Rheumatoid arthritis (RA)

Relevant HLA genes involved in susceptibility to RA are HLA-DRB1*04:01, *04:04, and *04:08 in Caucasians; HLA-DRB1*04:05 in Spaniards and Japanese; HLA-DRB1*01:01 and *01:02 in Israelis; HLA-DRB1*14:02 in some Native Americans such as Pima and Yakima Indians; HLA-DRB1*10:01 in Greeks (7); and HLA-DRB1*01:01, *04:01, *04:04, and *04:05 in Latin Americans (8). Although the pathogenic mechanisms of these alleles in RA are still unresolved, different hypotheses have been postulated as follows: first, presentation of arthritogenic antigens; second, alterations of peptide affinity during T cell repertoire selection; and third, molecular mimicry with microorganism peptide residues. Another approach is the classical shared epitope (SE) hypothesis, proposed by Gregersen, et al. (9), who by comparing aminoacid sequences encoded by the disease-associated HLA-DRB1 alleles listed above, demonstrated a conserved motif (L-LE-[Q/R]-[R/K]-R-A-A) including residues 70–74 in the third hypervariable region of the DRβ1 chain.

In addition, the HLA-DRB1 locus also harbors some protective alleles known as the DERAA sequence at the same position in the third hypervariable region of the DRB1 chain residues 70–74, specifically, aspartic acid (D) at position 70. The DERAA alleles are HLA-DRB1*01:03, *04:02, *11:02, *11:03, *13:01, *13:02, and *13:04. People carrying HLA-DRB1 alleles that express this DERAA sequence display a lower susceptibility to RA and have less severe disease than people with SE-negative and DERAA-negative HLA-DRB1 alleles (10). Alleles associated with SE and DERAA sequence are listed in Table 2 (11).

Table 2

SE and SE-negative HLA-DRB1 alleles.

It has been suggested that alleles carrying the SE induce the activation of autoreactive T cells. This is complemented by crystallographic studies in which it has been observed that a glutamine (Q) at position 70 and an arginine or lysine residue (R/K) at position 71 of the β chain establish a direct interaction with the T cell receptor (TCR) by selecting a specific population of T lymphocytes “SE recognizers.”

Other studies have shown that changes at residues 70 to 74 of the β-chain of the SE alleles can generate a total change in the range of peptides that are initially presented by these molecules through directed mutagenesis (12). In the SE, both its residues defined by specific genotypes and the LD that these alleles may have with other loci — either as HLA and non-HLA — are important. This type of genetic pattern also affects the risk depending on the genotypic conformation. For example, if the individual has one or both alleles for SE, the risk effect for the SE homozygous individual is 50% less and for the heterozygous one, 30% adducing a penetrance variability dependent on genotype status. Therefore, it can be concluded that the relative risk (RR) can be high with respect to the presence of SE but not enough for RA to be present in 100% of individuals who carry it (7).

Further, when the relationship between anti-cyclic citrullinated peptide antibodies (ACPA) and HLA-DRB1 have been studied, they have revealed that the association between DRB1 SE alleles and RA was restricted to ACPA-positive RA but not ACPA-negative RA patients in different populations (13). Just 12.7% of the phenotypic variance can be explained by susceptibility loci within the MHC region compared to ~4% for non-MHC loci. This leaves most of the MHC association to be explained by HLA-DRB1 in RA (14). Furthermore, there is evidence that four amino acids at positions 11, 13, 71, and 74 in the HLA-DRB1 molecule are important for the susceptibility to RA in ACPA-positive patients (Figure 1). These amino acids have side-chains pointing into the groove and are thus important for and possibly define the peptide binding properties of the HLA molecule. Moreover, amino acids 71 and 74 are part of the SE and, as mentioned above, are implicated in conferring risk to RA. The association at these four positions with ACPA-positive RA patients is different and depends on the HLA-DRB1 polymorphisms. Thus, HLA-DRB1*04:01, *04:08,*04:05, and *04:04 are the risk alleles most significantly associated with ACPA-positive RA in European individuals. Additional associations for HLA-B*08 and for a group of HLA-DP1 alleles with ACPA-positive RA have also been reported. For both molecules encoded by these HLA genes, there is a substitution in position 9 which may allow a functional impact on antigenic peptide presentation to T Cells (15) (Figure 1).

Figure 1

Three-dimensional ribbon models for the HLA-DR, HLA-B, and HLA-DP proteins. These structures are based on the Protein Data Bank (PDB) with a direct view of the peptide-binding groove. Key amino acid positions identified by the association analysis are (more...)

According to new insights into the functional role of the SE in RA pathogenesis, this is transduced not by means of an adaptative response but by an innate response transduction. De Almeida et al., suggested that in dendritic cells (DC), a SE-triggered signaling is transduced via cell surface calreticulin (CRT), a molecule involved in clearance of apoptotic cells. Signaling by CRT ligation would occur with the SE through the P-domain of CRT. Following an initial binding, activation of nitric oxide (NO) and reactive oxygen species (ROS) production is initiated, leading to two different outputs. In CD11c(+)CD8(+) DCs, the SE inhibits the enzymatic activity of indoleamine 2,3 dioxygenase (IDO), a key enzyme in immune tolerance and T cell regulation, whereas in CD11c(+)CD8(−) DCs, the ligand activates the production of IL-6 and IL-17 (16). Likewise, the same group demonstrated that the SE ligand interacts with cell-surface CRT on osteoclasts (OC) and activates NO and ROS production. The former is supported by the fact that SE activates Th17-dependent osteoclastogenesis by enhancing the differentiation of RANKL-expressing IL-17–producing T cells (17) (Figure 2).

Figure 2

New insights into the functional role of the SE in RA pathogenesis: A proposed model. The SE ligand, expressed on APC interacts with cell surface CRT. In RA, the affinity of SE-CRT interaction could increase leading to an aberrant activation of the SE (more...)

Multiple sclerosis (MS)

This condition corresponds to an autoimmune pathology with a predominant immune cell response characterized by the presence of autoreactive T cells that react against the myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and the proteolipid protein (PLP). The HLA-DRB1*15:01 and HLA-DQB1*06:02 alleles, which are in LD, are the main alleles associated with risk for MS in Caucasians and Latin Americans (18). Recently, in a large combined multinational cohort in the International Multiple Sclerosis Genetics Consortium (IMSGC) GWAS study, the HLA-DRB1*13:03 allele was also identified as being associated with MS (OR=2.43). Furthermore, HLA-DRB1*01:08 (OR=1.18) and HLA-DRB1*03:01 (which is strongly linked to HLA-DQB1*02:01; OR=1.26) showed significant associations. Evidence of an additive effect for each additional allele was also described (19). In the Sardinia region of Italy, where MS prevalence is high, HLA-DRB1*04, HLA-DRB1*03:01, and HLA-DRB1*13:01 (in addition to HLA-DRB1*15:01) positive associations with MS have been reported (20).

Several studies have explored phenotype-genotype correlation for associated HLA alleles in MS and reported that HLA-DRB1*15 has been associated with younger age at onset and a worse Expanded Disability Status Scale (EDSS) score as well as severe morbidity in patients with primary progressive MS (21). Both the carriage of HLA-DRB1*15 and the presence of oligoclonal bands in the cerebrospinal fluid have been reported to hasten disease progression (22).

MS studies in animal models [i.e., experimental allergic encephalomyelitis (EAE)] and human models have focused on the 84–102 MBP peptide, known as immunodominant epitope ENPVVHFFKNIVTPR, based on which the crystallographically complex HLA-DRB1*15:01 - MBP peptide has been disclosed. The most prominent feature of this peptide is the capability of the P4 pocket DRB1*15:01 molecule to bind hydrophobic residues due to the presence of an alanine (Ala), which receives the phenylalanine residue (Phe) peptide of MBP (2,23). The P4 not only accommodates the Phe, but because of its size, it can also incorporate residues, e.g., Ala (aromatic) and Lys, which interact perfectly with the negative charge of the pocket. Still, the role of the P4 anchor residues is not a prerequisite for developing the disease, so it is assumed that there are additional factors that may or may not be associated with HLA that can trigger the disease.

The potential of peptide-based therapy for treatment of MS and its relationship with the MHC molecules has been explored. Copaxone, is a Food and Drug Administration (FDA) approved drug for treatment of MS. The synthetic random amino acid copolymer, Copolymer 1 (Cop 1, Copaxone, glatiramer acetate) was the first drug based on four amino acids (L-alanine, L-lysine, L-glutamic acid, and L lysine) from MBP. Cop-1 suppresses EAE, slows the progression of disability, and reduces the relapse rate in MS. Cop 1 binds to various class II MHC molecules including HLA-DRB1*15:01, inhibits the T cell responses to several myelin antigens, shifts Th1 response to Th2, and upregulates T regulatory cell expression. Later, it was proved that Cop-1 causes demyelination arrest and induces remyelination when given to EAE mice (24).

Systemic lupus erythematosus (SLE)

The HLA, as per almost all the ADs, has been shown to exert the strongest genetic association and effect on SLE to date. The top association was found at HLA-DRB1. Studies examining HLA class II have consistently replicated the HLA-DR2 (DRB1*15:01), HLA-DR3 (DRB1*03:01), HLA-DRB1*08:01, and HLA-DQA1*01:02 alleles associated with the disease in American and European populations with a two fold RR conferred by each allele (25–28). The extended HLA 8.1 AH (ancestral haplotype) is considered a common European haplotype implicated in SLE susceptibility (See section below). GWAS in both European and Asian populations has shown that the strongest contribution to risk for SLE resides in the HLA region and consists of multiple genetic effects (29). The long-range LD within the HLA region has made assessing the relative contribution of each component gene to disease susceptibility difficult. However, the available evidence suggests that genetic variants such as HLA-DR2 and HLA-DR3, HLA-DPB1, HLA-G, and class III (such as MSH5 and SKIV2L) genes, in particular, predispose an individual to SLE (30).

Moreover, the role of SLE-associated HLA class II alleles in initiating SLE-relevant autoantibody responses has been demonstrated in humanized mice expressing the HLA-DR3 transgene but no other DR or DQ alleles (31). Microarray studies done on SLE patients have revealed that the MHC class I genes are under expressed when compared with controls (32). The MHC class I region is required for the detection of intracellular pathogens by CD8⁺ T cells, and its absence seems to lead to a failure to defend against such pathogens. A certain gene transcription signature in CD8⁺ T cells has been linked to SLE disease prognosis (33).

Type 1 diabetes mellitus (T1D)

Several alleles have been associated with and linked to susceptibility to T1D including HLA-DQB1*03:02 and DQB1*02:01 (34,35). It is known that individuals with both alleles have a higher RR of developing the disease when compared to the general population. Similarly, many DRB1*04 alleles, which are in LD with the DQB1*03:02 allele may modify the RR for the disease. In summary, the HLA association with T1D is one of the most complex. It was initially suggested that HLA-B8, HLA-B18, and HLA-B15 (B62) were higher in patients with this disease (36). Then, as the molecular tests were developed, the association expanded to HLA-DR3 alleles (i.e., HLA-DRB1*03:01), HLA-DR4 (HLA-DRB1*04), HLA DQB1*02:01, and HLA-DQB1*03:02. Although the quantity of alleles found associated with T1D in the DR and DQ loci is high, the role of the locus or loci conferring susceptibility/protection is unclear given that they are presented with low effects when compared to the identified susceptibility haplotypes of T1D (Table 3) (37). This can be explained by the variety of existing alleles in the HLA, population changes, and the pattern of inheritance for both susceptibility and protection alleles such as HLA-DRB1*15:01 and/or HLA-DQB1*06:02 (36,38).

Table 3

MHC markers associated with autoimmune type 1 diabetes mellitus and their relative risks (RR).

Studies of human cell lines of T lymphocytes restricted by DR and DQ alleles have reported autoantigens associated with the disease including insulin, glutamate decarboxylase (GAD65), and tyrosine phosphatase pancreatic islet antigens known as IA-2. In addition, transgenic mice experiments for HLA-DQ*03:02 helped identify the presence of GAD specific T lymphocytes (39) while others suggest that the peptide Ins B9.23 could be an immunodominant autoantigen restricted to HLA-DQ (40).

Initial reports indicate that HLA-DQ*03:02 is the preferred molecule for peptides with a negative charge in the anchor residue which binds to the P9 pocket (41). These observations are supported by binding experiments between Insulin B chain (residues 9–23, SHLVEALYLVCGERG) and the HLA molecule DQ*03:02 (42). Negatively charged peptides in the same position could make a bridge between the MHC molecule and Arg, which would help to stabilize the complex. This would increase its half-life in contrast to what was observed with peptides that had no negative charge. Furthermore, the molecules of HLA-DQ*03:02 are larger at P4, which allows them to accommodate hydrophobic peptide residues such as phenylalanine (Phe) and tyrosine (Tyr) while unable to accept positively charged residues. The P1 of the DQB1*03:02 molecules is highly polar. Therefore, it may contain positively charged residues such as histidine (His) and arginine (Arg). It has also been possible to establish a molecular characteristic for the molecule corresponding to the protective allele which is that, unlike DQ*03:02, DQ*06:02 prefers aliphatic residues attached to P9 (43). Similarly, the 57 residue of the β chain of the DQ molecules also contributes to the pattern of peptides bound by these molecules. However, studies suggest that P9 is what determines the selection of autoreactive peptides involved in the development of T1D.

Sjögren’s syndrome (SS)

SS is an autoimmune exocrinopathy characterized by a lymphocytic and plasma cell infiltration of the salivary and lachrymal glands. This is accompanied by de novo production of autoantibodies leading to keratoconjuntivitis sicca and xerostomia. A recent meta-analysis of association studies from around the world identified associations between HLA Class II and SS. A total of 1,166 cases and 6,470 controls from 23 studies were analyzed including 16 different populations. At the allelic level, DQA1*05:01, DQB1*02:01, and DRB1*03:01 alleles were found to be risk factors for the disease. Conversely, the DQA1*02:01, DQA1*03:01, and DQB1*05:01 alleles were protective factors (44). However, there are other risk alleles/haplotypes specific for each population such as DRB3*01:01 in Norwegians (45), DRB3*01:01 and DQB1*06:02 in Danes (46), DRB1*04:05-DQB1*04:01 in Japanese (47), DRB1*08:03-DQB1*06:01 in Chinese (47), and DRB1*11:01, DRB1*11:04, DQB1*03:01 in Israeli, Jews, and Greek (48).

Particular HLA class II alleles may play an important role in the regulation of the immune responses against the Ro and La ribonucleoproteins. The generation of these autoantibodies has been correlated with the alleles DRB1*03, DQA1*05:01, and DQB1*02:01 in SS patients (49–52). Likewise, while HLA-DR3 and HLA-DR8 were correlated with anti-Ro and anti-La responses in patients with SS and SLE, HLA-DR2 is associated with anti-Ro responses in the absence of anti-La (53). Furthermore, an induction of strong T and B cell responses by a human recombinant Ro60 protein was observed in transgenic mice carrying DR2, DR3, or DQ8 HLA genes but not in mice carrying DQ6 genes (54). Thereafter, using two different artificial neural networks (NetMHCIIpan and the Immune Epitope Database Analysis Resource), five La peptides (La_18–32, La_49–63, La_101–115, La_153–167, La_241–255), and three Ro peptides (Ro_125–139, Ro_244–258, Ro_523–537) with the ability to bind strongly to HLA-DRB1*03:01 risk allele were identified (44). Thus, differences in the biochemical characteristics of critical amino acids are directly related to either the risk or protection conferred by HLA Class II alleles associated with SS.

Celiac disease (CD)

CD is a complex disorder of the small intestine caused by an inappropriate immune response to ingested wheat gluten (See chapter 33). CD has a strong genetic component as illustrated by a monozygotic twin concordance of nearly 90% compared to 10% in first-degree relatives (55). A significant proportion of the genetic predisposition comes from HLA genes. HLA-DQ2 (encoded by HLA-DQA1*05:01-DQB1*02:01) or HLA-DQ8 (encoded by DQA1*03:01-DQB1*03:02) is expressed in 30%–35% of the populations where CD is prevalent with only 2%–5% of gene carriers developing CD. This implicates other genetic as well as environmental factors as contributors to the manifestation of CD (56).

The principal disease triggering component of wheat gluten belongs to a family of closely related proline-rich and glutamine-rich proteins called gliadins. When genetically predisposed individuals who express HLA-DQ2 or DQ8 are exposed to certain gliadin epitopes, these epitopes are presented on the surface of antigen presenting cells (APC) in the lamina propria. These, in turn stimulate proliferation of gliadin-specific CD4 T cells in the mucosa. A 33-mer peptide of α2-gliadin, in particular, which is extremely resistant to gastrointestinal digestion because of its rich proline content, is the most powerful immunodominantgliadin peptide. In CD patients, undigested gliadin fragments present in the intestinal lumen can be transported and released intact in the mucosa thereby triggering an immune response and perpetuating intestinal inflammation (57).

DQ2 and DQ8 molecules can only bind gliadin peptides if they have been enzymatically modified by tissue transglutaminase (TG2). This pleiotropic enzyme, which is present in many organs including the small intestine, catalyzes a deamination of certain glutamine residues, the most abundant amino acid in gluten, by converting them into glutamate residues. When deamidated, most of the resultant negatively charged gluten peptides bind more strongly to HLA-DQ2 (or HLA-DQ8), which leads to a more rigorous gluten-specific CD4⁺ Th1 T Cell activation (58).

Although DQ2- and DQ8-restricted T cells can recognize the same gliadin peptides in exactly the same registers (for instance peptides that share the core sequence QQPQQPFPQ), these peptides have been deamidated at different positions: deamidation at position P4 or P6 is mandatory for recognition by DQ2-restricted T cells, whereas deamidation at position P1 and/or P9 is critical for DQ8-restricted recognition. In addition, most of the characterized DQ2-restricted gliadin T Cell epitopes have proline residues at P1, whereas DQ8 is unlikely to tolerate a proline at P1 and so selects other sequences that are more likely to be sensitive to proteases, in particular, aminopeptidases (59).

Altogether, these data are significant for clinical practice because HLA-DQ2 and DQ8 are such strong disease risk factors that their absence has a negative predictive value for CD that is close to 100%. In addition, this knowledge will allow the design of new therapeutic approaches (60).

Ankylosing spondylitis (AS)

AD association with class I HLA alleles is rare, except in (AS), considered an autoinflammatory disease rather than an AD. HLA-B*27 has been observed in 96% of patients suffering from AS. It is clear that not all of the B*27 alleles are associated with the pathology. This is the main reason why the conformational differences in the α-chains have been analyzed. Lys at position 70 on the α-chain is a common residue of the B*27 allele group. Yet, specific combinations of polymorphic residues correspond to His 9, Glu 45, Cys 67, and Ala 71 and all are grouped to form pocket P2 of the molecule. The Glu 45 and Cys 67 are located in the deepest part of P2 and receive higher affinity anchor residues of peptides containing Arg. Furthermore, the Lys 70 which is common to all B*27 interacts with Asp 74 but does not seem to be critical in the association with AS in contrast to what is observed when the position has a Tyr 74 belonging to the B*27:01 allele which associates with MS. Although B*27 associations appear to be strictly dependent on the conformation of their residues, this leads us to think that autoantigenic peptides should be an important component in the susceptibility and pathophysiology of AS. So far these autoantigens have not been identified (61,62).

Ancestral 8.1. haplotype

Conserved DNA sequences that act as extended haplotypes or ancestral haplotypes (AHs) are a typical feature of the MHC because of a high LD phenomena observed between loci and alleles throughout the region. It is believed that about 30% of the MHC haplotypes are AH in populations such as Caucasian (63). The AH made by the MHC is identified as having identical allelic variants in the regions that are mapped between HLA-B and HLA-DRB1. Some of these AHs are accepted as susceptibility markers for ADs (64). The existence of these AHs has allowed alleles such as HLA-DRB1*03:01 and *04:01 to be established (65,66).

The association of AHs with ADs has been studied more in the Caucasian population, and it has been established that the 8.1 AH is made up of HLA-A*01,-C*07,-B*08 in the class I region and DRB1*03:01-DRB3*01:01-DQA1*05:011-DQB1*02:01-DPA1*01-DPB1*03:01-TAP1*01:01 TAP2*02:01 in the class II region including genes composed of C2-C4A-TNF2 in the class III region. This haplotype is associated with SLE, SS, and T1D. Functionally, it can be seen that HLA class II alleles that are part of this AH are the same as those susceptibility alleles discussed for each aforementioned AD. Furthermore, these alleles that constitute the extended haplotype possess well defined immunological characteristics (Table 4) that can be associated with the pathophysiology of ADs (64).

Table 4

Ancestral haplotype 8.1 immunological characteristics.

Another AH associated with ADs is the AH 7.2, which consists of the HLA-A*03:01-C*07-B*07:02 in class I and DRB1*15:01-DRB5*01:01-DQA1*01:02-DRB6*02:01-DQB1*06:02-DPA1*01-DPB1*04:01 for class II and includes the TNF1 gene in the class III region. This AH is associated with susceptibility to SLE and MS although its importance lies in the association with infectious diseases such as leprosy and tuberculosis, and it also behaves as protective for T1D (67). Although their molecular function is not clear, this AH seems to behave like a slow stimulator of the innate and acquired immune response since there is a diminished synthesis of complement factors C4A and C4B. In addition, the synthesis of cytokines and chemotactic factors is less effective which may partially explain the susceptibility to infectious diseases.

Many studies have been done to establish the role of these AH. Therefore, after obtaining the complete sequence draft for the human genome, eight well characterized AHs for the MHC were reported as part of the human MHC Haplotype Project (Table 5). Further characterization of these AH in different populations and deciphering of their different functions (68) including the gene mapping in the class III region is crucial for a better understanding of the association between MHC and ADs.

Table 5

Different HLA-homozygous typing haplotypes provided by The MHC Haplotype Project.

Shared HLA alleles in ADs

Through a meta-analysis, the genetic commonalities in ADs were analyzed by examining the contributions from HLA-II alleles which confer associated risk or protection on six ADs: RA, SLE, autoimmune hepatitis (AIH), MS, SS, and T1D in the Latin American (LA) population. A total of 3,727 cases and 8,465 controls were analyzed and different types of association between alleles and ADs were found (Table 6). These included three risk alleles for two or more ADs, four opposite associations (the same allele is a risk factor for one AD but a protective factor for another AD), thirteen risk alleles for a particular AD, and eight protective alleles that are disease-specific (8). The associations were grouped in the network in Figure 3.

Table 6

Associations between HLA class II and six ADs: SLE, RA, T1D, AIH, SS, and MS.

Figure 3

The complex interplay of HLA in six autoimmune diseases in Latin Americans.

Some HLA class II alleles for ADs in LA are similar to those reported for other population groups regardless of latitudinal gradient and admixture. For instance, DRB1*03:01, DRB1*04:05, DRB1*04:01, and DQB1*02:01 risk alleles for T1D in LA also confer susceptibility in Caucasians and Asians (69). DRB1*03:01 allele, which has been described as a risk factor for SS in the Colombian population, was also associated with the disease at the global level (44). However, there are other genes that influence the development of ADs in a particular population which are not replicated in another one (i.e., PADI4 and SLC22A4 genes) (70).

Two alleles were found to influence the risk of developing three different diseases. The DRB1*03:01 allele was found to be a risk for SLE, SS, and T1D while DRB1*04:05 allele was associated with AIH, T1D, and RA. In addition to sharing HLA alleles, these ADs share other characteristics which reinforce the common origin of ADs theory (Table 7). At the genetic level, AD association with non-HLA genes has been observed. For instance, PTPN22 1858T/C (71) and TNF-α -308G/A (72–74) are associated with SLE, SS, and T1D. Likewise, the CTLA4 gene has been reported to be a risk factor for AIH, T1D, and RA (14,75,76). Another consideration concerning genetic findings is the familial aggregation. Relatives of patients with ADs have a higher risk than general population of developing the same or other ADs (77). At the clinical level, shared autoantibodies in ADs have also been described. Antinuclear antibodies (ANAs) are present in multiple ADs such as SLE, SS, RA, T1D, AIH, and MS (8).

Table 7

Relationship between genetic and clinical features with HLA-ADs associations.

Regarding opposite associations, DQB1*06:02 and DRB1*15 alleles were found to be risk factors for MS but protective factors for T1D. These results are similar to those from other studies reporting that other MHC genes such as CDSN and HLA-DMB (rs3130981-A and rs151719-G respectively) are risk factors for MS but protective ones for T1D. However, there is also evidence of the inverse relationship. For instance, TAP2 (rs10484565-T), VARS2 (rs1264303-G), NOTCH4 (rs2071286-A), BTNL2 (rs2076530-G), and TRIM40 (rs757262-T) were found to be risk factors for T1D but protective factors for MS (78). Despite the presence of these genetically opposite associations, it is important to mention that clinical evidence supporting the coexistence of MS and T1D has been reported (79). Thus, these pleiotropic effects may be explained by the combined action of different alleles of several genes and environmental factors that change the biological context of the SNPs in different individuals and populations (Table 7).

In summary, the results of this meta-analysis validate the common origin of the AD paradigm. The finding of significant risk and protective alleles in LA and the fact that they are shared with other populations around the world highlights the primary role of some HLA regions in genetic susceptibility to ADs regardless of latitudinal gradient and ethnicity.