Elsevier

Human Immunology

Volume 60, Issue 3, March 1999, Pages 262-267
Human Immunology

Original Articles
Genetic differences in HLA-DQA1∗ and DQB1∗ allelic distributions between celiac and control children in Santiago, Chile

https://doi.org/10.1016/S0198-8859(98)00119-0Get rights and content

Abstract

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, Pc < 0.0005), DQB1∗0302 (0.430 vs 0.242, Pc = 0.002) and DQB1∗0201 (0.250 vs 0.125, Pc = 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, Pc = 0.01), DQA1∗0201 (0.105 vs 0.010, Pc < 0.0075) and DQB1∗0301 (0.250 vs 0.100, Pc = 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.

Introduction

Celiac disease (CD) or gluten sensitive enteropathy is associated with small bowel lesions consisting of severe degrees of crypt cell hyperplasia and villous atrophy induced by toxic gliadin components contained in the diet 1, 2, 3, 4, 5, 6, 7, 8, 9. Although its pathogenesis remains unclear it is agreed that the presence of genetic susceptibility and environmental variables, mainly exposure to dietary gluten are key factors in determinig its clinical appearance. There is evidence which suggests that breast milk may protect against celiac disease but this hypothesis remains to be demonstrated 5, 7. The genetic component is clearly evidenced by an increased prevalence among first-degree relatives of affected individuals, a high concordance rate in monozygotic twins (approximately 70%) and among HLA-identical twins (30%) 10, 11. The genetic control of this illness is related to the major histocompatibility complex (MHC) region of chromosome 6, which encodes the HLA class l and class II molecules 12, 13. Predisposition to the disease is closely associated with the inheritance of specific DQA1∗ and DQB1∗ alleles. In Northern Europe, CD is associated with HLA-B8, DR3, DR7 and DQ2 14, 15, 16. In contrast, in Southern Europe, where HLA-DR3 is less common, the disease is also associated with HLA-DR5. To reconcile the various HLA-DR associations observed in different ethnic groups, it has been accepted that celiac disease is associated with specific HLA-DQ2 alpha/beta heterodimers, encoded by the alleles DQB1∗0201 and DQA1∗0501, which indeed are the alleles found in over 90% of celiac patients 17, 18, 19.

There is little information about CD in Latin America. Its incidence in Chile has been calculated to be 1:1846 live births (unpublished data). The present study was carried out a) to describe the HLA-DQA1∗ and DQB1∗ allele distribution in Chilean patienrs with CD and b) to compare these with both the distribution observed in healthy Chilean individuals and the alleles described in celiac patients from other areas of the world.

Section snippets

Study population

The 95 celiac patients over 10 years of age who were registered in Hospital Exequiel González, Hospital Felix Bulnes and Hospital San Juan de Dios, Santiago, Chile, were contacted by mail and invited to particpate in this study. 62 were located at the addresses registered at the hospital and they attended the interview in which the study was explained. All families accepted to participate and provided written consent. The study was approved by the Committee on Ethics and Human Research, INTA,

HLA-DQB1 alleles

The allele distribution for DQB1 locus is shown in Table 1. In summary, the most common allele among controls was DQB1∗0301 (25.0%) as compared with celiac subjects (10%), p-value = 0.010. DQB1∗0302 allele frequency was higher in celiac patients than in controls (43% vs 24.2%, Pc < 0.002). Studies in Caucasians have revealed that DQB1∗0602 and DQB1∗0301 are more frequent among healthy subjects and therefore are thought to be protective alleles for CD. In the present study they were decreased

Discussion

Several genetic systems has been studied in the Chilean Indian tribes. Information concerning the HLA-A and B loci observed in this investigations probably reflect patterns due to major ancient migrations. The variations observed in the Amerindians populations could be the product of selective forces associated with climatic differences or artificial gradients produced by non-Indian admixture 28, 29. This is the first report of HLA-DQA1/DQB1 alleles distribution and haplotype combinations in

Acknowledgements

This study was supported by grants DID No 068/97 and DID No 063/97 (Universidad de Chile). We express our gratitude to all children participating in this study.

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