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HLA and Type 1 diabetes in Arab populations

Mohamed Mirza Jahromi

Population Genetics, Translational Research Group, Clinical Research Department, Research Division, Dasman Diabetes Institute, Kuwait

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

DOI: 10.15761/IOD.1000173

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Abstract

Type 1 diabetes is an immune-mediated disease with the destruction of the pancreatic β-cells, a process that is conditioned by multiple genes and other factors. Significant variations in human leukocyte antigen (HLA) genetic susceptibility to type 1 diabetes between Caucasians, Africans, Asians and other ethnic groups may have led to the variation in the incidence of type 1 diabetes globally. Type 1 diabetes is characterized by HLA identification. In this chapter, we will discuss global variations in genetic susceptibility of HLA with regard to type 1 diabetes with particular attention on the Arab population.

Haplotype configuration of HLA class I A, B, C and Class II –DR/DQ/DP was studied in Caucasians, Africans, Asians and in the Arab population to see if that is responsible for the exponential rise in the rate of type 1 diabetes.

Despite the highest global incidence and prevalence rates of type 1 diabetes in Arab population, there is a dearth amount of information regarding HLA genetic susceptibility to type 1 diabetes in the Arab world. Misjudgment of HLA risk according to HLA alleles rather than haplotypes is apparent. 

Key words

Autoimmune diabetes, HLA, Type 1 diabetes, ethnicity

Introduction

Type 1 diabetes is one of the most common endocrine and metabolic conditions in childhood. The number of children developing this form of diabetes is increasing exponentially. Usually, the incidence of type 1 diabetes is considered to account for 10-15 % of total diabetes [1]. Yearly, 86,000 new cases of type 1 diabetes are added to the number of children ≥ 14 years old. In 2015, it was estimated that the total of 542,000 children below 15 years old, which is equivalent to 2.82 per 1000,000 children at the same age had type 1 diabetes [2,3]. The overall incidence of type 1 diabetes varied from 0.1/100,000 per year in China, Papua New Guinea, and Venezuela to 57.6/100,000 per year in Finland with an approximately 600-fold gradient of among countries, Figure 1. The incidence varies within several other countries, including Italy, where Sardinia is notably discordant with the incidence in Italy as a whole (51.0 vs 12.1/100,000 population) [4]. China is another country where there is a 12-fold variation by region (0.13–1.61/100,000) [5]. In general, countries in Europe and North America have either a high or intermediate incidence. The incidence in North Africa is generally intermediate, similar to Southern Europe, and that in Asia is reported to be low in Japan, China and Korea, and also low in populations in South America with a high native Indian ancestry [3]. Interestingly, Saudi Arabia and Kuwait which are from high-income Arab countries are among top ten countries with the highest type 1 diabetes incidence rates globally [2]. Remarkably, the rate of the incidence of type 1 diabetes among Arab countries in the Gulf region, who have the same socioeconomic condition, culture and lifestyle, varies 12.5 folds (31.4 Saudi Arabia vs 2.5 Oman/100,000 population), Figure 2 [3].

Figure 1. Global reported rates of type 1 diabetes incidents/100,000 population in different countries.

The reported rates of incidence of type 1 diabetes in different countries in 2015. The rate of incidence varied from 0.1/100,000 per year in China, Papua New Guinea and Venezuela to 57.6/100,000 per year in Finland with an approximately 600-fold gradient of among countries. The incidence varies within several other countries in different folds. For example, Sardinia in Italy is notably discordant with the incidence in Italy as a whole (51.0 vs 12.1/100,000 population). China is another country where there is such a variation by region (0.13–1.61/100,000). Saudi Arabia and Kuwait which are from high income Arab countries are between top ten countries with high type 1 diabetes incidence rates.

Figure 2. Rates of type 1 diabetes in reported Arab countries.

The reported rates of type 1 diabetes in Arab countries in 2015. There is a 12.5 folds variation between the rates in high income oil producing Arab countries in the Gulf region (31.4 Saudi Arabia vs 2.5 Oman/ 100,000 population). 

Figure 3. Natural history of type 1 diabetes.

Natural history of type 1 diabetes predicts that the pathogenesis of type 1 diabetes starts in genetically susceptible individuals as soon as appropriate environmental factors trigger the autoimmunity of islet β-cells. Several biochemical processes transpire during this critical phase of the disease which is mostly undiagnosed, “Gray Zone’. The clinical diagnosis typically come about once the majority of β-cells have disappeared. Beta cell mass will be reduced throughout the process and by the time of diagnosis it reaches a minimum possible rate.

The Arab world comprises of 22 Arab-speaking countries, extending from the Atlantic Ocean to the Gulf. The 22 countries consist of a diverse population, with different ethnic, cultural, and religious backgrounds [6]. According to the World Health Organization (WHO) (www.who.int), the Arab countries are classified as, high-income countries, middle-income countries, and low-income countries. Each passing year, 10,200 newly diagnosed cases of type 1 diabetes with ≥ 14 years old children from Arab countries is estimated to be added to the total [3].

Type 1 diabetes, as other autoimmune diseases are caused by genetic and environmental factors [7]. Environmental factors exert their effects once there is a sufficient genetic susceptibility [7,8]. The process of autoimmunity of pancreatic β-cells proceeds and may lead to the production of different autoantibodies and biochemical processes which would lead to the more or less complete destruction of β-cells leading to the onset of type 1 diabetes. The undiagnosed phase from triggering β-cell destruction until diagnosis “Gray Zone” phase might be as the possible key to unraveling the type 1 diabetes puzzle. It should be clearly noted that less than half of genetically susceptible individuals develop type 1 diabetes, as illustrated by the low concordance of the disease in identical twins [9].

Genetic factors

The discovery of type 1 diabetes susceptibility genes started as early as 1974 [10], and six type 1 diabetes genes had been identified by 2006 [11]. Also, the advent of GWAS (Genome Wide Association Study) led to the identification of novel genes associated with type 1 diabetes reaching in excess of 40 by 2009 [12] and almost 60 by 2012 [13] GWAS. Interestingly, Onengut-Gumuscu and coworkers have recently suggested that the number of novel type 1 diabetes susceptibility genes may not necessarily increase dramatically [14].

 Most of type 1 diabetes associated diabetes-associated variants have been discovered utilizing cohorts of European ancestry because the SNP arrays were designed to optimally capture the haplotype diversity in this ethnicity. This is logical since the risk of type 1 diabetes is highest in Caucasoid populations. The current review, however, emphasizes the available variation and similarity reports of genetic susceptibility of HLA (Human Leukocyte Antigen) loci having the greatest impact amongst other genes. HLA complex is located on chromosome 6 in the 6p21.3 region containing the most polymorphic genes with more than 14,000 alleles [15]. Due to the high linkage disequilibrium, it is difficult to determine which gene or combinations of genes (haplotypes) in the HLA complex are directly responsible in the etiology of the disease. The HLA genes mainly responsible for type 1 diabetes are, class I (A, B and C) and class II (DR, DQ and DP) (Table 1). To date, out of 14,473 HLA class I, Class II and Class III alleles 14, 282 were reported for HLA Class I and Class II with a different mode of action which is responsible for the complex etiology of the disease [15,16]. HLA gene region is extremely polymorphic (Table 1), this complicates studying the significance of the HLA alleles in different diseases such as type 1 diabetes, and the use of GWAS [14]. However, HLA gene mediates T cell proliferation and activation [17]. In addition, type 1 diabetes is a T cell mediated disease [18,19] . Further, HLA is the most promising factor to be encountered for any future type 1 diabetes intervention and therapy. Fortunately, the advancement of biotechnology has revolutionized HLA science and facilitated HLA typing to an extremely detailed format and simplicity [12,14,20,21].

Table 1. Polymorphism at the classical HLA loci.

Locus

Number of alleles

Class I (n=10,591)

A

3,399

B

4,242

C

2,950

Class II (n=3,691)

DR

 

A

7

B

2,018

DQ

 

A

69

B

911

DP

 

A

43

B

650

Total Number

14,282

Type 1 diabetes associated number of alleles for each of the classical HLA loci are shown http://www.ebi.ac.uk/imgt/hla/stats.html.

HLA class I genes attach to killer T-cells (CD8+ or cytotoxic T-cells) that destroy them. Different ethnicities may, however, have similar or different HLA class I susceptibilities associated with the manifestation of type 1 diabetes [22-25].

HLA class II presents antigens to T-cells (CD4+). The role of HLA class II has been emphasized in the context of the antigen-presenting process in autoimmune type 1 diabetes [26], but it remains to be elucidated how a certain HLA class II can contribute to the molecular mechanisms of β-cell destruction in type 1 diabetes [26]. HLA class II DR, DQ and DP association with type 1 diabetes have been shown to vary amongst different populations and ethnicities [11]. In Caucasian populations, up to 90% of patients with type 1 diabetes are carriers of DR3 or DR4 [7,11,26,27]. HLA-DR3/DR4 is reported in 30% to 50% patients with type 1 diabetes which confer the highest diabetes risk with a synergistic mode of action [11]. However, DR4/DR9 has been reported to be a highly susceptible haplotype in Japanese. The absence of DR3 haplotypes in the Japanese population may contribute to the lower frequency of the disease in Japan [28]. On the other hand, in the Chinese population, the DR3/DR9 genotype is highly susceptible [29]. In the Japanese population, DR4 is a predisposing haplotype whereas DR8, DR9 and DR13 are general risk variants in Asian populations [30].

Furthermore, disease risk assessment for African-Americans differs greatly from risk assessment in other characterized populations. Both DRB1*07:01 and DRB1*03:03 haplotypes are at high risk when they include DQA1*03:01-DQB1*02:01 [27,31].

HLA-DP allelic and haplotype diversity contributes significantly to the risk for type 1 diabetes. In the Caucasian populations, DP 301 (DPA1*0103-DPB1*0301) and DP 202 (DPA1*103, DPB1*0202) is associated with susceptibility and DP402 (DPA1*0103-DPB1*0402) and DP 101(DPA1*0103-DPB1*0101) not. Additional evidence is presented in the susceptibility association of DP 202 (DPA1*0103-DPB1*0202) and for a contributory role of individual amino acids and DPA1 or a gene in linkage disequilibrium in DR3-DP101 positive haplotypes [32]. In controversy, in a more recent study on the Japanese population, it showed that the DP202 allele is also concurrent with type 1 diabetes [33]. Whereas, in the Venezuelan population, DP 202 was the only haplotype associated with type 1 diabetes [34,35]. Furthermore, haplotypes DPA2/DPB1 were susceptible to type 1 diabetes in American Indians [36]. These data and their comparison with HLA DR-DQ-DP haplotypes in more homogeneous ethnic groups support the existence of a weak association of type 1 diabetes with specific HLA-DP alleles and indicate how the distribution of these DP alleles could differ depending on the ethnic groups studied [36]. Table 2 summarizes the classification of HLA-DR in different populations and their diabetes risk level [7,11,23,25,27,30,33,35,37-46].

Table 2. Classification of HLA-DR alleles and their risk level.

HLA-DR

DQA1

DQB1

DRB1

Susceptibility

Populations

DR2

102

602

1501

Protective

 Almost all

DR2

102

502

1601

 Moderate Risk

Caucasians

DR2

103

601

1502

Neutral

Caucasians

DR3

501

201

301

High Risk

Caucasians, Koreans

DR4

301

302

401

High Risk

Caucasians

DR4

301

302

402

Moderate Risk

Caucasians

DR4

301

302

403

Neutral

Caucasians

DR4

301

302

404

Moderate Risk

Caucasians

DR4

301

302

405

High Risk

Caucasians

DR4

301

301

401

Neutral

Caucasians

DR4

301

303

401

Neutral

Caucasians

DR4*

405

303

401

High Risk

Japanese, Koreans

DR7

201

303

701

Protective

Caucasians

DR6

101

503

401

Protective

Caucasians

DR8*

802

301

302

High Risk

Japanese

DR9*

901

300

303

High Risk

Japanese, Koreans

DR13*

1302

102

604

High Risk

Japanese

HLA alleles versus haplotypes

HLA genes are not randomly transmitted from parent to their offspring, but as a block with a strong linkage disequilibrium between A, C, B, DR and DQ alleles, i.e. haplotypes. Only a limited number of type 1 susceptibility haplotypes seem to exist. For instance, in Finland with the world’s highest incidence of type 1 diabetes, only 37 different HLA haplotypes were identified among diabetic children who had either a parent or sibling with type 1 diabetes and another 18 haplotypes in children who did not have a first-degree relative with type 1 diabetes [47].

HLA and type 1 diabetes in Arabs

There are only a few HLA studies in the Arab countries that compare to their contribution to the rise of the burden of the disease globally, Table 2 [3,48-54]. The majority of the available studies have not used systematic HLA research standards. They have discussed HLA association randomly on allele based or haplotypes [48-54]. Others are quite out of date and have been performed serologically [53]. Nevertheless, these studies have set the stepping stone to elucidate the type 1 diabetes genetic risk factors in the Arab population [48-54]. The hallmark of HLA susceptibility is, however, considered from the haplotype point of view [1,26,27,55,56]. On the other hand, the advancement of technology and uniqueness of some of the Arab population in terms of consanguinity and uncharacterized type 1 diabetes can add valuable information to the understanding of type 1 diabetes pathogenesis. The gaining of novel knowledge for 'new' uncharacterized populations may enable us to discover new haplotypes and compare them with Caucasoid and Asian populations, in order to better understand both differences and similarities in the genetic predisposition of type 1 diabetes (Figure 1) [3,57]. In the Middle East and North Africa (MENA) region, the different HLA alleles/haplotypes reported from different Arab studies are tabulated in Table 3 [48-54]. There is an obvious need for proper HLA haplotype studies in Arab populations. Recently, however, a meta-analysis was published in 2015, analyzing 23333 articles, only 30 of them were from Arab populations. The studies in Arab populations have mainly discussed genetic susceptibility of type 1 diabetes related to HLA-DR or DQ alleles but not haplotype configurations [58]. Reviewing up to date reports about Arab HLA indicated that 80 %of patients with type 1 diabetes are carriers of DR3 or DR4. HLA-DR3/DR4 is reported in 13% - 75% patients with type 1 diabetes, which present the highest diabetes risk with an interactive approach [11]. Owing to the advancement of technology and knowledge about the HLA detailed risk of type 1 diabetes particularly in Caucasians Arab HLA in type 1 diabetes should be revised. A careful, systematic nationwide multicenter study is required to update our knowledge about HLA configuration in Arab population with type 1 diabetes.

Table 3. Classification of HLA-DR alleles and their risk level in Arab Populations.

HLA

 Susceptibility

 Populations

 DR DQA1 DQB1 DRB1

DR3

501

201

301

High Risk

 Bahraini, Kuwaiti, Egyptian, Tunisian

DR4

301

302

405

High Risk

 Saudi Arabia, Algerian

DR2

102

602

1501

 Neutral

Saudi Arabia, Algerian

Some studies have clearly discussed HLA haplotype rather than allelic variations. Either whole studies or parts which were based on allelic variations were not included in this table.

Furthermore, the presence of DR9 haplotype has been proposed to be a factor for the low rate type 1 diabetes in the Japanese population [29]. In fact, variation in HLA-DR locus in HLA haplotypes in different populations obviously explain part of the worldwide differences in the frequency of incidence of type 1 diabetes, but it is not fully understood how this is actually happening, since only limited comparisons of HLA haplotypes in type 1 diabetes among populations are available [30,55,59].

Discussion

The incidence of type 1 diabetes is increasing globally and has become an epidemic in some countries. Environmental factors may explain part of such differences, however, we might have to revise the hypothesis of equatorial gradient as the rate of the incidence of disease in the Arab countries, particularly in the Gulf, being in an environment totally different than Finland, the large Italian island of Sardinia or the United States of America that is growing continually.

Among genetic risk factors for type 1 diabetes, HLA accounts for the largest part of the genetic susceptibility and is the keystone of the genetic susceptibility to type 1 diabetes. Various HLA haplotypes were reported among different populations with variable rates of type 1 diabetes. Such variety of HLA haplotypes may explain the remarkable differences in type 1 incidence among populations. Undoubtedly, any future preventive management and therapy will encounter HLA configuration. HLA is not well studied in many populations, this is evidenced by the studies of type 1 diabetes in Saudi Arabia, considered the 4th and Kuwait the 8th top rate country in the world and the first two top countries in the MENA region.

Although Arab population contributes heavily to the rise of type 1 diabetes burden, only a few studies have been produced from this region. There is, therefore, a dire need for a systematic multicenter Arab population study of HLA in type 1 diabetes patients to identify Arab HLA risk haplotypes for the disease. The latter will contribute significantly to the characterization of Arab type 1 diabetes and its pathogenesis.

The last 35 year’s research in the genetic pathogenesis of type 1 diabetes in Caucasians, Japanese, Koreans, and Chinese, have accomplished quite a few fundamental steps towards unwrapping the puzzles of type 1 diabetes syndrome. The majority of present data is from Caucasian populations that have been studied extensively. As the incidence of type 1 diabetes spread unevenly around the world, with a gradient rate among the lowest and the highest of 600-fold, further well-designed trans-ethnic genetic studies that include detailed HLA haplotype information are essential. This would provide necessary insight about the etiology of type 1 diabetes and highlight the value of association mapping in diverse populations. There is also a dearth of knowledge about Arab HLA in type 1 diabetes. According to this review in Arab population, 80% of patients with type 1 diabetes have either DR3 or DR4, whereas, 13-75% of patients had DR3/DR4 haplotypes which resembles synergic mode of action. However, there is an immediate need to update our studies on Arab population due to the advancement of molecular technology and the highly polymorphic nature of HLA.

Concluding remarks

The global distribution of childhood type 1 diabetes clearly indicates large area-to-area variations. In comparison with the neighboring countries to the Arab countries, in general, the high-income oil-producing Arab countries, in particular, have the highest prevalence of type 1 diabetes. Rapid economic development coupled with fast aging populations have resulted in this dramatic increase. Over the past three decades, major social and economic changes have occurred in the majority of Arab countries especially in the Gulf region. These include progressive urbanization, decreased infant mortality and an increasing life expectancy.

Different populations may have similar or diverse HLA susceptibilities associated with the manifestation of type 1 diabetes. This short study had many limitations because of the very few studies of type 1 diabetes in the Arab countries, in general, and HLA as the most promising gene to solve the riddle of type 1 diabetes and speed the prevention of this terrible disease in particular. A careful multicenter Arab nationwide study with different culture and immunogenetics than America and Europe should help us to solve this endemic disease.

References

  1. Fsadni P, Fsadni C, Fava S, Montefort S (2012) Correlation of worldwide incidence of type 1 diabetes (DiaMond) with prevalence of asthma and atopic eczema (ISAAC). Clin Respir J 6: 18-25. [Crossref]
  2. Dos Santos Francisco R, Buhler S, Nunes JM, Bitarello BD, Franca GS, et al. (2015) HLA supertype variation across populations: new insights into the role of natural selection in the evolution of HLA-A and HLA-B polymorphisms. Immunogenetics 67: 651-663.
  3. Federation. ID (2015) Diabetes Atlas 7th edition.
  4. Forouhi NG, Wareham NJ (2014) Epidemiology of diabetes. Medicine (Abingdon) 42: 698-702. [Crossref]
  5. Tuomilehto J (2013) The emerging global epidemic of type 1 diabetes. Curr Diab Rep 13: 795-804. [Crossref]
  6. Tadmouri GO, Sastry KS, Chouchane L (2014) Arab gene geography: From population diversities to personalized medical genomics. Glob Cardiol Sci Pract 2014: 394-408. [Crossref]
  7. Jahromi MM, Eisenbarth GS (2006) Genetic determinants of type 1 diabetes across populations. Ann N Y Acad Sci 1079: 289-299. [Crossref]
  8. Jahromi MM, Eisenbarth GS (2007) Cellular and molecular pathogenesis of type 1A diabetes. Cell Mol Life Sci 64: 865-872. [Crossref]
  9. Atkinson MA, Eisenbarth GS (2001) Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 358: 221-229. [Crossref]
  10. Cudworth AG, Woodrow JC (1975) HL-A system and diabetes mellitus. Diabetes 24: 345-349. [Crossref]
  11. Noble JA, Erlich HA (2012) Genetics of type 1 diabetes. Cold Spring Harb Perspect Med 2: a007732. [Crossref]
  12. Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, et al. (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41: 703-707. [Crossref]
  13. Bergholdt R, Brorsson C, Palleja A, Berchtold LA, Floyel T, et al. (2012) Identification of novel type 1 diabetes candidate genes by integrating genome-wide association data, protein-protein interactions, and human pancreatic islet gene expression. Diabetes 61: 954-962.
  14. Onengut-Gumuscu S, Chen WM, Burren O, Cooper NJ, Quinlan AR, et al. (2015) Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet 47: 381-386. [Crossref]
  15. Robinson J, Halliwell JA, Marsh SG (2014) IMGT/HLA and the Immuno Polymorphism Database. Methods Mol Biol 1184: 109-121. [Crossref]
  16. The HLA informatics group. http://www.ebi.ac.uk/imgt/hla/stats.html. 2015.
  17. Dørum S, Bodd M, Fallang LE, Bergseng E, Christophersen A, et al. (2014) HLA-DQ molecules as affinity matrix for identification of gluten T cell epitopes. J Immunol 193: 4497-4506. [Crossref]
  18. Jahromi MM, Millward BA, Demaine AG (2010) Significant correlation between association of polymorphism in codon 10 of transforming growth factor-beta1 T (29) C with type 1 diabetes and patients with nephropathy disorder. J Interferon Cytokine Res 30: 59-66.
  19. Jahromi MM, Millward BA, Demaine AG (2000) A polymorphism in the promoter region of the gene for interleukin-6 is associated with susceptibility to type 1 diabetes mellitus. J Interferon Cytokine Res 20: 885-888. [Crossref]
  20. Aly TA, Baschal EE, Jahromi MM, Fernando MS, Babu SR, et al. (2008) Analysis of single nucleotide polymorphisms identifies major type 1A diabetes locus telomeric of the major histocompatibility complex. Diabetes 57: 770-776.
  21. Hosomichi K, Shiina T, Tajima A, Inoue I (2015) The impact of next-generation sequencing technologies on HLA research. J Hum Genet 60: 665-673. [Crossref]
  22. Noble JA, Valdes AM, Bugawan TL, Apple RJ, Thomson G, et al. (2002) The HLA class I A locus affects susceptibility to type 1 diabetes. Hum Immunol 63: 657-664. [Crossref]
  23. Tait BD, Colman PG, Morahan G, Marchinovska L, Dore E, et al. (2003) HLA genes associated with autoimmunity and progression to disease in type 1 diabetes. Tissue Antigens 61: 146-153. [Crossref]
  24. Valdes AM, Thomson G, Graham J, Zarghami M, McNeney B, et al. (2005) D6S265*15 marks a DRB1*15, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus. Diabetologia 48: 2540-2543.
  25. Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, et al. (2007) Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450: 887-892. [Crossref]
  26. Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, et al. (2008) HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 57: 1084-1092.
  27. Noble JA, Johnson J, Lane JA, Valdes AM (2011) Race-specific type 1 diabetes risk of HLA-DR7 haplotypes. Tissue Antigens 78: 348-351. [Crossref]
  28. Zhang XM, Wang HY, Luo YY, Ji LN (2009) HLA-DQ, DR allele polymorphism of type 1 diabetes in the Chinese population: a meta-analysis. Chin Med J (Engl) 122: 980-986. [Crossref]
  29. Katahira M, Ishiguro T, Segawa S, Kuzuya-Nagao K, Hara I, et al. (2008) Reevaluation of human leukocyte antigen DR-DQ haplotype and genotype in type 1 diabetes in the Japanese population. Horm Res 69: 284-289. [Crossref]
  30. Ikegami H, Noso S, Babaya N, Hiromine Y, Kawabata Y (2008) Genetic Basis of Type 1 Diabetes: Similarities and Differences between East and West. Rev Diabet Stud 5: 64-72. [Crossref]
  31. Noble JA, Johnson J, Lane JA, Valdes AM (2013) HLA class II genotyping of African American type 1 diabetic patients reveals associations unique to African haplotypes. Diabetes 62: 3292-3299.
  32. Varney MD, Valdes AM, Carlson JA, Noble JA, Tait BD, et al. (2010) HLA DPA1, DPB1 alleles and haplotypes contribute to the risk associated with type 1 diabetes: analysis of the type 1 diabetes genetics consortium families. Diabetes 59: 2055-2062.
  33. Jassam N, Amin N, Holland P, Semple RK, Halsall DJ, et al. (2014) Analytical and clinical challenges in a patient with concurrent type 1 diabetes, subcutaneous insulin resistance and insulin autoimmune syndrome. Endocrinol Diabetes Metab Case Rep 2014: 130086.
  34. Liao Y, Cai B, Li Y, Chen J, Ying B, et al. (2015) Association of HLA-DP/DQ, STAT4 and IL-28B variants with HBV viral clearance in Tibetans and Uygurs in China. Liver Int 35: 886-896. [Crossref]
  35. Solberg OD, Mack SJ, Lancaster AK, Single RM, Tsai Y, et al. (2008) Balancing selection and heterogeneity across the classical human leukocyte antigen loci: a meta-analytic review of 497 population studies. Hum Immunol 69: 443-464.
  36. Howson JM, Walker NM, Clayton D, Todd JA; Type 1 Diabetes Genetics Consortium (2009) Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A. Diabetes Obes Metab 11 Suppl 1: 31-45. [Crossref]
  37. Valdes AM, Erlich HA, Noble JA (2005) Human leukocyte antigen class I B and C loci contribute to Type 1 Diabetes (T1D) susceptibility and age at T1D onset. Hum Immunol 66: 301-313. [Crossref]
  38. Awata T, Kuzuya T, Matsuda A, Iwamoto Y, Kanazawa Y (1992) Genetic analysis of HLA class II alleles and susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia 35: 419-424.
  39. Awata T, Kuzuya T, Matsuda A, Iwamoto Y, Kanazawa Y, et al. (1990) High frequency of aspartic acid at position 57 of HLA-DQ beta-chain in Japanese IDDM patients and nondiabetic subjects. Diabetes 39: 266-269. [Crossref]
  40. Kawabata Y, Ikegami H, Kawaguchi Y, Fujisawa T, Shintani M, et al. (2002) Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes. Diabetes 51: 545-551. [Crossref]
  41. Murao S, Makino H, Kaino Y, Konoue E, Ohashi J, et al. (2004) Differences in the contribution of HLA-DR and -DQ haplotypes to susceptibility to adult- and childhood-onset type 1 diabetes in Japanese patients. Diabetes 53: 2684-2690. [Crossref]
  42. Ohtsu S, Takubo N, Kazahari M, Nomoto K, Yokota F, et al. (2005) Slowly progressing form of type 1 diabetes mellitus in children: genetic analysis compared with other forms of diabetes mellitus in Japanese children. Pediatr Diabetes 6: 221-229.
  43. Yasunaga S, Kimura A, Hamaguchi K, Ronningen KS, Sasazuki T (1996) Different contribution of HLA-DR and -DQ genes in susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). Tissue Antigens 47: 37-48. [Crossref]
  44. Thomson G, Valdes AM, Noble JA, Kockum I, Grote MN, et al. (2007) Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis. Tissue Antigens 70: 110-127.
  45. Kasahara M, Kiuchi T, Uryuhara K, Uemoto S, Fujimoto Y, et al. (2002) Role of HLA compatibility in pediatric living-related liver transplantation. Transplantation 74: 1175-1180.
  46. Maruyama T, Shimada A, Kasuga A, Kasatani T, Ozawa Y, et al. (1994) Analysis of MHC class II antigens in Japanese IDDM by a novel HLA-typing method, hybridization protection assay. Diabetes Res Clin Pract 23: 77-84. [Crossref]
  47. Tuomilehto-Wolf E, Tuomilehto J (1993) Is the high incidence of diabetes in young children diagnosed under the age of 4 years determined by genetic factors in Finland? The DIME Study Group. Diabete Metab 19: 167-172.
  48. Fekih-Mrissa N, Klai S, Zaouali J, Gritli N, Mrissa R (2013) Association of HLA-DR/DQ polymorphism with myasthenia gravis in Tunisian patients. Clin Neurol Neurosurg 115: 32-36. [Crossref]
  49. Aribi M, Moulessehoul S, Benabadji AB, Kendoucitani M (2004) HLA DR phenotypic frequencies and genetic risk of Type 1 diabetes in west region of Algeria, Tlemcen. BMC Genet 5: 24. [Crossref]
  50. Mosaad YM, Auf FA, Metwally SS, Elsharkawy AA, El-Hawary AK, et al. (2012) HLA-DQB1* alleles and genetic susceptibility to type 1 diabetes mellitus. World J Diabetes 3: 149-155. [Crossref]
  51. Al-Jenaidi FA, Wakim-Ghorayeb SF, Al-Abbasi A, Arekat MR, Irani-Hakime N, et al. (2005) Contribution of selective HLA-DRB1/DQB1 alleles and haplotypes to the genetic susceptibility of type 1 diabetes among Lebanese and Bahraini Arabs. J Clin Endocrinol Metab 90: 5104-5109.
  52. Al-Hussein KA, Rama NR, Ahmad M, Rozemuller E, Tilanus MG (2003) HLA-DPB1*0401 is associated with dominant protection against type 1 diabetes in the general Saudi population and in subjects with a high-risk DR/DQ haplotype. Eur J Immunogenet 30: 115-119.
  53. Behbehani K, Richens ER, Abdella N, Jayyab AK, Shaltout A, et al. (1987) HLA associations in an Arab type 1 diabetic population. Dis Markers 5: 165-169. [Crossref]
  54. Haider MZ, Shaltout A, Alsaeid K, Qabazard M, Dorman J (1999) Prevalence of human leukocyte antigen DQA1 and DQB1 alleles in Kuwaiti Arab children with type 1 diabetes mellitus. Clin Genet 56: 450-456. [Crossref]
  55. Cruz TD, Valdes AM, Santiago A, Frazer de Llado T, Raffel LJ, et al. (2004) DPB1 alleles are associated with type 1 diabetes susceptibility in multiple ethnic groups. Diabetes 53: 2158-2163. [Crossref]
  56. Zayed H (2016) Genetic Epidemiology of Type 1 Diabetes in the 22 Arab Countries. Curr Diab Rep 16: 37. [Crossref]
  57. Shaw JE, Sicree RA, Zimmet PZ (2010) Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 87: 4-14. [Crossref]
  58. Hamzeh AR, Nair P, Al-Khaja N, Al Ali MT (2015) Association of HLA-DQA1 and -DQB1 alleles with type I diabetes in Arabs: a meta-analyses. Tissue Antigens 86: 21-27. [Crossref]
  59. Lipner EM, Tomer Y, Noble JA, Monti MC, Lonsdale JT, et al. (2015) Linkage Analysis of Genomic Regions Contributing to the Expression of Type 1 Diabetes Microvascular Complications and Interaction with HLA. J Diabetes Res 2015: 694107. [Crossref]

Editorial Information

Editor-in-Chief

Katsunori Nonogaki

Article Type

Research Article

Publication history

Received date: February 14, 2017
Accepted date: March 07, 2017
Published date: March 10, 2017

Copyright

© 2017 Jahromi MM. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Jahromi MM (2017) HLA and Type 1 diabetes in Arab populations. Integr Obesity Diabetes. 3: Doi: 10.15761/IOD.1000173

Corresponding author

Mohamed M Jahromi

Senior Scientist, Translational Research Group, Dasman Diabetes Institute, P.O Box 1180, Dasman 15462, Kuwait

Figure 1. Global reported rates of type 1 diabetes incidents/100,000 population in different countries.

The reported rates of incidence of type 1 diabetes in different countries in 2015. The rate of incidence varied from 0.1/100,000 per year in China, Papua New Guinea and Venezuela to 57.6/100,000 per year in Finland with an approximately 600-fold gradient of among countries. The incidence varies within several other countries in different folds. For example, Sardinia in Italy is notably discordant with the incidence in Italy as a whole (51.0 vs 12.1/100,000 population). China is another country where there is such a variation by region (0.13–1.61/100,000). Saudi Arabia and Kuwait which are from high income Arab countries are between top ten countries with high type 1 diabetes incidence rates.

Figure 2. Rates of type 1 diabetes in reported Arab countries.

The reported rates of type 1 diabetes in Arab countries in 2015. There is a 12.5 folds variation between the rates in high income oil producing Arab countries in the Gulf region (31.4 Saudi Arabia vs 2.5 Oman/ 100,000 population). 

Figure 3. Natural history of type 1 diabetes.

Natural history of type 1 diabetes predicts that the pathogenesis of type 1 diabetes starts in genetically susceptible individuals as soon as appropriate environmental factors trigger the autoimmunity of islet β-cells. Several biochemical processes transpire during this critical phase of the disease which is mostly undiagnosed, “Gray Zone’. The clinical diagnosis typically come about once the majority of β-cells have disappeared. Beta cell mass will be reduced throughout the process and by the time of diagnosis it reaches a minimum possible rate.

Table 1. Polymorphism at the classical HLA loci.

Locus

Number of alleles

Class I (n=10,591)

A

3,399

B

4,242

C

2,950

Class II (n=3,691)

DR

 

A

7

B

2,018

DQ

 

A

69

B

911

DP

 

A

43

B

650

Total Number

14,282

Type 1 diabetes associated number of alleles for each of the classical HLA loci are shown http://www.ebi.ac.uk/imgt/hla/stats.html.

Table 2. Classification of HLA-DR alleles and their risk level.

HLA-DR

DQA1

DQB1

DRB1

Susceptibility

Populations

DR2

102

602

1501

Protective

 Almost all

DR2

102

502

1601

 Moderate Risk

Caucasians

DR2

103

601

1502

Neutral

Caucasians

DR3

501

201

301

High Risk

Caucasians, Koreans

DR4

301

302

401

High Risk

Caucasians

DR4

301

302

402

Moderate Risk

Caucasians

DR4

301

302

403

Neutral

Caucasians

DR4

301

302

404

Moderate Risk

Caucasians

DR4

301

302

405

High Risk

Caucasians

DR4

301

301

401

Neutral

Caucasians

DR4

301

303

401

Neutral

Caucasians

DR4*

405

303

401

High Risk

Japanese, Koreans

DR7

201

303

701

Protective

Caucasians

DR6

101

503

401

Protective

Caucasians

DR8*

802

301

302

High Risk

Japanese

DR9*

901

300

303

High Risk

Japanese, Koreans

DR13*

1302

102

604

High Risk

Japanese

Table 3. Classification of HLA-DR alleles and their risk level in Arab Populations.

HLA

 Susceptibility

 Populations

 DR DQA1 DQB1 DRB1

DR3

501

201

301

High Risk

 Bahraini, Kuwaiti, Egyptian, Tunisian

DR4

301

302

405

High Risk

 Saudi Arabia, Algerian

DR2

102

602

1501

 Neutral

Saudi Arabia, Algerian

Some studies have clearly discussed HLA haplotype rather than allelic variations. Either whole studies or parts which were based on allelic variations were not included in this table.