HLA-DQ and risk gradient for celiac disease
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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