A study of Italian pediatric celiac disease patients confirms that the primary HLA association is to the DQ(α1∗0501, β1∗0201) heterodimer (original) (raw)
Tissue Antigens, 1992
Abstract: This study characterizes by serological and molecular methods the HLA class I and class II alleles in a group of celiac disease children, their parents and a control group of Sardinian descent. We found the DR3-DQw2 haplotype in all patients which was, in almost all cases (84%), associated with the HLA-A30, B18, DR3, DRw52, DQw2 extended haplotype named “Sardinian haplotype” because of its frequency (12–15%) in this Caucasian population. This is the first time that this DQw2-linked haplotype has been reported with such a high frequency in CD. However, no different distribution of “Sardinian haplotype” was found comparing CD patients with 91 haplotyped DQw2-positive controls. This finding indicates that the DQw2 antigen in Sardinians is almost always associated with the A30, B18, DR3, DRw52, DQw2 extended haplotype. The DQA1 and DQB1 second exon sequence analysis of the B18,DR3 and B8,DR3 haplotypes showed the DQA1*0501 and DQB1*0201 alleles which shared the already published sequences. DPB1 subtyping showed the DPB1*0301 allele more frequently (p < 0.005) in CD patients but this difference was no longer significant when patients and controls, both heterozygous for the DR3-DQw2 haplotype, were compared. We suggest that the divergent HLA extended haplotypes and DP allele associated with CD, described in different Caucasian populations, can be explained by the particular DQw2 linkage disequilibrium in each population.
Susceptibility to develop celiac disease is primarily associated with HLA-DQ alleles
Human Immunology, 1990
We have recently reported that the susceptibility to develop celiac disease (CD) seems to be primarily associated to a particular combination of an HLA-DQA1 (DQAI*0501) and an HLA-DQB I (DQB 1 "0201) allele; i.e., a particular DQ ~//3 heterodimer. To investigate whether certain DP alleles might also contribute to the genetic susceptibility, DPAI and DPB1 genes of 94 CD patients and 132 healthy controls were examined by probing in vitro amplified DNA with sequence-specific oligonucleotide probes corresponding to all hitherto known DPA 1 and DPB 1 alleles. The frequencies of the DPAI*0201 and of the DPBI*OIO1 alleles were increased in CD patients compared to healthy controls (0.31 versus 0.14 and 0.25 versus 0.08, respectively). However, these DP alleles were in linkage disequilibrium with CD-associated DQ alleles in the normal population, and the difference in frequency of these DP alleles was no longer significant when CD patients and healthy controls carrying the CD-associated DQAI*0501 and DQB 1"0201 alleles were compared. DQB 1"0201 homozygous individuals were overrepresented among DQBl*O2Ol-positive patients compared to controls. When DQBI*0201 heterozygous patients and controls were compared, nearly identical frequencies of the DPAI*0201 and the DPB I *O I O1 alleles were found. Thus, the observed increase of the DPA I *0201 and DPB I *O l O l alleles among CD patients seems mainly to be caused by linkage disequilibrium to the CDassociated DQ alleles.
Tissue Antigens, 2003
Although HLA-DQ genes are the major celiac disease (CD) susceptibility genes, results from Finnish families suggest that not all DQ2-encoding haplotypes confer equal susceptibility to CD, implying the effect of other gene(s) in the HLA region. The aim of the present work was to extend and confirm the aforementioned results in a southern European population (Italian) and to better localize the additional risk factor/s. The association of nine loci spanning the HLA region from DR to HFE, 4.5-Mb telomeric of HLA-A, was tested. The analysis was performed by comparing marker frequencies in DR3-DQ2 haplotypes transmitted and non-transmitted to the affected offspring in 156 Italian CD families selected for having at least one DR3-positive parent. The same analysis was performed independently in 101 Finnish CD families selected with the same criteria. Three alleles, MICA-A5.1, MICB-CA24 and MIB-350, all characteristic of the B8-DR3 extended haplotype, showed a significantly increased frequency in DR3 transmitted haplotypes in the Italian families. DR3 haplotypes carrying the combination of these alleles conferred an approximate fourfold increased CD risk. B8-DR3 transmitted haplotypes were significantly more conserved telomerically down to the MIC-Class I region. Similar results were seen in the Finnish families. The major conclusion that holds true in both populations is that, while DQ2 is an absolute requirement for the development of CD, the presence of an additional genetic factor within the MIC-Class I region confers an approximate 4-fold increased risk of the disease.
HLA-DQ and risk gradient for celiac disease
Human Immunology, 2009
Celiac disease (CD) is a rare example of multifactorial disorder in which a genetic test is of great clinical relevance, as the disease rarely develops in the absence of specific HLA alleles. We typed DR-DQ genes in 437 Italian children with celiac disease, 834 first-degree relatives, and 551 controls. Of patients, 91% carried DQ2 and/or DQ8 heterodimers, 6% only had 2 chain, 2% was ␣5 positive, and four were DQ2/DQ8/2/␣5 negative. Only the presence of ␣5 resulted negatively associated to disease (p ϭ 2 ϫ 10 Ϫ4 ), whereas we confirmed the effect of the  half of DQ2 dimer on CD predisposition (p ϭ 4 ϫ 10 Ϫ12 ). Considering 1:100 disease prevalence, we obtained a risk gradient ranging from 1:7 for DQ2 and DQ8 individuals down to 1:2518 for subjects lacking all predisposing factors. The DQB1*02 and DQB1*0302 concurrence (p ϭ 9 ϫ 10 Ϫ4 ), besides the DQB1*02/*02 homozygosity, had an additional role in disease genetic determination. The CD prevalence rose to 17.6% in sisters, 10.8% in brothers, and 3.4% in parents. In the three groups, the subjects carrying high-risk HLA molecules were 57%, 71%, and 58%; among them, 29%, 15%, and 6% respectively had CD. Those siblings and parents with no susceptible factors were not affected. These findings indicate the impact of the HLA test for CD in clinical practice.
Human Immunology, 1999
Celiac disease is a permanent gluten intolerance strongly associated with HLA class II antigens. The over presentation of particular HLA alleles and haplotypes has been described in several populations. Different lines of evidence obtained during the last years suggest that a particular HLA-DQ heterodimer, encoded by the DQA1*0501 and DQB1*0201 genes in cis or trans conformation, confers the primary disease susceptibility. We report the HLA class II allelic distribution and DQA1/ DQB1 genotypes in 62 Chilean celiac patients compared with 124 control subjects in Santiago, Chile. We found a pronounced increase of the "susceptible" alleles :DQA1*0501 (0.480 vs 0.169, P c Ͻ 0.0005), DQB1*0302 (0.430 vs 0.242, P c ϭ 0.002) and DQB1*0201 (0.250 vs 0.125, P c ϭ 0.037) in celiac patients in comparison with control children. As for "protective" alleles, we detected a high frequency of DQA1*0101 (0.310 vs 0.160, P c ϭ 0.01), DQA1*0201 (0.105 vs 0.010, P c Ͻ 0.0075) and DQB1*0301 (0.250 vs 0.100, P c ϭ 0.010) in controls. In relation to risk haplotypes, the main combination observed was the conformation DQ8 (DQB1*0302/DQA1*0301) over DQ2 (DQB1*0201/DQA1*0501). In conclusion, results show that celiac disease in Chilean patients is primarily associated with DQ8 conformation. This is concordant with the high frequency of DR4 alleles (in linkage disequilibrium with DQB1*0302) detected in Amerind groups in Chile, where DQB1*0302 is more frequent than DQB1*0201.
Genotype DQ2.5/DQ2.2 (ββ2/ββ2) and High Celiac Disease Risk Development
Celiac Disease - From the Bench to the Clinic, 2019
Celiac disease (CD) is a genetically determined immune-mediated disorder in which gluten immunogenic peptides are presented to CD4 T cells by HLA-DQ2.5, DQ8, DQ2.2, and their combinations. CD is considered one of the most wellcharacterized autoimmune diseases, having a described environmental factor, a well-established pathogenesis, associated genetic factors, and a well-established laboratory diagnosis, although it is still considered a difficult-to-classify disease. In the last decades, advances in laboratory diagnosis with the emergence of molecular biology techniques have allowed a specific characterization of the CD-associated genotypes and, although clinically the disease management was not modified by this factor, the follow-up of patients at risk of CD development has greatly benefited from the possibility of specifically finding the inherited genotype, and whether it represents a greater or lesser risk for developing the disease. In some populations, it is already possible to calculate the exact risk associated to the inherited genome by each individual, but the genotypes available in several countries sometimes disregard the relevance of searching beyond the genotypes DQ2.5/ DQ2.5, DQ2.5/DQ8, and DQ2.5/DQ2.2, which also present a high risk for developing the disease.
Human Immunology, 1997
The DQAl"0501 and DQB1*0201 alleles (hereafter DQ2) confer genetic susceptibility to celiac disease (CD). Some studies have indicated that the DPBl, DMB, and TAP loci, that are located close to the DQ genes, could also together with DQ or independently confer genetic susceptibility to CD. Some others have claimed that these associations result merely from linkage disequilibrium, a hallmark of the MHC, that often makes the precise mapping of susceptibility genes difficult.
Human Immunology, 2003
Genetic susceptibility to celiac disease is strongly associated with HLA-DQA1*05-DQB1*02 (DQ2) and HLA-DQA1*03-DQB1*0302 (DQ8). Study of the HLA associations in patients not carrying these heterodimers has been limited by the rarity of such patients. This European collaboration has provided a unique opportunity to study a large series of such patients. From 1008 European coeliacs, 61 were identified who neither carry the DQ2 nor DQ8 heterodimers. Fifty seven of these encoded half of the DQ2 heterodimer. The remaining 4 patients had a variety of clinical presentations. Three of them carried the DQA1*01-DQB*05 haplotype as did 20/61 of those carrying neither DQ2 nor DQ8. This may implicate a role of the DQA1*01-DQB*05 haplotype. None of these four patients carried the DQB1*06 allele that has previously been reported in this sub-group of patients. Of the 16 DQ2 heterodimer negative patients without DRB1*04 or DRB1*07 haplotypes, it was inferred that none encoded the previously implicated DRB4 gene as none had a DRB1*09 haplotype. These results underline the primary importance of HLA-DQ alleles in susceptibility to celiac disease, and the extreme rarity of celiac patients carrying neither the DQ2 or DQ8 heterodimers nor one half of the DQ2 heterodimer alone.
Journal of Biomedical Science, 2012
Celiac disease (CD) is a multifactorial disorder with an estimated prevalence in Europe and USA of 1:100 and a female:male ratio of approximately 2:1. The disorder has a multifactorial etiology in which the triggering environmental factor, the gluten, and the main genetic factors, Human Leukocyte Antigen (HLA)-DQA1 and HLA-DQB1 loci, are well known. About 90-95% of CD patients carry DQ2.5 heterodimers, encoded by DQA1*05 and DQB1*02 alleles both in cis or in trans configuration, and DQ8 molecules, encoded by DQB1*03:02 generally in combination with DQA1*03 variant. Less frequently, CD occurs in individuals positive for the DQ2.x heterodimers (DQA16 ¼*05 and DQB1*02) and very rarely in patients negative for these DQ predisposing markers. HLA molecular typing for Celiac disease is, therefore, a genetic test with a negative predictive value. Nevertheless, it is an important tool able to discriminate individuals genetically susceptible to CD, especially in at-risk groups such as first-degree relatives (parents, siblings and offspring) of patients and in presence of autoimmune conditions (type 1 diabetes, thyroiditis, multiple sclerosis) or specific genetic disorders (Down, Turner or Williams syndromes).