Meta-Analysis and Systematic Review of HLA DQ2/DQ8 in Adults with Celiac Disease.

Although people with human leukocyte antigens (HLA) DQ2 and/or DQ8 are more likely to develop celiac disease (CD), the condition cannot be fully explained by this genetic predisposition alone. Multiple, as yet unidentified, factors contribute to the genesis of CD, including genetics, the environment, and the immune system. In order to provide insight into a prospective possibility and an expanded screening technique, we aim to undertake a comprehensive and meta-analytical study of the assessment and distribution of HLA class II (HLA-DQ2/DQ8) in adult CD patients. A systematic review was conducted using an electronic search of databases (PubMed, Google Scholar, Embase, and Direct Science) from January 2004 to February 2022. DQ2/DQ2 homozygotes have the highest risk of developing CD. DQ2/DQ8 typing is an effective test to exclude CD from the differential diagnosis of a patient with CD symptoms. Although other non-HLA genes have been associated with CD, they are rarely considered at diagnosis because they account for only a small proportion of the heritability of CD. This finding, together with the information gathered previously, may be useful in considering widely available and economically feasible screening options for celiac disease in young people.

The Role of CD1 Gene Polymorphism in the Genetic Susceptibility to Spondyloarthropathies in the Moroccan Population and the Possible Cross-Link with Celiac Disease.

Spondyloarthropathies (SpA) are a group of chronic inflammatory disorders usually affecting the axial spine and asymmetrical peripheral joints. Strong evidence links genetic and environmental factors to SpA pathogenesis. The HLA-B27 is the most important genetic factor associated with SpA. Nevertheless, the involvement of other HLA and non-HLA loci has been also reported. Some patients with SpA may also manifest features of celiac disease (CeD), thus suggesting a genetic overlap across these autoimmune diseases. Recently, CD1 glycoproteins, a class of molecules able to bind and present non peptidic antigens to T cells, aroused interest for their contribution to the pathogenesis of CeD. Therefore, to evaluate whether functional polymorphisms of CD1A and E genes also influence susceptibility to SpA, we analyzed 86 patients from Morocco affected by SpA and 51 healthy controls, using direct sequencing analysis. An increase of CD1E*01/01 homozygous genotype (p = 0.046) was found in SpA, compared with controls. CD1E*01/01 genotype was associated particularly to patients with sacroiliac joints/spine/peripheral joints pain (p = 0.0068), while a decrease of CD1E*01/02 genotype was evidenced compared to controls (p = 0.0065). Results from haplotypes analysis demonstrated that CD1A*02-E*02 decreased the risk of SpA, while CD1A*02-E*01 increased risk to develop disease. Our data indicate a relationship between CD1 genes and susceptibility to SpA in the Moroccan population and suggest the existence of shared genetic risk loci across SpA and CeD that might be useful to explain common pathogenetic features and define novel therapeutic strategies.

Pathophysiology and immunogenetics of celiac disease.

Celiac disease (CD) is a chronic inflammatory enteropathy caused by gluten (protein from wheat, rye and, barley) in genetically predisposed individuals carrying the HLA-DQ2/HLA-DQ8 genotype. This pathology has a multifactorial etiology in which HLA genes, the microbiome, gluten and, other environmental factors are involved in the development of the disease. Its pathogenesis involves both innate and adaptive immunity as well as upregulation of IL-15. The objective of this review is to examine the results of current studies on genetic and environmental variables to better understand the pathogenesis of this enteropathy. The complex etiology of celiac disease makes our understanding of the pathogenesis of the disease incomplete, and a better knowledge of the many genetic and environmental components would help us better understand the pathophysiology of celiac disease.

CD1 gene polymorphism and susceptibility to celiac disease: Association of CD1E*02/02 in Moroccans.

CD1 glycoproteins are a class of antigen presenting molecules that bind and present non-peptidic antigens (lipids and glycolipids) for immune recognition. CD1 polymorphisms, although limited, could have a critical role in antimicrobial, anticancer, and autoimmune responses and disease susceptibility. Ethnic differences and interactions between genetic and environmental factors make it attractive the study of these molecules in autoimmune inflammatory disorders, such as celiac disease (CD), in which a strong genetic predisposition (HLA-DQ2/DQ8) and pressure of environmental factors have a central role. CD1A, CD1D and CD1E polymorphisms in exon 2 were assessed in patients from Morocco affected by CD, using direct sequencing analysis, in order to investigate possible associations with the disease in a North African population. Differences in genotype and haplotype distribution of CD1E between celiac patients and controls were found: in particular, an increase of CD1E*02/02 homozygous (OR 2.93, CI 1.30-6.59, p = 0.007) and CD1A*02-E*02 estimated haplotypes in CD, compared with controls. Frequencies of CD1A and CD1D genotypes/alleles were not different between groups. CD1E*02/02, previously suggested as a potential immune protective genotype to malaria susceptibility, could be an additional gene involved in celiac risk in this geographic area.

HLA Typing and Celiac Disease in Moroccans.

Genetic and environmental factors are responsible for differences in the prevalence of some diseases across countries. Human leukocyte antigen (HLA) allele frequencies in North African populations show some differences in their distribution compared to Europeans, Mediterraneans, and sub-Saharans, and some specific alleles and haplotypes could be clinically relevant. Celiac disease (CD) has been fast increasing in prevalence in North Africa; but few immunogenetic data are available for this area, in which a high prevalence of the disease has been described. In this report, we assess and discuss results of HLA class II (HLA-DQA1/DQB1/DRB1) typing in Moroccan patients with CD and compare them with a control population from Morocco-genetically well characterized-and with other North African, Mediterranean, and European populations. The classical HLA-DQ associations were confirmed in Moroccans with CD. The high frequency of DQ2.5 homozygosity (45.2%) found in Moroccans with CD was noteworthy as compared with other populations (23%-32%). The genetic risk gradient for CD, identified by previous studies, has been confirmed in Moroccans with some differences, mainly concerning DQ8 genotypes. This study provides the immunogenetic framework of CD in Moroccans and confirms the need to learn more about associations with additional HLA and non-HLA genetic factors.

CD1A, D and E gene polymorphisms in a North African population from Morocco.

CD1 molecules are specialized in capturing and presenting lipids and glycolipids to distinct subsets of T and NKT cells. Glycolipid presentation could play a significant role in the immune response against microbial infections. There are five closely linked CD1 genes in humans, named CD1A, B, C, D, and E, which all show a limited polymorphism. In this study, exon 2 polymorphisms of CD1A, CD1D and CD1E were investigated and allele, genotype and haplotype frequencies of these loci were reported in a Moroccan population. A comparison with allele, genotype and haplotype frequencies observed in other geographic areas was also performed. Results confirmed the presence of ethnic differences in CD1 polymorphism, mainly in CD1D (in this population two additional CD1D variant alleles, CD1D(∗)03 and CD1D(∗)04, were described) and E genes. These data could be useful to evaluate a possible pathogenetic role of CD1 in diseases. Increasing the knowledge in this field may offer possibilities for the development of new immunotherapeutic approaches.

MICA polymorphism in a population from north Morocco, Metalsa Berbers, using sequence-based typing.

The MICA gene encodes a family of nonclassical major histocompatibility complex class I molecules. Data on MICA polymorphism in different populations are still limited. In the present study, MICA allele frequencies (af) were assessed in 82 unrelated healthy individuals from a Moroccan Berber population named Metalsa (ME) by means of sequence-based typing of exons 2, 3, 4, and 5. In consideration of the linkage disequilibrium existing between MICA and human leukocyte antigen (HLA) class I alleles, MICA/HLA-B, MICA/HLA-Cw, and MICA/HLA-A haplotype frequencies (hf) were estimated. A wide allelic distribution including 16 different MICA alleles was found in ME. The most common MICA alleles were MICA*00801 (af = 0.268), *004 (0.232), *00902 (0.140), *00901 (0.085), and *00901 (0.073). The most common MICA/HLA-B haplotypes were MICA*004-B*4403 and MICA*009-B*50 (hf = 0.113 for both these haplotypes). Some known MICA and HLA-B associations were confirmed in this population. Noteworthy was the high frequency of MICA*009 (af = 0.226); the high frequency of B*50 found in ME (af = 0.114) permitted us to evidence the associations of MICA*00902 with B*5001 (hf = 0.068) or *5002 (hf = 0.045), whereas MICA*00901 was mainly associated with B*5101 (hf = 0.038), which corresponds to the previously described association MICA*009/A6-HLA-B*51. This study extends the previous knowledge on MICA polymorphism to a North African white population and may have implications for disease associations and transplantation.

MICA∗078: A novel allele identified in a Moroccan individual affected by celiac disease.

A novel MICA allele, MICA(∗)078, has been identified during HLA/MICA high resolution typing of Moroccan patients with celiac disease. MICA(∗)078 shows an uncommon variation at a highly conserved nucleotide position (nt 493, G → A), resulting in one amino acid change at codon 142 (V → I) of MICA gene (compared to MICA(∗)002:01), located in the α2-domain, in which V142 is the common residue.

Sequence-Based analysis of the HLA-DRB1 polymorphism in Metalsa Berber and Chaouya Arabic-speaking groups from Morocco.

To examine the genetic diversity in Morocco, the polymorphism at the HLA-DRB1 locus was investigated in two populations: the Metalsa group consisting of Berbers from north Morocco (who speak the Tarifit language and live in the Nador area), and the Chaouya group who are Arabic-speaking people from west Morocco (Atlantic coast) living in the Settat area. The DRB1 alleles of 197 healthy unrelated individuals were identified by direct DNA sequencing of exon 2 using fluorescently-labeled primers. A total of 28 and 29 alleles at DRB1 locus were identified in the Metalsa and Chaouya groups, respectively. The most frequent alleles in the Metalsa group are DRB1*03011 (20.2%), DRB1*0701 (12.12%), and DRB1*1302 (11.11%). In the Chaouya group, DRB1*0701 (16.33%), DRB1*15011 (12.76%), and DRB1*03011 (11.73%) are most common. Each population exhibits some specific variants and some uncommon alleles. The frequency of the DRB1*03011 allele differs significantly between the two populations (p = 0.0311). The DRB1 frequency distributions in the two groups suggest the effects of balancing selection. The interpopulation analysis highlighted a strong relatedness, based on genetic distances, between the two Moroccan groups and the other north Africans (the Moroccans from El Jadida area, Moroccan Souss Berbers, Algerians, and Tunisians), and to a lesser extent with the Iberians, French, and Ethiopians.