Fundamental Elucidation of HLA in Type 1 Diabetes of Arab Populations

Aims/Hypothesis): Type 1 diabetes is an immune-mediated disease with destruction of the pancreatic β-cells, a process that is conditioned by multiple genes and other factors. HLA counts as the major susceptibility gene. Significant variations in HLA genetic susceptibility to type 1 diabetes between Caucasians, African and Asian and other ethnic groups may have led to the variation in incidence of type 1 diabetes globally. Type 1 diabetes is characterized upon HLA identification. In this chapter we discuss global variations in genetic susceptibility of HLA with regard to type 1 diabetes globally with a particular attention to Arab population. Methods): Haplotype configuration of HLA class I A, B, C and Class II –DR/DQ/DP were studied in Caucasians, African and Asian and in Arab population to see if that is responsible for the exponential rise in the rate of type 1 diabetes. Results): Although Arabs have one of the highest global incidence and prevalence rates of type 1 diabetes, unfortunately, there is a dearth amount of information regarding HLA genetic susceptibility to type 1 diabetes in the Arab world. HLA haplotype configurations contribute to its risk value. However, out of an insufficient present study there are examples of misjudgment of HLA risk according to HLA alleles rather than haplotypes. Conclusion): To date HLA outlooks for the characterization of type 1 diabetes. There is an ethnicity difference in HLA characteristics which is responsible for variation in type 1 diabetes. Although Arab population have contributed heavily in the rise of burden of type 1 diabetes, however, there is significantly a dearth amount of studies on HLA in Arab population. Obviously, any future prediction, prevention or cure of the disease will be based on the HLA genetics. There is a dire need for a systematic screening of HLA for Arab population with type 1 diabetes, identification of Arab HLA haplotypes-risk values and identify those who are prone to get the disease.


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 is added to the number of children below 15 years old.In 2015 it was estimated that the total of 542,000 children below 15 years old equivalent to 2.82 per 1000,000 children at the same age had type 1 diabetes [2].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) [3] .China is another country where there is a 12fold variation by region (0.13-1.61/100,000) [4].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 [2].Interestingly, Saudi Arabia and Kuwait which are from high income Arab countries are between top ten countries with high type 1 diabetes incidence rates [2].Remarkably, the rate of incidence of type 1 diabetes varies 12.5 fold in high income oil producing Arab countries in the Gulf region (31.4Saudi Arabia vs 2.5 Oman/ 100,000 population), Figure 2.

Human Leukocyte Antigen (HLA)
HLA counts for almost 50 % of type 1 diabetes genetic susceptibility [5].HLA complex is located on chromosome 6 in the 6p21.31region containing the most polymorphic genes with more than 14,000 alleles [6].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.It is believed that HLA haplotype configuration lead to variation of rates of type 1 diabetes [7] 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 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 [6].Family studies have shown that in the Caucasoid population, several HLA class I alleles result in the predisposition of type 1 diabetes and may also be involved in type 2 diabetes [8].The same susceptibility alleles have been reported in East Asian populations [7].Different ethnicities may, however, have similar or different HLA class I susceptibilities associated with the manifestation of type 1 diabetes [9][10][11][12][13].
The role of HLA class II has been emphasized in the context of the antigen-presenting process in type 1 diabetes [14], but it remains to be elucidated how a certain HLA class II can contribute toward the molecular mechanisms of β-cell destruction in type 1 diabetes [15,16].HLA class II DR, DQ and DP association with type 1 diabetes have been shown to vary amongst different populations and ethnicities as well [7,[17][18][19][20].In Caucasian populations up to 90% of patients with type 1 diabetes are carriers of DR3 or DR4 [21,22].HLA-DR3/DR4 is reported in 30% to 50% patients with type 1 diabetes which confers the highest diabetes risk with a synergistic mode of action [8] 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 lower frequency of the disease in Japan [23].On the other hand, in the Chinese population the DR3/DR9 genotype is highly susceptible [24].In the Japanese population DR4 is a predisposing haplotype whereas DR8, DR9 and DR13 are general risk variants in Asian populations [25].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 of high risk when they include DQA1*03:01-DQB1*02:01 [26,27].
HLA alleles 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.Remarkably, 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 [41].There are only a few HLA studies in Arab countries that compare their contribution in the rise of the burden of the disease globally, Table 3 [2,[42][43][44][45][46][47][48].These studies have set the stepping stone to elucidate the type 1 diabetes genetic risk factors in the Arab population [42][43][44][45][46][47][48].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 in 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 other African, Caucasoid and Asian populations; to understand both differences and similarities in the genetic predisposition of type 1 diabetes [2].There is a dire need for systematic HLA haplotype studies in Arab populations.Recently, however, a meta-analysis was published in 2015 analyzing 23,333 articles; interestingly, only 30 of them were from Arab population.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 [49].The hallmark of HLA susceptibility, however, is considered from haplotype configuration [5,7,41,50] .Furthermore, the presence of DR9 haplotype has been proposed to be a factor for the low rate type 1 diabetes in the Japanese population [7] In fact, variation in HLA-DR locus in HLA haplotypes in different populations obviously explain part of the world-wide 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 [19,23,40].Indeed HLA is considered as the key for characterization of type 1 diabetes.Systematic screening of Arab type 1 diabetes patients with their first degree relatives for HLA-risk haplotypes will elucidate those who are prone to get type 1 diabetes.Any future advancement, predication and prevention of the disease will be based of the HLA characteristics of the disease.HLA characterization of Caucasian population with type 1 diabetes is almost well-known, however, still further studies are on-going [5,51,52] which reflect the significant impact of this gene in the pathogenesis of the disease.

Discussion
The global distribution of childhood type 1 diabetes clearly indicates large area-to-area variations.Comparing to the neighboring countries to Arab countries in general and high-income Oil-producing Arab countries in particular have the highest prevalence of type 1 diabetes, Figure 2. Rapid economic development coupled with ageing populations have resulted in a dramatic increase in the prevalence of type 1 diabetes.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 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 paucity of T1D in Arab countries studies 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.Careful multicenter Arab population-wide study with different culture and immunogenetics than America and Europe should help us to solve this endemic disease.A suitable screening regimen to characterize Arab type 1 diabetes, no doubt, will help to identify those who are prone to get the disease in the early stages of their life.Undoubtedly this would unravel puzzle of type 1 diabetes and reducing the disease related economic burden.

Concluding Remarks
The incidence of type 1 diabetes is increasing globally and has become 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 disease in high income oil producing Arab countries, being in an environment totally different than Finland and Sardinia or the United States of America, is growing continuously.HLA counts for almost 50 % of type 1 diabetes genetic susceptibility and is a key indicator for characterization of 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 Arab populations.Although Arab population contribute heavily on the rise of type 1 diabetes burden only few studies have been produced from this region.There is a dire need for 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 in characterization of Arab type 1 diabetes and its pathogenesis.

Legends:
Table 1 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

Table 3
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.

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

Table 3 : Classification of HLA-DR alleles and their risk level in Arab Populations
2016 by the author; licensee Preprints, Basel, Switzerland.This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/). ©