Reevaluation of the relative risk for susceptibility to celiac disease of HLA-DRB1, -DQA1, -DQB1, -DPB1, and -TAP2 alleles in a French population

doi:10.1016/0198-8859(95)00011-R

Human Immunology

Volume 43, Issue 3, July 1995, Pages 190-199

https://doi.org/10.1016/0198-8859(95)00011-R Get rights and content

Abstract

In a population of 46 children with CD recruited in the Paris area of France, an excess of DRB1∗03 and DRB1∗07 alleles and of DR3/DR7, DR3/ DR3, and DR11(or12)/DR7 phenotypes was found (RRs of 6.3, 9.3, 24.6,15, and15.1, respectively), which is reminiscent of the markers of susceptibility observed in southern rather than in northern European celiac patients. More importantly, the highest association with CD was not found in individuals expressing the DQA1∗0501 -DQB1^∗0201 heterodimer in single dosage (RR = 24.9) or in homozygous state, but in people co-expressing one copy of DQA1∗0501-DQB1∗0201 on one haplotype and a second copy of DQB1∗0201 on the second haplotype (RR = 35.7). This suggests that in our population either DQB1∗0201 or a gene closely linked to DQB1∗0201 influences the susceptibility to CD conferred by the DQA1∗0501-DQB1∗0201 heterodimer. Significant positive or negative RRs conferred by some TAP2 or DPB1 alleles were found. However, they were moderate compared to the RR conferred by the expression of a second copy of DQB1∗0201. Moreover, they were no longer significant when patients were compared with HLA-DR matched controls. This suggests that associations of CD with TAP2 and DPB1 alleles are secondary to linkage disequilibria and argues against the contribution of these alleles in resistance and/or susceptibility to CD. Thus the “raison d'être” of a “DQB1∗0201 second haplotype effect” in susceptibility to CD remains to be elucidated.

References (43)

JJ Keuning et al.
HLA-Dw3 associated with celiac disease
Lancet
(1976)
R Tosi et al.
Evidence that celiac disease is intimately associated with a DC locus allelic specificity
Clin Immunol Immunopathol
(1983)
MC Mazzilli et al.
A study of Italian pediatric celiac disease patients confirms that the primary HLA association is to the DQ(α 1∗050 l,β1∗0201) heterodimer
Hum Immunol
(1992)
R Tosi et al.
A radioimmunoassay typing study of non-DQw2-associated celiac disease
Clin Immunol Immuno-pathol
(1986)
A Spurkland et al.
HLA-DR and -DQ genotypes of celiac disease patients serologically typed to be non-DR3 or non-DR5/7
Hum Immunol
(1992)
DA Savage et al.
Frequency of HLA-DPB1 alleles, including a novel DPB1 sequence, in the Northern Ireland population
Hum Immunol
(1992)
KS Ronningen et al.
Distribution of HLA class II alleles among Norwegian Caucasians
Hum Immunol
(1990)
M Colonna et al.
Reassessment of HLA association with celiac disease in special reference to the DP association
Hum Immunol
(1990)
I Djilali-Saiah et al.
Polymorphisms of antigen processing (TAP, LMP) and HLA class II genes in celiac disease
Hum Immunol
(1994)
LM Sollid et al.
HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis
Gas-troenterology
(1993)

MA Hall et al.

HLA-DQ2 second-domain polymorphisms may explain increased trans-associated risk in celiac disease and dermatitis herpetiformis

Hum Immunol

(1993)

JL Tiwari et al.

HLA and Disease Associations

(1985)

ML Mearin et al.

HLA-DR phenotypes in Spanish coeliac children: their contribution to the understanding of the genetics of the disease

Gut

(1983)

M Morellini et al.

A study of HLA class II antigens in Italian paediatric population with coeliac disease

Dis Markers

(1988)

LM Sollid et al.

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

J Exp Med

(1989)

LM Sollid et al.

The primary association of celiac disease to a given HLA-DQ α/β heterodimer explains the divergent HLA-DR associations observed in various Caucasian populations

Tissue Antigens

(1990)

S Scholz et al.

HLA and diseases: involvement of more than one HLA-linked determinant of disease susceptibility

Immunol Rev

(1983)

R Ploski et al.

On the HLA-DQ(α1∗0501,β1∗0201) associated susceptibility in celiac disease: a possible gene dosage effect of DQB1∗0201

Tissue Antigens

(1993)

M DeMarchi et al.

HLA-DR3 and -DR7-negative celiac disease

TL Bugawan et al.

A combination of a particular HLA-DPβ allele and an HLA-DQ heterodimer confers susceptibility to celiac disease

Nature

(1989)

MF Kagnoff et al.

Structural analysis of the HLA-DR, -DQ and -DP alleles on the celiac disease associated HLA-DR3 (DRw17) hap-lotype

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Reevaluation of the relative risk for susceptibility to celiac disease of HLA-DRB1, -DQA1, -DQB1, -DPB1, and -TAP2 alleles in a French population

Abstract

Lancet

Clin Immunol Immunopathol

Hum Immunol

Clin Immunol Immuno-pathol

Hum Immunol

Hum Immunol

Hum Immunol

Hum Immunol

Hum Immunol

Gas-troenterology

Hum Immunol

HLA and Disease Associations

HLA-DR phenotypes in Spanish coeliac children: their contribution to the understanding of the genetics of the disease

Gut

A study of HLA class II antigens in Italian paediatric population with coeliac disease

Dis Markers

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

J Exp Med

The primary association of celiac disease to a given HLA-DQ α/β heterodimer explains the divergent HLA-DR associations observed in various Caucasian populations

Tissue Antigens

HLA and diseases: involvement of more than one HLA-linked determinant of disease susceptibility

Immunol Rev

On the HLA-DQ(α1∗0501,β1∗0201) associated susceptibility in celiac disease: a possible gene dosage effect of DQB1∗0201

Tissue Antigens

HLA-DR3 and -DR7-negative celiac disease

A combination of a particular HLA-DPβ allele and an HLA-DQ heterodimer confers susceptibility to celiac disease

Nature

Structural analysis of the HLA-DR, -DQ and -DP alleles on the celiac disease associated HLA-DR3 (DRw17) hap-lotype