HLA-DR and -DQ genotypes of celiac disease patients serologically typed to be non-DR3 or non-DR5/7

doi:10.1016/0198-8859(92)90104-U

Human Immunology

Volume 35, Issue 3, November 1992, Pages 188-192

https://doi.org/10.1016/0198-8859(92)90104-U Get rights and content

Abstract

The susceptibility to develop celiac disease (CD) seems to be primarily associated to a particular HLA-DQ α/ß heterodimer encoded by the DQA1∗0501 and DOB1∗0201 alleles, in cis position on the DR3-DQ2 haplotype or in trans position by DR5-DQ7/DR7-DQ2 heterozygotes. However, exceptional patients exist who are neither DR3 nor DR5/DR7, particularly among Southern European populations. We therefore examined the DRB1, DQA1, and DQB1 alleles of 13 Spanish CD patients who were serologically typed to be neither DR3 nor DR5/DR7. Five patients were found to carry the DQA1∗0501 and DQB1∗0201 alleles either in cis or in trans position, three of them had previously been serologically mistyped. However, two of these patients carried DQA1∗0501 and DQB1∗0201 on haplotypes other than DR3 or DR5 in combination with DR7. One of the latter patients carried an unusual DR4-DQ2 haplotype, while another had an unusual DR8-DQ2 haplotype. Four of the remaining eight patients carried DR4-DQ8 haplotypes. Taken together, our findings provide further evidence that the DQ α/ß heterodimer encoded by the DQA1∗0501 and the DQB1∗0201 alleles confers the primary HLA-associated susceptibility to develop CD. However, our studies also corroborate that a second (and “weaker”) HLA-associated CD susceptibility gene may be present on some DR4-carrying haplotypes.

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The HLA complex and coeliac disease
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The Human Leukocyte Antigen (HLA) has a crucial role in the development and pathogenesis of coeliac disease (CD). The genes HLA-DQA1 and HLA-DQB1, both lying in this region and encoding the HLA-DQ heterodimer, are the main genetic predisposing factors to CD. Approximately 90% of CD patients carry the heterodimer HLA-DQ2.5, leaving only a small proportion of patients with lower risk heterodimers (HLA-DQ8, HLA-DQ2.2 or HLA-DQ7.5). These HLA-DQ molecules act as receptors present in the surface of antigen presenting cells and show high affinity for deamidated gluten peptides, which bind and present to CD4⁺ T cells. This triggers the immunological reaction that evolves into CD. Since specific HLA genetics is present in almost the totality of CD patients, HLA typing has a very high negative predictive value, and it can be used to support diagnosis in specific scenarios. HLA risk has been associated to different CD-related features, such as age at onset, clinical outcomes, antibody levels and grade of histological lesion; but further research is needed. HLA-DQ genotypes have been also suggested to modulate the composition of the gut microbiota.
Celiac disease associated SNP rs17810546 is located in a gene silencing region
2020, Gene
GWAS studies have identified variant rs 17810546 in a non-coding region on chromosome 3 as a risk factor for several auto-immune diseases, including Celiac Disease. In silico analysis reveals that this variant is located in a transcription regulatory site. By means of reporter constructs we show that this region can override the expression rate of a gene as determined by its native promoter and that this modulation is influenced by the genetic composition of the haplotype which rs17810546 forms with a nearby other variant, rs761008. Secondly, we present data that this genetically imprinted modulation could be involved in Celiac Disease through the IL12A gene which is located 40 Kb downstream of this regulatory region. Based on our findings it is most likely that the IL12A gene does so as part of the cytokine IL-35.
Profiling Celiac Disease-Related Transcriptional Changes
2018, International Review of Cell and Molecular Biology
Celiac disease (CD) is a chronic, autoimmune disease of the small intestine with a strong but complex genetic component. The disease is triggered by the consumption of dietary gluten through the presentation of immunogenic gliadin peptides to T helper lymphocytes by HLA-DQ2 and DQ8 heterodimers, which are the major contributors to the genetic risk. Recent large-scale genotyping efforts have identified a large number of additional association signals, but the functional role of the underlying genes in the pathogenesis of the disease is still unclear. In the last years, several whole transcriptome analyses have been performed in different tissues, including whole duodenal biopsies, isolated gut epithelial cells or peripheral blood from gluten-consuming CD patients at diagnosis, treated patients on gluten-free diet and nonceliac controls, sometimes after in vitro challenge with gluten-derived gliadin peptides. Although the results from the different experiments are difficult to reconcile, the main findings point to an exacerbation of the immune response, together with the dysregulation of signaling and cell cycle pathways. The effect of associated SNPs on the expression of candidate genes and the role of the noncoding genome are the new territories that the CD research community has only begun to explore.
Celiac Disease, the Microbiome, and Probiotics
2017, The Microbiota in Gastrointestinal Pathophysiology: Implications for Human Health, Prebiotics, Probiotics, and Dysbiosis
Celiac disease (CD) is a common chronic autoimmune enteropathy caused by gluten intake. To date, the only available therapy is strict adherence to a gluten-free diet (GFD). CD is an unusual autoimmune disease in that the trigger and genes are known, although much of the mechanisms of disease pathogenesis are still being investigated. It has been hypothesized that the intestinal microbiome is somehow involved in CD, either as a decrease in “beneficial” bacteria or an increase in “harmful” bacteria. Many studies have described a dysbiosis in CD patients, although the cause and effect of this dysbiosis is yet to be determined. Therapeutic trials aimed at altering this dysbiosis have looked to probiotics as a possible treatment for CD, although data are limited and at this point cannot be recommended.
Human leukocyte antigen (HLA) DQ2/DQ8 prevalence in recurrent pregnancy loss women
2016, Autoimmunity Reviews
Citation Excerpt :
It is now accepted that the alleles encoding HLA-DQ2, specifically, HLA-DQ2.5 (DQA1*05 and DQB1*02) are expressed in around 90% of CD patients. Most of the remaining patients (without HLA-DQ2.5) carry the alleles encoding HLA-DQ8 molecules (DQA1*03 and DQB1*03:02 alleles) [50-52]. In almost all CD patients who carry neither HLA-DQ2.5 nor HLA-DQ8, one of the two alleles encoding HLA-DQ2.5 is present: most commonly DQB1*02 (HLA-DQ2.2) and in a minority of cases, DQA1*05 (HLADQ7.5) [51].
Over the last few years, medical scholars have reported the significant association between recurrent pregnancy loss (RPL) and celiac disease (CD). Various pathogenic mechanisms underlying the pregnancy failure in CD have been suggested: among them the ability of anti-transglutaminase antibodies to impair the trophoblast invasiveness and endometrial endothelial cells differentiation and disrupt early placentation. CD shows a complex non-Mendelian pattern of inheritance, involving major histocompatibility complex (MHC) genes. The strongest effects are mapped to the classical human leukocyte antigen (HLA)-DQA1 and HLA-DQB1 genes. Specifically, the common haplotypes DQ2.5, DQ2.2, and DQ8 have been shown to increase CD risk by six-fold on average. MHC region contains genes with immunological functions and is responsible for the strongest association signals observed in most immune-mediated diseases. The aim of our study was to investigate the prevalence of the HLA-DQ2/DQ8 haplotypes in RPL, outside of CD.
The study population included women with history of RPL (≥ 3 spontaneous pregnancy losses) and women with at least two previous uncomplicated term pregnancies (control group, CTR). All women gave their informed consent to use their data for research purposes.
97 RPL women and 55 CTR were considered in the study. Mean age of the RPL sample was 37.7 (standard deviation, SD, 3.0; min 27; max 39). Mean age of the control group was 35.6 (SD 3.0; min 26 years; m, max 38). A significantly increased prevalence of HLA-DQ2/DQ8 haplotype positivity was found in RPL population compared to control women (52.6% vs 23.6%; p < 0.01).
Our observations show for the first time a higher proportion of individuals HLA DQ2/DQ8 positive in women with RPL as compared to controls (and to general population estimates). Further studies are needed to better understand (i) the possible pathogenic mechanism to this observation; (ii) the clinical and therapeutic implications of our observation in order to provide a new approach to RPL couples.
The genetics of celiac disease: A comprehensive review of clinical implications
2015, Journal of Autoimmunity
Citation Excerpt :
This is conditioned to the presence of at least one copy of the HLA-DQA1*05 allele. Most of the remaining patients (without HLA-DQ2.5) carry the DQA1*03 and DQB1*03:02 alleles, which encode the HLA-DQ8 molecule [29]. A gene dosage effect for HLA-DQ8 has been also proposed [30].
Celiac disease (CD) is a complex immune-related disease with a very strong genetic component. Multiple genetic findings over the last decade have added to the already known MHC influence numerous genetic variants associated to CD susceptibility. Currently, it is well-established that 6 MHC and 39 non-MHC loci, including a higher number of independent genetic variants, are associated to disease risk. Moreover, additional regions have been recently implicated in the disease, which would increase the number of involved loci. Together, the firmly described genetic variants account for roughly 31% of CD heritability, being 25% explained by the MHC influence. These new variants represent markers of disease risk and turn the identification of the causal genes and the causal variants inside the associated loci, as well as their precise biological role on the disease, into a major challenge in CD research. Numerous studies have been developed with this aim showing the high impact of risk variants on gene expression. These studies also indicate a central role of CD4⁺ T cells in CD pathogenesis and point to B cells as important players, which is in accordance with the key steps highlighted by the immunological models of pathogenesis. We comprehensively summarize the current knowledge about the genetic architecture of CD, characterized by multiple low-risk variants located within diverse loci which are most likely affecting genes with immune-related functions. These findings are leading to a better understanding of CD pathogenesis and helping in the design of new treatments. The repertoire of potential drug targets for CD has largely broadened last years, bringing us closer to get alternative or complementary treatments to the life-long gluten-free diet, the only effective treatment so far. Epigenetics and microbiota are emerging as potent factors modulating disease risk and putatively affecting disease manifestation, which are also being explored as therapeutic targets.

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Human Immunology

Abstract

References (23)

Susceptibility to develop celiac disease is primarily associated with HLA-DQ alleles

Hum Immunol

A radioimmunoassay typing study of non-DQw2-associated celiac disease

Clin Immunol Immunopathol

The distribution of HLA class II alleles among Norwegian Caucasians

Hum Immunol

HLA-DP typing by DNA amplification and hybridization with allele-specific oligonucleotides

Hum Immunol

Celiac disease

Evidence for a primary association of celiac disease to a particular HLA-DQ α/ß heterodimer

J Exp Med

T lymphocyte recognition of a celiac disease-associated cis- or trans-encoded HLA-DQ α/ß heterodimer

J Immunol

HLA-DR3 and DR7-negative celiac disease

Genetic markers in Australian Caucasian subjects with coeliac disease

Tissue Antigens

HLA-DQß gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus

Nature

Allelic sequence variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility

Cited by (110)

The HLA complex and coeliac disease

Celiac disease associated SNP rs17810546 is located in a gene silencing region

Profiling Celiac Disease-Related Transcriptional Changes

Celiac Disease, the Microbiome, and Probiotics

Human leukocyte antigen (HLA) DQ2/DQ8 prevalence in recurrent pregnancy loss women

The genetics of celiac disease: A comprehensive review of clinical implications