Elsevier

Human Immunology

Volume 70, Issue 1, January 2009, Pages 55-59
Human Immunology

HLA-DQ and risk gradient for celiac disease

https://doi.org/10.1016/j.humimm.2008.10.018Get rights and content

Abstract

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 β2 chain, 2% was α5 positive, and four were DQ2/DQ8/β2/α5 negative. Only the presence of α5 resulted negatively associated to disease (p = 2 × 10−4), whereas we confirmed the effect of the β half of DQ2 dimer on CD predisposition (p = 4 × 10−12). 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 = 9 × 10−4), 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.

Introduction

Celiac disease (CD, MIM 212750) is a chronic intestinal inflammation resulting in villous atrophy and flattening of the mucosa. The disease occurs in genetically predisposed individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. The treatment consists of lifelong gluten exclusion from the diet that leads to histologic and clinical remission and prevents the development of refractory CD and long-term complications such as malignancy, osteoporosis, infertility, and autoimmunity.

Originally considered a rare malabsorption syndrome in childhood, CD is now recognized as a common disorder that may arise at any age, with a growing proportion of new cases diagnosed in adults and in patients with extraintestinal manifestations. Recent accurate epidemiologic studies have revealed that CD affects approximately 1% of the general population, both in Europe and in North America [1]. The prevalence of the disease increases among patients with anemia or autoimmune diseases, with short stature, or with Down, Turner, or Williams syndrome [2]. Moreover, CD clusters in families with a prevalence among first-degree relatives ranging from 2.8% to 17.2% in different series [3].

Although CD is one of the most common lifelong diseases in western countries, most affected individuals remain undiagnosed [1]. This is apparently because many patients have atypical symptoms or none at all. The disease is characterized by the production of anti-tissue transglutaminase (anti-tTG) and anti-endomysial (EmA) antibodies. Serologic screening for the presence of these autoantibodies in individuals with characteristic symptoms of CD or with associated conditions is usually the initial step in detecting new cases. Although anti-tTG and EmA appear to be good markers of the active phase of the disease, the definitive diagnosis requires a small-bowel biopsy showing the typical histologic abnormalities (villous atrophy, crypt hyperplasia, and leukocyte infiltration).

CD mostly develops in HLA-DQ2 (DQA1*05 and DQB1*02)–positive individuals, whereas most of the remaining cases are HLA-DQ8 (DQA1*03 and DQB1*0302) positive. The close association can be explained by the fact that the DQ2 and DQ8 α/β heterodimers mediate the activation of gluten-reactive CD4+ T cells in the gut. In particular, the disease-associated HLA-DQ molecules expressed on antigen-presenting cells specifically bind gluten-derived peptides, modified by the enzyme tTG, and present them to intestinal T cells. The resulting T response leads to the production of the disease-specific antibodies and to the secretion of pro-inflammatory cytokines with consequent mucosa atrophy and clinical manifestations.

The European Genetic Cluster on Celiac Disease has demonstrated that practically all CD patients carry HLA-DQ2 and/or HLA-DQ8 molecules or one chain of the DQ2 heterodimer, coded by DQA1*05 (α5 chain) or DQB1*02 (β2 chain) alleles, and that CD occurs only exceptionally in the absence of at-risk DQ factors [4]. Moreover, a gene dosage effect for the DQB1*02 allele has been described in several studies [5], [6]. Given the strong association, the HLA typing is routinely used as a genetic test for CD; the presence of susceptible DQ variants does not predict certain developments of the disease but strongly modifies the risk, whereas their absence makes CD very unlikely with a negative predictive value close to 100% [7]. We have recently reported evidence of gender differences in this association, with a different negative predictive value for the HLA test in female and male subjects, indicating the need to consider the gender in the disease-risk calculation [8].

Despite the fact that the diagnostic significance of the HLA test for CD is not absolutely certain, it is generally considered that it may be of help in the definition of uncertain cases. The analysis is also recommended in at-risk groups, such as first-degree relatives of patients, to decide the follow-up [2]. Indeed, the HLA genes are lifelong stable markers and their typing may discern subjects genetically susceptible or nonsusceptible to the disease long before the possible appearance of clinical or serologic signs.

The HLA-DQ association with the risk of CD has been extensively discussed, but knowledge of the practical usage of the HLA typing as a genetic test for the disease remains limited and the clinical implications of the results are still not clearly defined. We present here our experience with the HLA testing in a cohort of Italian pediatric celiac patients and first-degree relatives collected over the last 20 years, with the aim to contribute to the development of clinical practice guidelines for the use of the HLA typing as a predictive test for CD.

Section snippets

Patients and relatives

All subjects (N = 1271) except two siblings were described in a previous report (8). Briefly, they included 145 CD patients and 292 nuclear families (292 index cases, 34 affected and 216 unaffected siblings, and 20 affected and 564 unaffected parents).

The 437 index cases had a median age of 5 years 8 months at sample collection. Age in siblings ranged from 1 to 20 years with a median of 10 years. No differences were observed between affected and unaffected cohorts.

All relatives were tested for

Results

The case-control study of the 437 celiac children and 551 controls was previously described [8]. Briefly, 91.1% patients and 29.0% controls carried DQ2 and/or DQ8 heterodimers. Among the DQ2/DQ8-negative individuals, the frequencies of cases carrying DQB1*02 (β2), DQA1*05 (α5), or neither of the two alleles were 66.7%, 23.1%, and 10.2%, respectively versus 14.1%, 53.4%, and 32.5% of the controls, showing a positive association with CD of the β2 phenotype (p = 4.3 × 10−12) but a negative

Discussion

Celiac disease is a rare example of multifactorial disorder in which a genetic test is of great importance in clinical practice. From this point of view, the peculiarity of CD is due to several issues: the gluten ingestion is known to be the environmental triggering factor, and a gluten-free diet represents a valid therapy that leads to complete remission of the clinical signs; the disease is largely underdiagnosed, because most patients have silent or atypical forms; untreated CD significantly

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