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The Relationship Between Human Leukocyte Antigen Class II Genes and Type 1 Diabetes, Autoimmune Thyroid Diseases, and Autoimmune Polyendocrine Syndrome Type 3

Written By

Masahito Katahira

Submitted: 10 October 2013 Published: 19 March 2014

DOI: 10.5772/57498

From the Edited Volume

HLA and Associated Important Diseases

Edited by Yongzhi Xi

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1. Introduction

Common genetic risk factors have been associated with type 1 diabetes (T1D) and autoimmune thyroid diseases (AITD). Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are typical AITD. T1D and AITD are major components of autoimmune polyendocrine syndrome (APS)-2 and/or APS-3. The human leukocyte antigen (HLA) has been extensively studied in these diseases [1]. However, population studies have shown that HLA associations may vary depending on the ethnic origin [2]. In Caucasian populations, the highest-risk HLA haplotype for T1D is DRB1*03:01-DQA1*05-DQB1*02 (DR3) and/or DRB1*04-DQA1*03:01-DQB1*03:02 (DR4) [2, 3], and the corresponding haplotype for AITD is DR3 [4, 5]. DRB1*15-DQB1*06:02 and DRB1*07:01-DQA1*02:01 (DR7) haplotypes confer strong protection against both T1D [2, 3] and AITD [6, 7]. However, in the Japanese population, the DR3 haplotype is absent, and the DR4 and DR7 haplotypes are rare [8–10], which may be more helpful for examining the susceptibility and resistance to T1D and AITD of HLA DR-DQ haplotypes, with the exception of DR3, DR4, and DR7.

DR3 and DR4 haplotypes occur very frequently among Caucasian patients with T1D, and only a small percentage (approximately 10%) of Caucasian patients with T1D carry neither of these haplotypes [11, 12]. At the DQB1 locus, “non-Asp” alleles, which code for an amino acid other than aspartate at codon 57, confer an increased risk for T1D in Caucasian populations [13]. The risk due to DR4 haplotypes is primarily attributable to an association with the DQB1*03:02 allele, which codes for an Ala at codon 57 [14]. The risk conferred by the DR3 haplotype may be associated with DQA1 alleles that encode the amino acid Arg at codon 52, such as DQA1*05:01 [15]. Recently, a similar mechanism was shown to be important in the etiology of AITD. Tomer et al. identified an Arg at position 74 of the HLA-DRβ1 chain (DRβ-Arg-74), encoded by the DRB1*03:01 allele, as the critical DR amino acid conferring susceptibility to GD [16, 17]. Further analysis has shown that the presence of Gln at position 74 was protective not only for GD [16] but also for APS-3 [18].

In the Japanese population, in contrast to Caucasians and other Asians, the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which differs from the DR4 haplotype in Caucasians, and the DRB1*08:02-DQA1*03:01-DQB1*03:02, DRB1*09:01-DQA1*03:02-DQB1*03:03 (DR9), and DRB1*13:02-DQA1*01:02-DQB1*06:04 (DR13) haplotypes confer susceptibility to T1D [9, 19]. The DRB1*15:01-DQB1:06:02, DRB1*15:02-DQB1*06:01, and DRB1*08:03-DQB1*06:01 haplotypes confer protection against T1D [9, 10, 19]. On the other hand, the DRB1*08:03-DQB1*06:01 and DR9 haplotypes confers susceptibility to AITD [19–23], whereas the DR13 and DRB1*15:01-DQB1:06:02 haplotypes confer protection against AITD [7, 23–29]. Taken together, regarding susceptibility and resistance to T1D and AITD, the DR3, DR4, DR7, DR9, and DRB1*15:01-DQB1:06:02 haplotypes have the same effect. On the contrary, DRB1*08:03-DQB1*06:01 and DR13 haplotypes have an adverse effect on these diseases.

In this chapter, we will review HLA class II genes that confer susceptibility and resistance to T1D and AITD, and discuss the relationship between HLA class II genes and T1D, AITD, and APS-3. Furthermore, we focus on amino acids at position 74 of the HLA-DRβ1 chain, position 52 of the HLA-DQα1 chain, and position 57 of the HLA-DQβ1 chain as key factors involved in susceptibility and resistance to T1D and AITD, and we discuss key amino acids and their involvement in susceptibility and resistance to T1D and AITD.

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2. Nomenclature

In 1980, Neufeld and Blizzard suggested a classification of APS based on clinical criteria alone, and described four main types [30]. Of the four types, APS-2 and APS-3 are mainly associated with AITD and/or T1D. APS-2 is characterized by Addison’s disease (AD) associated with AITD and/or T1D. APS-2 is quite rare with an incidence of 1.4-4.5 cases for every 100,000 individuals [31, 32]. While all patients with APS-2 have AD [30, 32–35], AITD and T1D are reported to occur in 69–82% and 30–52% of patients with APS-2, respectively [30, 34, 35]. APS-3 has been defined as an association between a clinical entity of AITD and an additional autoimmune disease such as T1D (Type 3A), chronic atrophic gastritis, pernicious anemia (Type 3B), vitiligo, alopecia, myasthenia gravis (Type 3C). AD and/or chronic hypoparathyroidism were categorically excluded from APS-3 [30]. Although AITD consists of HT, idiopathic myxedema, asymptomatic thyroiditis, GD, endocrine ophthalmopathy, and pretibial myxedema, GD or HT comprise the majority of AITD. Thus, in discussing the relationship between HLA and T1D and/or AITD, it is necessary to focus on APS type 3A (APS-3A) rather than APS-2 or APS type 3B/3C, and GD or HT may be considered as AITD.

In Caucasian populations, including those in Northern Europe, the incidence rates of T1D are high, in excess of 30 cases/100,000 individuals per year. In contrast, the Japanese population has one of the lowest incidence rate of T1D in the world, at 1.6 cases/100,000 individuals per year, suggesting that the Japanese population may either lack an important susceptibility gene or have a unique T1D protective gene [36, 37]. However, AITD is the most frequent autoimmune disease in the population, present in approximately 7–8% of the general population [38, 39]. When thyroid disease is caused by environmental factors such as levels of iodine, incidence rates have been found to vary between locations and over time [4043]. Studies regarding the incidence rates of AITD have come from a limited range of geographical areas. Therefore, it is difficult to comment on the absence or presence of variances in incidence rates of AITD between different geographical locations. Coexistence of T1D and AITD is common, with 15 to 30% of T1D subjects having AITD [4446], whereas the prevalence of glutamic acid decarboxylase antibodies (GADAb) in AITD patients is around 5% [47, 48]. There is a need to distinguish T1D with AITD (T1D+AITD, APS-3A) from T1D without AITD (T1D-AITD). Conversely, we may not need to distinguish AITD with T1D from AITD without T1D (AITD-T1D). Abbreviations are listed in Table 1.

Abbreviations AITD T1D
GD HT
AITD-T1D GD-T1D + - -
HT-T1D - + -
T1D-AITD - - +
T1D+AITD (APS-3A) T1D+GD + - +
T1D+HT - + +

Table 1.

Relationship among T1D, AITD, and APS-3A

+, present; -, absent


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3. T1D

HLA class II genes are closely related to the onset of T1D in all ethnic groups. Recently, Thomson et al. investigated whether HLA DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups using data from 38 studies worldwide [49]. They introduced a new static, the patient/control (P/C) ratio of haplotype or genotype frequencies within a study that allows comparison of absolute penetrance values within and across studies. Mean P/C ratios are listed in Table 2. When the mean P/C ratio is >1.10, we consider that the haplotype confers susceptibility to T1D, whereas when the mean P/C ratio is <0.90, we consider that the haplotype confers protection against T1D. When the mean P/C ratio is 0.90–1.10, we consider the haplotype as neutral to T1D.

DRB1 DQB1 Mean P/C ratio Effect on T1D a
*01 *05:01 0.85 P
*03:01 *02 3.72 S
*04 *03:01 0.73 P
*04:01 *03:02 6.23 S
*04:02 *03:02 5.10 S
*04:03 *03:02 0.64 P
*04:05 *03:02 7.15 S
*04:05 *04:01 2.35 S
*04:06 *03:02 0.31 P
*07:01 *02 0.66 P
*08 *03:02 3.25 S
*08 *04:02 1.92 S
*08:03 *06:01 0.38 P
*09:01 *03:03 1.12 S
*12 *03:01 0.47 P
*13 *06:04 0.93 N
*14 *03:01 0.25 P
*15 *06:01 0.46 P
*15 *06:02 0.22 P
*16 *05:02 0.95 N

Table 2.

DRB1-DQB1 haplotype P/C ratios with regard to susceptibility to T1D

a Effect on T1D is classified as: S, susceptible; N, neutral; P, protective.


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4. AITD

The results of HLA association studies in AITD have been less consistent than in T1D. Moreover, data on HLA haplotypes in HT have been less definitive than on those in GD. A general methodological problem has been disease definition [50]; though the diagnosis of GD may be relatively straightforward, the definition of HT has been more controversial. Three varieties of thyroid autoantibodies are commonly used and widely available in clinical diagnostic laboratories: anti-thyroglobulin antibodies (TgAb), anti-thyroid peroxidase autoantibodies (TPOAb), and antibodies to thyrotropin receptor (TRAb). TgAb and TPOAb are found in almost 100% of patients with HT, whereas these antibodies are also detectable in 50% to 90% of patients with GD and are common in the general population. The low levels of TPOAb and TgAb found in many individuals are of uncertain significance in the presence of normal thyroid function [51].

Table 3 shows previous reports on the relationship between HLA class II and AITD. The most probable HLA-DR and -DQ haplotypes were deduced from linkage disequilibria [8–10]. Alleles in parentheses following the reference number indicate that the reference reported susceptibility or resistance of the allele, but not the haplotype, to the disease. There is no parenthesis following the reference number if the references reported susceptibility or resistance with 4-digit DRB1-DQB1, DQA1-DQB1, or DRB1-DQA1-DQB1 haplotypes. In cases with more than 2 haplotypes sharing the same allele, the allele is listed redundantly in each haplotype. However, considering the ethnicities that the references examined, the allele is removed from the corresponding haplotypes; for example, the DRB1*08:02-DQA1*03:01-DQB1*03:02 haplotype is rare in Caucasian populations [49] and thus in the reference examining Caucasian populations, the DQA1*03:01 allele is listed only in the DRB1*04:01-DQA1*03:01-DQB1*03:02 haplotype, and not in the DRB1*08:02-DQA1*03:01-DQB1*03:02 haplotype.

DRB1 DQA1 DQB1 Effect on GD a Effect on HT a Effect on AITD-T1D a
Ref. no. Ref. no.
*01:01 *01:01 *05:01 P 24 (DR1), 52 (DR1), 21 (DRB1), 26 (DQB1), 27 (DQB1)
*03:01 *05:01 *02:01 S 21 (DRB1), 29 (DRB1), 27 (DQA1) S 53 (DR3), 7 (DQB1) S 57 (DQB1)
*04:01 *03:01 *03:02 P 54 (DQB1) S 6 (DQA1), 7
*04:01 *03:03 *03:01 S 6 (DQB1), 55 (DRB1*04-DQB1)
*04:05 *03:01 *03:02 S 7 (DRB1), 6 (DQA1)
*04:05 *03:03 *04:01 S 56 N 58 (DRB1)
*07:01 *02:01 *02:02 P 21 (DRB1), 29 (DRB1) P 7 (DRB1*07), 6 (DRB1*07-DQA1-DQB1*02)
*08:02 *03:01 *03:02 S 29 (DRB1)
*08:02 *04:01 *04:02 S 29 (DRB1) S 6 (DRB1*08-DQA1-DQB1*04)
*08:03 *01:03 *06:01 S 20-22 S 23 b
*09:01 *03:02 *03:03 S 22, 23 b N 58 (DRB1)
*12:02 *06:01 *03:01 P 21 (DRB1), 54 (DRB1)
*13:02 *01:02 *06:04 P 21 (DRB1), 29 (DRB1) P 7 (DQB1), (DRB1*13-DQA1-DQB1*06), 23 b
*14:03 *05:01 *03:01 S 29 (DRB1), 20
*15:01 *01:02 *06:02 S/P 54 (DRB1) / 27 (DQB1) P 24 (DR2), 25 (DR2), 6 (DRB1*15-DQA1-DQB1*06), 23 b, 26
*15:02 *01:03 *06:01 P 24 (DR2), 25 (DR2), 6 (DRB1*15-DQA1-DQB1*06)
*16:02 *01:02 *05:02 S 54 (DRB1), 21

Table 3.

Effects of HLA DR-DQ genes on GD, HT, or AITD

a Effect on GD, HT, or AITD-T1D is classified as: S, susceptible; N, neutral; P, protective.


b HT-T1D


With the exception of the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype, there are no controversial results concerning susceptibility and resistance to AITD. Additionally, except for the DRB1*04:01-DQA1*03:01-DQB1*03:02 haplotype, no haplotype has been found to have an adverse effect on GD and HT. Chen et al. demonstrated, for the first time, that the DRB1*15:01 allele confers susceptibility to GD and that the DQB1*03:02 allele confers protection against GD in the Taiwan Chinese population [54]. Further investigations in other ethnic groups may be necessary to confirm whether their conclusions are widely applicable.

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5. T1D-AITD and T1D+AITD

Few previous reports have been published on the relationship between HLA class II and T1D-AITD. In contrast, there are a number of reports concerning the relationship between HLA class II and T1D+AITD, which includes T1D+GD and T1D+HT. The results are shown in Table 4. As in Table 3, alleles in parentheses following the reference number indicate that the reference reported susceptibility or resistance of the allele, but not the haplotype, to the disease. There is no parenthesis following the reference number if the references reported the susceptibility or resistance of 4-digit DRB1-DQB1, DQA1-DQB1, or DRB1-DQA1-DQB1 haplotypes to the disease. In cases with more than 2 haplotypes sharing the same allele, the allele is listed redundantly in each haplotype. However, with consideration of the ethnicities that the references examined, the allele may be removed from the corresponding haplotypes.

DRB1 DQA1 DQB1 Effect on T1D-AITD a Effect on T1D+AITD a
Ref no. Ref no.
*01:01 *01:01 *05:01 S 59 P 18 (DR1), 63b (DQB1*05)
*03:01 *05:01 *02:01 S 57 (DQB1), 60 S 18 (DR3), 57 (DQB1), 60
*04:01 *03:01 *03:02 S 57 (DQB1) S 18 (DR4), 63b (DQB1), 57 (DQB1)
*04:05 *03:01 *03:02 S 60 N 60
*04:05 *03:03 *04:01 S/N 61 (DR4) / 60 S 58 (DRB1), 22, 59, 60
*07:01 *02:01 *02:02 N 18 (DR7)
*08:02 *03:01 *03:02 S 61 (DQA1) S 61c (DQA1), 22c, 59
*08:02 *04:01 *04:02 S 22
*08:03 *01:03 *06:01 P 61 (DQA1) P 61 (DQA1)
*09:01 *03:02 *03:03 S 59 S 62 (DR9), 58 (DRB1), 22, 59
*13:02 *01:02 *06:04 S 59 P 18 (DR6), 60 (DR13)
*15:01 *01:02 *06:02 P 62 (DR2), 57 (DQB1), 59 P 18 (DR2), 62 (DR2), 57 (DQB1), 59
*15:02 *01:03 *06:01 P 62 (DR2), 61 (DQA1) P 62 (DR2), 61c (DQA1)

Table 4.

Effects of HLA DR-DQ genes on T1D-AITD and T1D+AITD

a Effect on T1D-AITD or T1D+AITD is classified as: S, susceptible; N, neutral; P, protective.


b T1D+HT; c T1D+GD


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6. Relationship between GD and amino acid

Badenhoop et al. demonstrated that Arg at position 52 of the DQα1 chain plays an important role in susceptibility to GD [27]. It was recently shown that Arg at position 74 of the DRβ1 chain is important for the development of GD in a significant number of patients [16, 17]. Further analysis has shown that the presence of Gln at position 74 of the DRβ1 chain was protective for GD [16]. Table 5 shows the susceptibility and resistance of HLA DR-DQ genes to GD, and amino acids at position 74 of the DRβ1 chain and position 52 of the DQα1 chain. When more than 2 references reported susceptibility, we considered that the haplotype confers susceptibility to GD (abbreviated as “S”). When more than 2 references reported protection against the disease, we considered that the haplotype confers protection against GD (abbreviated as “P”). When only one reference reported susceptibility, we considered that the haplotype either confers susceptibility or is neutral to GD (abbreviated as “S/N”). When only one reference reported a protective effect, we considered that the haplotype either confers protection against or is neutral to GD (abbreviated as “P/N”). Badenhoop et al. showed that susceptibility to GD is conferred by the DQA1*05:01 allele as well as Arg at position 52 of the DQα1 chain [27]. DRβ-Arg-74 and DRβ-Gln-74 are always present on DR3 and DR7, respectively [16]. These amino acids are indicated in bold. The amino acids at position 52 of the DQα1 chain that are encoded by the haplotypes listed in Table 5 are Arg, Gln, and Ser. The effect on GD of the haplotypes which encode Arg or Ser at position 52 of the DQα1 chain varies from susceptible to protective. Amino acids at position 74 of the DRβ1 chain that are encoded by the haplotypes listed in Table 5 are Ala, Arg, Gln, and Leu. The effect on GD of these haplotypes also varies from susceptible to protective. However, haplotypes that encode Leu at position 74 of the DRβ1 chain, indicated by italics, are virtually all susceptible to GD. Interestingly, DR3 encodes Arg at both position 52 of the DQα1 chain and position 74 of the DRβ1 chain. Moreover, 3 of 4 haplotypes that encode Leu at position 74 of the DRβ1 chain encode Arg at position 52 of the DQα1 chain. These findings may indicate that amino acids at position 74 of the DRβ1 chain, rather than those at position 52 of the DQα1 chain, play an important role in susceptibility or protection for GD.

DRB1 DQA1 DQB1 Effect on GD a Amino acid at position 52 of DQα1 chain Amino acid at position 74 of DRβ1 chain
*01:01 *01:01 *05:01 P Ser Ala
*03:01 *05:01 *02:01 S Arg Arg
*04:01 *03:01 *03:02 P/N Arg Ala
*04:05 *03:03 *04:01 S/N Arg Ala
*07:01 *02:01 *02:02 P Gln Gln
*08:02 *03:01 *03:02 S/N Arg Leu
*08:02 *04:01 *04:02 S/N Arg Leu
*08:03 *01:03 *06:01 S Ser Leu
*12:02 *06:01 *03:01 P Arg Ala
*13:02 *01:02 *06:04 P Ser Ala
*14:03 *05:01 *03:01 S Arg Leu
*15:01 *01:02 *06:02 S/N, P/N Ser Ala
*16:02 *01:02 *05:02 S Ser Ala

Table 5.

Relationship between effect on GD and amino acids

a Effect on GD is classified as: S, susceptible; P, protective; S/N, susceptible or neutral; P/N, protective or neutral.


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7. Relationship between T1D±AITD and amino acid

It is well known that DQα-Arg-52 confer susceptibility to T1D [15]. Todd et al. demonstrated that DQβ-Asp-57 is neutral or negatively associated with T1D, and that Ala, Val, or Ser at position 57 of the DQβ1 chain is positively associated with T1D [13]. Table 6 lists the amino acids at position 52 of the DQα1 chain and position 57 of the DQβ1 chain in each haplotype. Although the effect on T1D of haplotypes with both DQα-Arg-52 and DQβ-Asp-57 is usually protective or neutral, DRB1*04:05-DQA1*03:03-DQB1*04:01 and DRB1*09:01-DQA1*03:02-DQB1*03:03 haplotypes confer susceptibility to T1D. In addition, the effect of some haplotypes with Ala, Val, or Ser at position 57 of the DQβ1 chain on T1D is protective or neutral (DRB1*01:01-DQA1*01:01-DQB1*05:01, DRB1*07:01-DQA1*02:01-DQB1*02:02, DRB1*13:02-DQA1*01:02-DQB1*06:04, and DRB1*16:02-DQA1*01:02-DQB1*05:02). In Table 6, areas of the effect on T1D are shaded in the haplotypes that conflict with the theory that DQα-Arg-52 or “non-Asp” at position 57 of the DQβ1 chain confers susceptibility to T1D, and that DQβ-Asp-57 confers protection against T1D.

DRB1 DQA1 DQB1 Effect of HLA DR-DQ gene DQα1 DQβ1 DRβ1
AITD a T1D-AITD a T1D b T1D+AITD a 52 57 26 67 71 74
*01:01 *01:01 *05:01 P S/N P P Ser Val Leu Leu Arg Ala
*03:01 *05:01 *02:01 S S S S Arg Ala Tyr Leu Lys Arg
*04:01 *03:01 *03:02 S S/N S S Arg Ala Phe Leu Lys Ala
*04:01 *03:03 *03:01 S P Arg Asp Phe Leu Lys Ala
*04:05 *03:01 *03:02 S S/N S N Arg Ala Phe Leu Arg Ala
*04:05 *03:03 *04:01 S/N S/N S S Arg Asp Phe Leu Arg Ala
*07:01 *02:01 *02:02 P P N Gln Ala Phe Ile Arg Gln
*08:02 *03:01 *03:02 S/N S/N S S Arg Ala Phe Phe Arg Leu
*08:02 *04:01 *04:02 S N S/N Arg Asp Phe Phe Arg Leu
*08:03 *01:03 *06:01 S P/N P P/N Ser Asp Phe Ile Arg Leu
*09:01 *03:02 *03:03 S S/N S S Arg Asp Tyr Phe Arg Glu
*12:02 *06:01 *03:01 P P Arg Asp Leu Phe Arg Ala
*13:02 *01:02 *06:04 P S/N N P Ser Val Phe Ile Glu Ala
*14:03 *05:01 *03:01 S P Arg Asp Phe Leu Arg Leu
*15:01 *01:02 *06:02 P P P P Ser Asp Phe Ile Ala Ala
*15:02 *01:03 *06:01 P P P P Ser Asp Phe Ile Ala Ala
*16:02 *01:02 *05:02 S N Ser Ser Phe Leu Arg Ala

Table 6.

Effects of HLA DR-DQ genes on AITD, T1D-AITD, T1D, or T1D+AITD

a Effect on AITD, T1D-AITD, or T1D+AITD is classified as: S, susceptible; P, protective; S/N, susceptible or neutral; P/N, protective or neutral.


b Effect on T1D is classified as: S, susceptible; N, neutral; P, protective.


Table 6 also shows the effects of HLA DR-DQ genes on AITD, T1D-AITD, and T1D+AITD. When more than 2 references reported susceptibility to the disease, we considered that the haplotype confers susceptibility (abbreviated as “S”), regardless of a single report demonstrating that the haplotype confers protection against the disease. When more than 2 references reported protection against the disease, we considered that the haplotype confers protection (abbreviated as “P”), regardless of one report demonstrating to the disease. When only one reference reported susceptibility, we considered that the haplotype confers susceptibility or is neutral (abbreviated as “S/N”). When only one reference reported protection against the disease, we considered that the haplotype confers protection or is neutral (abbreviated as “P/N”). Recently, Menconi et al. demonstrated that amino acids at position 74 of the DRβ1 chain play an important role in susceptibility and resistance to APS-3A, i.e., T1D+AITD as well as GD [18]. DRβ-Tyr-26, DRβ-Leu-67, DRβ-Lys-71, and DRβ-Arg-74 are positively associated with APS-3A, while DRβ-Ala-71 and DRβ-Gln-74 are negatively associated with APS-3A. These amino acids are indicated in bold in Table 6.

In this section, we discuss the relationship between the above-mentioned HLA DR-DQ genes, amino acids at positions 26, 67, 71, and 74 of the DRβ1 chain, and T1D with or without AITD.

DRB1*01:01-DQA1*01:01-DQB1*05:01 and DRB1*13:02-DQA1*01:02-DQB1*06:04 haplotypes

While these haplotypes encode Val at position 57 of the DQβ1 chain, they confer protection or are neutral to T1D. Although they confer protection against AITD and T1D+AITD, they tend to confer susceptibility to T1D-AITD (S/N in Table 6). Since 15 to 30% of subjects with T1D have AITD [44–46], the effect of AITD on T1D may result in resistance of subjects with these haplotypes to T1D.

DRB1*04:05-DQA1*03:03-DQB1*04:01 and DRB1*09:01-DQA1*03:02-DQB1*03:03 haplotypes

These haplotypes are the major haplotypes which confer susceptibility to T1D in East Asians, especially in the Japanese population where the DR3 haplotype is absent and the DR4 haplotype is rare [8–10]. While these haplotypes encode Asp at position 57 of the DQβ1 chain, they confer susceptibility to T1D+AITD. DRβ-Leu-67 in the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype and DRβ-Tyr-26 in the DRB1*09:01-DQA1*03:02-DQB1*03:03 haplotype might play an important role in susceptibility to T1D+AITD. Since 15 to 30% of subjects with T1D have AITD [44–46], the effect of these amino acids on T1D may be susceptibility, and that on T1D-AITD might be susceptibility or neutrality, which is weaker than that on T1D or T1D+AITD.

DRB1*07:01-DQA1*02:01-DQB1*02:02 and DRB1*16:02-DQA1*01:02-DQB1*05:02 haplotypes

There are few reports concerning the effect of HLA DR-DQ genes on T1D-AITD in the Caucasian [57], Japanese [59, 61, 62], and Taiwan Chinese [60] populations (Table 4). The DRB1*07:01-DQA1*02:01-DQB1*02:02 and DRB1*16:02-DQA1*01:02-DQB1*05:02 haplotypes are rare in the Japanese population [8–10, 49]. Therefore, it is difficult to explain the protective or neutral effect of these haplotypes with “non-Asp” at position 57 of the DQβ1 chain on T1D by examining the effect of these haplotypes on T1D-AITD. However, Menconi et al. demonstrated that DRβ-Gln-74 is negatively associated with T1D+AITD, although they failed to demonstrate that the DR7 allele, which encodes Gln at position 74 of the DRβ1 chain, confers protection against T1D+AITD [18] (Table 6). The DR3 and DR4 haplotypes encode Ala at position 57 of the DQβ1 chain, which confers strong susceptibility to T1D [2]. Since the DR7 haplotype also encodes Ala at position 57 of the DQβ1 chain, the effect of this haplotype might potentially result in susceptibility to T1D-AITD. Since 15 to 30% of subjects with T1D have AITD [44–46], DRβ-Gln-74 might play a role in protection against T1D.

There are several reports concerning the effect of HLA DR-DQ genes on T1D+AITD, which also studied Caucasian [18, 57, 63], Japanese [22, 58, 59, 61, 62], and Taiwan Chinese [60] populations (Table 4). The DRB1*16:02-DQA1*01:02-DQB1*05:02 haplotype is rare in the Caucasian population as well as in the Japanese population [49], and Menconi et al. did not examine patients and controls with the DR16 allele [18]. Moreover, the positive effect of DQβ-Ser-57 on T1D is weaker than that of DQβ-Ala-57 or DQβ-Val-57 [2]. To our knowledge, the evidence of the effect of the DRB1*16:02-DQA1*01:02-DQB1*05:02 haplotype on T1D is insufficient.

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8. Conclusion

T1D and AITD share common genetic risk factors. The prevalence of given HLA haplotypes varies among populations, but given the same DR and DQ haplotypes, the influence of HLA on T1D and/or AITD is similar on populations throughout the world. By clarifying the region of the diseases on which certain reports were focused, we can explain to some extent and speculate on the relationship between HLA haplotypes, specific amino acids, and T1D and/or AITD.

References

  1. 1. Betterle C, Zanchetta R. Update on autoimmune polyendocrine syndromes (APS). Acta Biomed 2003;74(1) 9-33.
  2. 2. She JX. Susceptibility to type I diabetes: HLA-DQ and DR revisited. Immunol Today 1996;17(7) 323-329.
  3. 3. Baisch JM, Weeks T, Giles R, Hoover M, Stastny P, Capra JD. Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus. N Engl J Med 1990;322(26) 1836-1841.
  4. 4. Mangklabruks A, Cox N, DeGroot LJ. Genetic factors in autoimmune thyroid disease analyzed by restriction fragment length polymorphisms of candidate genes. J Clin Endocrinol Metab 1991;73(2) 236-244.
  5. 5. Heward JM, Allahabadia A, Daykin J, Carr-Smith J, Daly A, Armitage M, Dodson PM, Sheppard MC, Barnett AH, Franklyn JA, Gough SC. Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves' disease: replication using a population case control and family-based study. J Clin Endocrinol Metab 1998;83(10) 3394-3397.
  6. 6. Zeitlin AA, Heward JM, Newby PR, Carr-Smith JD, Franklyn JA, Gough SC, Simmonds MJ. Analysis of HLA class II genes in Hashimoto's thyroiditis reveals differences compared to Graves' disease. Genes Immun 2008;9(4) 358-363.
  7. 7. Kokaraki G, Daniilidis M, Yiangou M, Arsenakis M, Karyotis N, Tsilipakou M, Fleva A, Gerofotis A, Karadani N, Yovos JG. Major histocompatibility complex class II (DRB1*, DQA1*, and DQB1*) and DRB1*04 subtypes' associations of Hashimoto's thyroiditis in a Greek population. Tissue Antigens 2009;73(3) 199-205.
  8. 8. Nakajima F, Nakamura J, Yokota T. Analysis of HLA haplotypes in Japanese, using high resolution allele typing. MHC 2001;8(1) 1-32 [in Japanese].
  9. 9. Katahira M, Segawa S, Maeda H, Yasuda Y. Effect of human leukocyte antigen class II genes on acute-onset and slow-onset type 1 diabetes in the Japanese population. Hum Immunol 2010;71(8) 789-794.
  10. 10. Yasunaga S, Kimura A, Hamaguchi K, Rønningen KS, Sasazuki T. Different contribution of HLA-DR and -DQ genes in susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). Tissue Antigens. 1996;47(1) 37-48.
  11. 11. Sanjeevi CB, Lybrand TP, DeWeese C, Landin-Olsson M, Kockum I, Dahlquist G, Sundkvist G, Stenger D, Lernmark Å. Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM. Members of the Swedish Childhood Diabetes Study. Diabetes 1995;44(1) 125-131.
  12. 12. Rønningen KS, Spurkland A, Iwe T, Vartdal F, Thorsby E. Distribution of HLA-DRB1, -DQA1 and -DQB1 alleles and DQA1-DQB1 genotypes among Norwegian patients with insulin-dependent diabetes mellitus. Tissue Antigens 1991;37(3) 105-111.
  13. 13. Todd JA, Bell JI, McDevitt HO. HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 1987;329(6140) 599-604.
  14. 14. Nepom BS, Palmer J, Kim SJ, Hansen JA, Holbeck SL, Nepom GT. Specific genomic markers for the HLA-DQ subregion discriminate between DR4+ insulin-dependent diabetes mellitus and DR4+ seropositive juvenile rheumatoid arthritis. J Exp Med 1986;164(1) 345-350.
  15. 15. Khalil I, Deschamps I, Lepage V, al-Daccak R, Degos L, Hors J. Dose effect of cis- and trans-encoded HLA-DQαβ heterodimers in IDDM susceptibility. Diabetes. 1992;41(3) 378-84.
  16. 16. Ban Y, Davies TF, Greenberg DA, Concepcion ES, Osman R, Oashi T, Tomer Y. Arginine at position 74 of the HLA-DRβ1 chain is associated with Graves' disease. Genes Immun 2004;5(3) 203-208.
  17. 17. Simmonds MJ, Howson JM, Heward JM, Cordell HJ, Foxall H, Carr-Smith J, Gibson SM, Walker N, Tomer Y, Franklyn JA, Todd JA, Gough SC. Regression mapping of association between the human leukocyte antigen region and Graves disease. Am J Hum Genet 2005;76(1) 157-163.
  18. 18. Menconi F, Osman R, Monti MC, Greenberg DA, Concepcion ES, Tomer Y. Shared molecular amino acid signature in the HLA-DR peptide binding pocket predisposes to both autoimmune diabetes and thyroiditis. Proc Natl Acad Sci USA 2010;107(39) 16899-16903.
  19. 19. Katahira M, Ishiguro T, Segawa S, Kuzuya-Nagao K, Hara I, Nishisaki T. Reevaluation of human leukocyte antigen DR-DQ haplotype and genotype in type 1 diabetes in the Japanese population. Horm Res 2008;69(5) 284-289.
  20. 20. Katsuren E, Awata T, Matsumoto C, Yamamoto K. HLA class II alleles in Japanese patients with Graves' disease: weak associations of HLA-DR and -DQ. Endocr J 1994;41(6) 599-603.
  21. 21. Park MH, Park YJ, Song EY, Park H, Kim TY, Park DJ, Park KS, Cho BY. Association of HLA-DR and -DQ genes with Graves disease in Koreans. Hum Immunol 2005;66(6) 741-747.
  22. 22. Hashimoto K, Maruyama H, Nishiyama M, Asaba K, Ikeda Y, Takao T, Iwasaki Y, Kumon Y, Suehiro T, Tanimoto N, Mizobuchi M, Nakamura T. Susceptibility alleles and haplotypes of human leukocyte antigen DRB1, DQA1, and DQB1 in autoimmune polyglandular syndrome type III in Japanese population. Horm Res 2005;64(5) 253-260.
  23. 23. Katahira M, Hanakita M, Ito T, Suzuki M. Effect of human leukocyte antigen class II genes on Hashimoto's thyroiditis requiring replacement therapy with levothyroxine in the Japanese population. Hum Immunol 2013;74(5) 607-609.
  24. 24. Azuma Y, Sakurami T, Ueno Y, Ohishi M, Saji H, Terasaki PI, Park MS. HLA-DR antigens in Japanese with Hashimoto's thyroiditis and Graves' disease. Endocrinol Jpn 1982;29(4) 423-427.
  25. 25. Sakurami T, Ueno Y, Iwaki Y, Park MS, Terasaki PI, Saji H. HLA-DR specificities among Japanese with several autoimmune diseases. Tissue Antigens 1982;19(2) 129-133.
  26. 26. Tamai H, Kimura A, Dong RP, Matsubayashi S, Kuma K, Nagataki S, Sasazuki T. Resistance to autoimmune thyroid disease is associated with HLA-DQ. J Clin Endocrinol Metab 1994;78(1) 94-97.
  27. 27. Badenhoop K, Walfish PG, Rau H, Fischer S, Nicolay A, Bogner U, Schleusener H, Usadel KH. Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease. J Clin Endocrinol Metab 1995;80(7) 2112-2117.
  28. 28. Zeitlin AA, Heward JM, Newby PR, Carr-Smith JD, Franklyn JA, Gough SC, Simmonds MJ. Analysis of HLA class II genes in Hashimoto's thyroiditis reveals differences compared to Graves' disease. Genes Immun 2008;9(4) 358-363.
  29. 29. Jang HW, Shin HW, Cho HJ, Kim HK, Lee JI, Kim SW, Kim JW, Chung JH. Identification of HLA-DRB1 alleles associated with Graves' disease in Koreans by sequence-based typing. Immunol Invest 2011;40(2) 172-182.
  30. 30. Neufeld M, Blizzard RM. Polyglandular autoimmune diseases. In: Pinchera A, Doniach D, Fenzi GF, Baschieri L. (ed) Symposium on Autoimmune Aspects of Endocrine Disorders. New York: Academic Press; 1980. p357-365.
  31. 31. Chen QY, Kukreja A, Maclaren NK. The autoimmune polyglandular syndromes. In: De Groot LJ, Jameson JL. (ed) Endocrinology 4th Edition. Philadelphia: Saunders; 2001. p587-599.
  32. 32. Betterle C, Volpato M, Greggio AN, Presotto F. Type 2 polyglandular autoimmune disease (Schmidt's syndrome). J Pediatr Endocrinol Metab 1996;9(Suppl 1) 113-123.
  33. 33. Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore) 1981;60(5) 355-362.
  34. 34. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 2002;23(3) 327-64.
  35. 35. Papadopoulos KI, Hallengren B. Polyglandular autoimmune syndrome type II in patients with idiopathic Addison's disease. Acta Endocrinol (Copenh) 1990;122(4) 472-478.
  36. 36. Tuomilehto J, Virtala E, Karvonen M, Lounamaa R, Pitkäniemi J, Reunanen A, Tuomilehto-Wolf E, Toivanen L. Increase in incidence of insulin-dependent diabetes mellitus among children in Finland. Int J Epidemiol 1995;24(5) 984-992.
  37. 37. Matsuura N, Fukuda K, Okuno A, Harada S, Fukushima N, Koike A, Ito Y, Hotsubo T. Descriptive epidemiology of IDDM in Hokkaido, Japan: the Childhood IDDM Hokkaido Registry. Diabetes Care 1998;21(10) 1632-1636.
  38. 38. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996;335(2) 99-107.
  39. 39. Weetman AP. Graves' disease. N Engl J Med. 2000;343(17) 1236-1248.
  40. 40. Perros P, McCrimmon RJ, Shaw G, Frier BM. Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med 1995;12(7) 622-627.
  41. 41. Bürgi H, Kohler M, Morselli B. Thyrotoxicosis incidence in Switzerland and benefit of improved iodine supply. Lancet 1998;352(9133) 1034.
  42. 42. Lewiński A, Szybiński Z, Bandurska-Stankiewicz E, Grzywa M, Karwowska A, Kinalska I, Kowalska A, Makarewicz J, Nauman J, Słowińska-Klencka D, Sowiński J, Syrenicz A, Zonenberg A, Huszno B, Klencki M. Iodine-induced hyperthyroidism--an epidemiological survey several years after institution of iodine prophylaxis in Poland. J Endocrinol Invest 2003;26(2 Suppl) 57-62.
  43. 43. Laurberg P, Pedersen KM, Vestergaard H, Sigurdsson G. High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs. high incidence of Graves' disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland. J Intern Med 1991;229(5) 415-420.
  44. 44. Stanbury JB, Ermans AE, Bourdoux P, Todd C, Oken E, Tonglet R, Vidor G, Braverman LE, Medeiros-Neto G. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 1998;8(1) 83-100.
  45. 45. Umpierrez GE, Latif KA, Murphy MB, Lambeth HC, Stentz F, Bush A, Kitabchi AE. Thyroid dysfunction in patients with type 1 diabetes: a longitudinal study. Diabetes Care 2003;26(4) 1181-1185.
  46. 46. Barker JM, Yu J, Yu L, Wang J, Miao D, Bao F, Hoffenberg E, Nelson JC, Gottlieb PA, Rewers M, Eisenbarth GS. Autoantibody "subspecificity" in type 1 diabetes: risk for organ-specific autoimmunity clusters in distinct groups. Diabetes Care 2005;28(4) 850-855.
  47. 47. Aksoy DY, Yürekli BP, Yildiz BO, Gedik O. Prevalence of glutamic acid decarboxylase antibody positivity and its association with insulin secretion and sensitivity in autoimmune thyroid disease: A pilot study. Exp Clin Endocrinol Diabetes 2006;114(8) 412-416.
  48. 48. Moriguchi M, Noso S, Kawabata Y, Yamauchi T, Harada T, Komaki K, Babaya N, Hiromine Y, Ito H, Yamagata S, Murata K, Higashimoto T, Park C, Yamamoto A, Ohno Y, Ikegami H. Clinical and genetic characteristics of patients with autoimmune thyroid disease with anti-islet autoimmunity. Metabolism 2011;60(6) 761-766.
  49. 49. Thomson G, Valdes AM, Noble JA, Kockum I, Grote MN, Najman J, Erlich HA, Cucca F, Pugliese A, Steenkiste A, Dorman JS, Caillat-Zucman S, Hermann R, Ilonen J, Lambert AP, Bingley PJ, Gillespie KM, Lernmark A, Sanjeevi CB, Rønningen KS, Undlien DE, Thorsby E, Petrone A, Buzzetti R, Koeleman BP, Roep BO, Saruhan-Direskeneli G, Uyar FA, Günoz H, Gorodezky C, Alaez C, Boehm BO, Mlynarski W, Ikegami H, Berrino M, Fasano ME, Dametto E, Israel S, Brautbar C, Santiago-Cortes A, Frazer de Llado T, She JX, Bugawan TL, Rotter JI, Raffel L, Zeidler A, Leyva-Cobian F, Hawkins BR, Chan SH, Castano L, Pociot F, Nerup J. Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis. Tissue Antigens 2007;70(2) 110-127.
  50. 50. Jacobson EM, Huber A, Tomer Y. The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology. J Autoimmun 2008;30(1-2) 58-62.
  51. 51. Salvatore D, Davies TF, Schlumberger MJ, Hay ID, Larsen PR. Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM. (ed.) Williams textbook of endocrinology. 12th ed. Philadelphia: Elsevier Saunders; 2011. p327-361.
  52. 52. Dong RP, Kimura A, Okubo R, Shinagawa H, Tamai H, Nishimura Y, Sasazuki T. HLA-A and DPB1 loci confer susceptibility to Graves' disease. Hum Immunol 1992;35(3) 165-172.
  53. 53. Tandon N, Zhang L, Weetman AP. HLA associations with Hashimoto's thyroiditis. Clin Endocrinol (Oxf) 1991;34(5) 383-386.
  54. 54. Chen PL, Fann CS, Chu CC, Chang CC, Chang SW, Hsieh HY, Lin M, Yang WS, Chang TC. Comprehensive genotyping in two homogeneous Graves' disease samples reveals major and novel HLA association alleles. PLoS One 2011;6(1) e16635.
  55. 55. Petrone A, Giorgi G, Mesturino CA, Capizzi M, Cascino I, Nistico L, Osborn J, Di Mario U, Buzzetti R. Association of DRB1*04-DQB1*0301 haplotype and lack of association of two polymorphic sites at CTLA-4 gene with Hashimoto's thyroiditis in an Italian population. Thyroid 2001;11(2) 171-175.
  56. 56. Iwama S, Ikezaki A, Kikuoka N, Kim HS, Matsuoka H, Yanagawa T, Sato H, Hoshi M, Sakamaki T, Sugihara S. Association of HLA-DR, -DQ genotype and CTLA-4 gene polymorphism with Graves' disease in Japanese children. Horm Res 2005;63(2) 55-60.
  57. 57. Santamaria P, Barbosa JJ, Lindstrom AL, Lemke TA, Goetz FC, Rich SS. HLA-DQB1-associated susceptibility that distinguishes Hashimoto's thyroiditis from Graves' disease in type I diabetic patients. J Clin Endocrinol Metab 1994;78(4) 878-883.
  58. 58. Ikegami H, Awata T, Kawasaki E, Kobayashi T, Maruyama T, Nakanishi K, Shimada A, Amemiya S, Kawabata Y, Kurihara S, Tanaka S, Kanazawa Y, Mochizuki M, Ogihara T. The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease: a multicenter collaborative study in Japan. J Clin Endocrinol Metab 2006;91(3) 1087-1092.
  59. 59. Katahira M, Maeda H, Tosaki T, Segawa S. The human leukocyte antigen class II gene has different contributions to autoimmune type 1 diabetes with or without autoimmune thyroid disease in the Japanese population. Diabetes Res Clin Pract 2009;85(3) 293-297.
  60. 60. Chuang LM, Wu HP, Chang CC, Tsai WY, Chang HM, Tai TY, Lin BJ. HLA DRB1/DQA1/DQB1 haplotype determines thyroid autoimmunity in patients with insulin-dependent diabetes mellitus. Clin Endocrinol (Oxf) 1996;45(5) 631-636.
  61. 61. Chikuba N, Akazawa S, Yamaguchi Y, Kawasaki E, Takino H, Yoshimoto M, Ohe N, Yamashita K, Yano A, Nagataki S. Immunogenetic heterogeneity in type 1 (insulin-dependent) diabetes among Japanese--class II antigen and autoimmune thyroid disease. Diabetes Res Clin Pract 1995;27(1) 31-37.
  62. 62. Chikuba N, Akazawa S, Yamaguchi Y, Kawasaki E, Takino H, Takao Y, Maeda Y, Okuno S, Yamamoto H, Yokota A, Yoshimoto M, Nagataki S. Type 1 (insulin-dependent) diabetes mellitus with coexisting autoimmune thyroid disease in Japan. Intern Med 1992;31(9) 1076-1080.
  63. 63. Sumník Z, Drevínek P, Snajderová M, Kolousková S, Sedláková P, Pechová M, Vavrinec J, Cinek O. HLA-DQ polymorphisms modify the risk of thyroid autoimmunity in children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2003;16(6) 851-858.

Written By

Masahito Katahira

Submitted: 10 October 2013 Published: 19 March 2014