autoimmune diseases is provided by human leukocyte antigen (HLA) genotypes [6] .

Of all autoimmune conditions, the familial clustering of autoimmune diseases is the most pronounced for T1D and autoimmune thyroid disease (AITD) [7],[8] . In fact, the prevalence of thyroid autoimmunity in relatives of T1D patients is as high as 48%, compared with a general population prevalence of only 3-10% [9],[10],[11] .

Moreover, T1D and AITD frequently occur within the same individual [7],[12] . Up to 50% of the T1D patients were reported to be positive for thyroid antibodies [6] , and ~50% of them progress to develop clinical AITD [13] . When T1D and AITD occur in the same individual, the phenotype is classified as one of the variants of autoimmune polyglandular syndrome type 3 (APS3 variant) [14] .

The hallmark of AITD is infiltration of the thyroid with thyroid reactive lymphocytes; the end results are two clinically opposing syndromes: HT manifesting by hypothyroidism and GD manifesting by hyperthyroidism. In HT, the lymphocytic infiltration of the thyroid gland leads to apoptosis of thyroid cells and hypothyroidism [15] .In contrast, in GD, lymphocytic infiltration of the thyroid leads to the activation of thyroid-stimulating hormone receptor (TSHR)-reactive B cells that secrete TSHR-stimulating antibodies causing hyperthyroidism [16] .

The aim of this study was to identify the frequency of HLA DRB1-DQB1 alleles in autoimmune T1D with or without AITD to clarify the susceptibility and the resistance of the two diseases.


  Participants and methods Top


About 75 unrelated patients with autoimmune T1D were recruited from the Internal Medicine Outpatient Clinic Tanta University Hospital and 40 healthy individuals served as the control group (17 male and 23 female), with a mean age of 39 ± 4.3 years. An informed consent was obtained from all participants before enrollment in the study. The study design followed the Institutional Committee for the Protection of Human Subjects adopted by the 18th World Medical Assembly, Helsinki, Finland. Patients were divided into two groups depending on the combination of AITD. A total of 50 autoimmune T1D patients with a mean age of 40.6 ± 2.0 years had no AITD (30 male and 20 female) and 25 autoimmune T1D patients with a mean age of 40.5 ± 3.9 years had AITD (eight male and 17 female). All patients had diabetes according to the WHO criteria [17] . Thorough history taking and clinical assessment were performed with special stress on manifestations pointing toward functional thyroid disorders. Thyroid ultrasonograraphy was also performed. AITD includes GD and HT, both diagnosed as described previously [18] . Control individuals were recruited from those who visited the hospital for general health examination; all the participants were clinically euthyroid, and none of them was positive for the studied immunological markers.


  Methods Top


Sampling: Five milliliters fasting venous blood samples were collected from patients and controls under aseptic precautions by venepuncture; 2 ml were put into a sterile EDTA tube for PCR and the other 3 ml were put in a clean plain test tube; after centrifugation, the separated serum was stored at −20°C until use. The following laboratory investigations were performed for patients and controls. Thyroid function tests were performed on a TOSOH AIA System Analyzer (Tosoh Europe N.V. transport street 4,B-3980 Tessenderto, Begium), including the thyroid profile serum (free T4, FT3, and TSH), serum thyroid peroxidase antibodies (anti­TPO), and serum thyroglobulin antibodies (anti-TG). A qualitative ELISA test for the detection of circulating autoantibodies against glutamic acid decarboxylase (GAD) antigens was performed (MPI, Diagnostics Division, Orangeburg, New York, USA;

HLA-DRB1 and HLA-DQB1 alleles were determined by PCR-SSOP methods using Innolipa (Innogenetics, Ghent, Belgium). This test is a line probe assay based on the reverse-hybridization principle [19] . DNA is first extracted from the whole blood and amplified; biotinylated DNA material is chemically denatured, and the single strands are hybridized with specific oligonucleotide probes immobilized as parallel lines on membrane-based strips. This process is followed by a stringent wash step to remove any mismatched amplified material. Thereafter, streptavidin conjugated with alkaline phosphatase is added and bound to any biotinylated hybrid formed previously. Incubation with a substrate solution containing a chromogen results in a purple-brown precipitate. The reaction is stopped by a wash step, and the reactivity pattern of the probes is recorded. The site and the molecular weight of the hybridized probe define a certain allele.

Statistics

Statistical analysis was undertaken using the SPSS computer software (version 17; SPSS Inc., Chicago, Illinois, USA). Results are given as means ± SD, unless otherwise indicated. Appropriate statistical tests were used for comparison between the studied groups. Odds ratio and 95% confidence interval for it were calculated. Results were considered to be statistically significant at a P value less than 0.05.


  Results Top


A total of 75 unrelated patients with autoimmune T1D with or without AITD and 40 healthy individuals as the control group were included; the characteristics of these patients are shown in [Table 1]. Patients with autoimmune T1D included patients with latent autoimmune diabetes in adults, and they mostly had antiglutamic acid decarboxylase antibodies (GAD-Ab).
Table 1 Clinical characteristics in autoimmune T1D patients with or without AITD

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The frequency of DRB1*0101, DRB1*0301, DRB1*0402, and DRB1*0403 alleles was significantly higher in both T1D patients with and T1D patients without AITD in comparison with control individuals [(24, 24 vs. 0%, P < 0.05), (24, 20 vs. 2.5%, P < 0.05), (24, 20 vs. 0%, P < 0.05), and (18, 20, vs. 0%, P < 0.05), respectively]. The frequency of DRB1*0401 allele was significantly higher only in T1D patients without AITD in comparison with control individuals (20%, 2.5%, P < 0.05). The total DR*04 alleles was higher in both T1D patients with and T1D patients without AITD in comparison with control individuals. However, the frequency of DRB1*1001, DRB1*1101, and DRB1*1501 alleles was significantly lower in both T1D patients with and T1D patients without AITD in comparison with control individuals [(2, 4 vs. 30%, P < 0.05), (2, 4 vs. 30%, P < 0.05), and (2, 0 vs. 50%, P < 0.001), respectively] [Table 2].
Table 2 The HLA DRBl allele frequency in autoimmune T1D patients with and without AITD and control participants

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The frequency of DQB1*0201, and DQB1*0302 alleles was significantly higher in both T1D patients with and T1D patients without AITD in comparison with control individuals [(42.5, 40 vs. 2.5%, P < 0.05) and (30, 24 vs. 0%, P < 0.05), respectively]. The frequency of DQB1*0402 allele was significantly higher in T1D patients without AITD in comparison with control individuals (20%, 0%, P < 0.05). The frequency of DQB1*0301 allele was significantly higher only in T1D patients with AITD in comparison with control individuals (28%, 2.5%, P < 0.05). However, the frequency of DQB1*0404, DQB1*0601, DQB1*0602, and DQB1*0603 alleles was significantly lower in both T1D patients with and T1D patients without AITD in comparison with control individuals [(4, 4 vs. 25%, P < 0.05), (4, 4 vs. 25%, P < 0.05), (4, 4 vs. 42.5%, P < 0.001) and (2, 4 vs. 30%, P < 0.05), respectively] [Table 3].
Table 3 The HLA DQBl allele frequency in autoimmune T1D patients with and without AITD and control participants

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  Discussion Top


One strong candidate locus is the HLA, known to influence both T1D and AITD, but to different extents [20] .

The present study confirmed the association between certain HLA class II alleles and both T1D and AITD. Analysis of the frequencies of alleles in our patients compared with the control group revealed that an increased frequency of DRB1*0101, DRB1*0301, DRB1*0402, DRB1*0403 and total DR*04 alleles with DQB1*0201, and DQB1*0302 alleles in both T1D patients with and T1D patients without AITD in comparison with the control group. The frequency of DRB1*0401 allele was significantly higher only in T1D patients without AITD in comparison with the control group. The frequency of DQB1*0301 allele was significantly higher only in T1D patients with AITD in comparison with the control group. However, the frequency of DRB1*1001, DRB1*1101, and DRB1*1501 with DQB1*0404, DQB1*0601, DQB1*0602, and DQB1*0603 alleles was significantly lower in both T1D patients with and T1D patients without AITD in comparison with the control group.

DRB1*04, DRB1*0301, and DRB1*0101 and DQB1*0201 and DQB1*0302 conferred susceptibility to both T1D patients with and T1D patients without AITD. The frequency of DQB1*0301 conferred susceptibility only to T1D patients with AITD. However, DRB1*1001, DRB1*1101, and DRB1*1501 and DQB1*0404, DQB1*0601, DQB1*0602, and DQB1*0603 alleles conferred protection to both T1D patients with and T1D patients without AITD in our study participants.

Wu and colleagues stated that both susceptible and protective DR-DQ haplotypes exist in all populations. In the early 1970s, several groups discovered that there is a relationship between HLA class I and T1D. Later, it was found that lymphocyte-defined HLA-D antigens and HLA class II DR3 (HLA-DRB1*0301, DQB1*0201) and DR4 (HLA-DRB1*04, DQB1*0302) were much more closely associated with T1D, accounting for ~40% of the genetic risk for T1D development, and the DR3/DR4 combination, two susceptible alleles, could produce a higher-risk genetic combination [21] .

This study is in agreement with Noble and Valdes, who stated that the most T1D predisposing genotype is comprised of haplotypes DRB1*03:01-DQA1*05:01-DQB1*02:01and DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04(or DQB1*02) and is commonly abbreviated with the short serology notation 'DR3/DR4.' In addition, some haplotypes confer strong protection from disease, such as DRB1*15:01-DQA1*01:02-DQB1*06:02 (abbreviated 'DR2') [22] .

The present study is in agreement with Abd El-Samea et al. [23] , who stated that the frequencies of alleles in type one diabetes patients compared with the control group revealed that DRB1*04 and DRB1*0101 and DQB1*02 were positively associated with type I diabetes, whereas DRB1*15011, DRB1*1001, and DRB1*1101 and DQB1*0301, DQB1*0404, DQB1*0601, DQB1*0602, and DQB1*0603 alleles were significantly increased in controls.

The present study showed shared alleles between T1D and AITD patients; the frequency of DQB1*0301 also conferred susceptibility only to T1D patients with AITD. This is in agreement with Golden et al. [24] , who reported that the HLA class II locus contributes to the shared risk for T1D and AITD, and the major HLA haplotype contributing to this association is DR3-DQB1*0201.

This is also in agreement with Zamani et al. [25] , who suggested that the primary susceptibility allele in GD is indeed HLA-DR3 (HLA-DRB1*03). Jacobson et al. [26] reported an association of HT with HLA-DR3 and HLA-DR4 in Caucasians. Badenhoop et al. [27] reported that an association between HT and HLA-DQw7 (DQB1*0301) has also been reported in Caucasians. Messaaoui et al. [28] stated that the DQA1*0301-DQB1*0301 haplotype seems to confer susceptibility to thyroid autoimmunity.

In the present study, the frequency of HD was more than that of GD (28-72%, respectively) and it was more in female patients, which is in accordance with the study by Abosmaha and colleagues, who found that patients with T1D had a significantly higher incidence of hypothyroidism (21.26%) that was two-fold that in normal people, and only 7.49% had hyperthyroidism; this explains the result that the sex seems to play a major role in the development of autoimmunity; most of the known autoimmune diseases tend to show a female preponderance, and the reasons for this are unclear. Apart from inherent genetic susceptibility, several animal models suggest a role for sex steroids. Another theory suggests that female patients have a higher tendency to acquire autoimmunity due to the X chromosome [29] .


  Conclusion Top


Thus, DRB1*04, DRB1*0301, and DRB1*0101 and DQB1*0201 and DQB1*0302 confer susceptibility to both diseases. The frequency of DQB1*0301 confers susceptibility only to T1D patients with AITD. However, DRB1*1001, DRB1*1101, and DRB1*1501 and DQB1*0404, DQB1*0601, DQB1*0602, and DQB1*0603 alleles confer protection to both diseases in our participants. Patients with T1D should undergo annual screening for thyroid dysfunction.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3]


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