Hla types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the european genetics cluster on celiac disease

doi:10.1016/S0198-8859(03)00027-2

Human Immunology

Volume 64, Issue 4, April 2003, Pages 469-477

https://doi.org/10.1016/S0198-8859(03)00027-2 Get rights and content

Abstract

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.

Introduction

Celiac disease is a strongly heritable disease with concordance between monozygotic twins of at least 75% compared to 11% in dizygotic twins [1]. A significant proportion of the genetic predisposition comes from human leukocyte antigen (HLA) linked genes, estimated to account for up to 40% of the genetic load [2]. Indeed, in European Caucasian populations, more than 90% of celiacs carry HLA-DQA1*05-DQB1*02 encoding the DQ2 heterodimer 3, 4. Usually, the alpha and beta chains of this heterodimer are encoded together on a DRB1*03 (DR3) haplotype. However, they may also be encoded in trans with the DQA1*05 allele usually on DRB1*11, DRB1*12, or DRB1*13 haplotypes, and the DQB1*02 allele usually on a DRB1*07 (DR7) haplotype 5, 6. The DQ8 heterodimer (coded by DQA1*03-DQB1*0302), carried on a DRB1*04 (DR4) haplotype, is commonly encoded for by celiacs who do not carry the DQ2 heterodimer [7]. Only a small number of celiacs carry neither the DQ2 nor DQ8 heterodimers, many of whom have been reported to encode just one chain of the DQ2 heterodimer [8].

For those celiacs without the DQ2 heterodimer, a role for the DRB4 gene, found on almost all DRB1*04 and DRB1*07 haplotypes and encoding the DR53 molecule, has been suggested 9, 10. However, the hypothesis has not been supported in more recent studies 11, 12, 13. The DPB1*0101 allele has been proposed to affect the level of susceptibility attributed to the DR3 haplotype, although this may be due to linkage disequilibrium with other loci [14]. The role of DPB1 has not been studied in DQ2 and DQ8 heterodimer negative patients. In type 1 diabetes, also a disease associated with the DR3-DQ2 and the DR4-DQ8 haplotypes, the degree of susceptibility conferred by the DR4-DQ8 haplotype is determined by the subtypes of DRB1*04, with an additional influence from HLA-B 15, 16. Indeed, HLA class I alleles have also been suggested to have an additional influence on the risk attributable to DR3-DQ2 haplotypes in celiacs, with A*01-B*08-DR3-DQ2 haplotypes more often transmitted to celiacs than other DR3-DQ2 haplotypes from Finland 17, 18.

We have postulated that by examining a large series of celiacs without the known HLA-DQ risk genotypes, we may reveal associations with class I or additional class II HLA loci. Investigations of the HLA associations of celiacs without the DQ2 heterodimer have been limited by the rarity of such patients. The multinational collaboration that forms this European genetics consortium has provided a unique opportunity. Here, we present the largest such study to date, with extensive genotyping of both HLA class II and class I genes.

Section snippets

Subjects

Celiac patients (1008 patients) were recruited from Finland, France, Italy, Norway, Sweden, and the UK. All patients included were unrelated, some were from multiplex families (one patient taken from a family containing two or more celiacs) and some from simplex families (where only one member is known to be affected). The groups contributed patients as follows: Finnish group, 100 celiac patients; French group, 92 celiac patients; Italian group, 302 celiac patients; combined Norwegian and

Results

The numbers of patients without the DQ2 heterodimer are shown in Table 1. The proportion of patients negative for the DQ2 in these nonrandom population samples was higher in the Southern European population (France and Italy) than the Northern European population (Finland, Norway, Sweden, UK) (15.5% vs 9.8%; p = 0.007). This difference reflected the increased proportion of southern European patients without either the DQ2 or DQ8 heterodimers compared with northern Europeans (9.6% vs 3.7%; p =

Discussion

This European collaborative project has allowed HLA associations to be studied among the largest reported series of coeliac patients without the DQ2 or DQ8 heterodimers. The most noteworthy result was that of the 61/1008 patients identified without the DQ2 or DQ8 heterodimer, 57 of them encoded one half of the DQ2 heterodimer. This has confirmed the findings of much smaller series 8, 12, 13, 27, 28, and has in itself important clinical implications. HLA-DQ typing has been proposed as part of a

Acknowledgements

We thank the families who took part in this study. This paper was supported by a grant from the Commission of the European communities, specific RTD programme “Quality of life and management of living resources”: QLKT-1999-00037, “Evaluation of the prevalence of coeliac disease and its genetic components in the European population”. This article does not necessarily reflect its views and in no way anticipates the Commission’s future policy in this area. We acknowledge the Norwegian Foundation

References (37)

L.M. Sollid et al.
HLA susceptibility genes in coeliac diseasegenetic mapping and role in pathogenesis
Gastroenterology
(1993)
M.C. Mazzilli et al.
A study of Italian paediatric coeliac disease patients confirms that the primary HLA association is to the DQ (α1*0501, β1*0201) heterodimer
Hum Immunol
(1992)
A. Spurkland et al.
HLA DR and DQ genotypes of coeliac disease patients serologically typed to be non-DR3 and non-DR5/7
Hum Immunol
(1992)
A. Polvi et al.
HLA-DQ2 negative coeliac disease in Finland and Spain
Hum Immunol
(1998)
A. Polvi et al.
Coeliac patients predominantly inherit HLA-DPB1*0101 positive haplotype from HLA-DQ2 homozygous parent
Hum Immunol
(1997)
A. Meddeb-Garnaoui et al.
Re-evaluation of the relative risk for susceptibility to coeliac disease of HLA-DRB1, -DQA1, -DQB1, and TAP2 alleles in a French population
Hum Immunol
(1995)
M. Fernandez-Arquero et al.
HLA-linked genes acting as additive susceptibility factors in coeliac disease
Hum Immunol
(1995)
I. Djilali-Saiah et al.
Polymorphism of antigen processing (TAP, LMP) and HLA class II genes in coeliac disease
Hum Immunol
(1994)
D.G. Doherty et al.
HLA DQA, DQB, and DRB genotyping by oligonucleotide analysisdistribution of alleles and haplotypes in British Caucasoids
Hum Immunol
(1992)
M. Congia et al.
A gene dosage effect of the DQA1*0501/DQB1*0201 allelic combination influences the clinical heterogeneity of celiac disease
Hum Immunol
(1994)

W.J. Bolsover et al.

A family study confirms that the HLA-DP associations with coeliac disease are the result of an extended HLA-DR3 haplotype

Hum Immunol

(1991)

L. Greco et al.

The first large population based twin study of coeliac disease

Gut

(2002)

S. Bevan et al.

Contribution of the MHC region to the familial risk of coeliac disease

J Med Genet

(1999)

L.M. Sollid et al.

Evidence for a primary association of coeliac disease to a particular HLA-DQ α/β heterodimer

J Exp Med

(1989)

L.M. Sollid

The molecular basis of coeliac disease

Annu Rev Immunol

(2000)

F. Clot et al.

HLA-DR53 molecules are associated with susceptibility to coeliac disease and selectively bind gliadin derived peptides

Immunogenetics

(1999)

F. Bougerra et al.

Synergistic effect of two HLA heterodimers in the susceptibility to coeliac disease in Tunisia

Genet Epidemiol

(1997)

J. Partanen

The HLA-DRB4 gene does not explain genetic susceptibility in HLA-DQ2 negative coeliac disease

Immunogenetics

(2000)

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^☆: K. Karell, A. S. Louka, and S. J. Moodie contributed equally to this study.

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Original contributionHla types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the european genetics cluster on celiac disease☆

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Acknowledgements

Gastroenterology

Hum Immunol

Hum Immunol

Hum Immunol

Hum Immunol

Hum Immunol

Hum Immunol

Hum Immunol

Hum Immunol

Hum Immunol

Hum Immunol

The first large population based twin study of coeliac disease

Gut

Contribution of the MHC region to the familial risk of coeliac disease

J Med Genet

Evidence for a primary association of coeliac disease to a particular HLA-DQ α/β heterodimer

J Exp Med

The molecular basis of coeliac disease

Annu Rev Immunol

HLA-DR53 molecules are associated with susceptibility to coeliac disease and selectively bind gliadin derived peptides

Immunogenetics

Synergistic effect of two HLA heterodimers in the susceptibility to coeliac disease in Tunisia

Genet Epidemiol

The HLA-DRB4 gene does not explain genetic susceptibility in HLA-DQ2 negative coeliac disease

Immunogenetics

Original contribution
Hla types in celiac disease patients not carrying the DQA105-DQB102 (DQ2) heterodimer: results from the european genetics cluster on celiac disease☆