Serologic and Genetic Markers of Celiac Disease: A Sequential Study in the Screening of First Degree Relatives

Department of Pediatrics, University of Rome La Sapienza, Viale Regina Elena 324, 00161 Rome, Italy.
Journal of Pediatric Gastroenterology and Nutrition (Impact Factor: 2.63). 01/2006; 42(2):150-154. DOI: 10.1097/01.mpg.0000189337.08139.83


Objectives: The prevalence of celiac disease (CD) among the relatives and the complications of an undiagnosed CD prompted us to identify a useful disease screening strategy.
Methods: We studied 441 first degree relatives of 208 CD patients by immunoglobulin (Ig)A antiendomysium antibodies (EMA) and radioimmunoprecipitation assay (RIA) IgA antitransglutaminase autoantibodies (TGAA). Of these, 364 were typed for human leukocyte antigen-DRB1, -DQA1, and -DQB1 genes by the polymerase chain reaction sequence specific primers method. It was suggested to the autoantibody-positive subjects that they should undergo intestinal biopsy.
Results: TGAA were positive in 46 of 439 relatives, EMA in 38; intestinal lesions related to CD were present in 40 subjects. We also found two immunodeficient fathers with duodenal villous atrophy. In three serology-positive subjects, permission for intestinal biopsy was refused; for another three serology-positive cases, duodenal mucosa was normal. Thus, the strict CD prevalence resulted 9.5%, the enlarged prevalence 10.9%. The DQ2/DQ8 heterodimers were carried in 231 of 364 subjects and in 38 of 40 biopsy-proven celiac patients. Three DQ2-positive parents became positive to the serology during a long-lasting follow-up.
Conclusions: On the basis of a carefully conducted study, CD prevalence in our series was seen as very high. These data suggest an accurate algorithm to select candidates for intestinal biopsy among CD high-risk subjects. First, an evaluation of the sensitive RIA TGAA and of total IgA (in IgA deficiency RIA IgG anti-tissue transglutaminase assay) should be performed. Then, an evaluation of the TGAA and the genetic study would be advisable 2 to 3 years later in negative subjects. Those carrying the DQ2/DQ8 heterodimers should continue the serologic follow-up; the others need a clinical follow-up.

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    • "HLA typing is routinely requested by clinicians to provide additional support in dubious CD cases, i.e. uncertain or discrepant serology and/or biopsy, and in at-risk categories [50,51] (Figure 2). HLA is a useful test in screening first-degree relatives due to the higher prevalence of CD among relatives of celiac patients [24,49]. Family studies showed that celiac autoimmunity occurs almost exclusively in the presence of high-risk DQ molecules (DQ2.5, DQ8 and DQ2.x with a double dose of DQB1*02). "
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    ABSTRACT: Celiac disease (CD) is a multifactorial disorder with an estimated prevalence in Europe and USA of 1:100 and a female:male ratio of approximately 2:1. The disorder has a multifactorial etiology in which the triggering environmental factor, the gluten, and the main genetic factors, Human Leukocyte Antigen (HLA)-DQA1 and HLA-DQB1 loci, are well known. About 90-95% of CD patients carry DQ2.5 heterodimers, encoded by DQA1*05 and DQB1*02 alleles both in cis or in trans configuration, and DQ8 molecules, encoded by DQB1*03:02 generally in combination with DQA1*03 variant. Less frequently, CD occurs in individuals positive for the DQ2.x heterodimers (DQA1=*05 and DQB1*02) and very rarely in patients negative for these DQ predisposing markers. HLA molecular typing for Celiac disease is, therefore, a genetic test with a negative predictive value. Nevertheless, it is an important tool able to discriminate individuals genetically susceptible to CD, especially in at-risk groups such as first-degree relatives (parents, siblings and offspring) of patients and in presence of autoimmune conditions (type 1 diabetes, thyroiditis, multiple sclerosis) or specific genetic disorders (Down, Turner or Williams syndromes).
    Journal of Biomedical Science 10/2012; 19(1):88. DOI:10.1186/1423-0127-19-88 · 2.76 Impact Factor
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    • "No differences were observed between affected and unaffected cohorts. All relatives were tested for anti-tTG and EmA antibodies, and selected individuals underwent a small-intestinal biopsy, as previously described [9]. Informed consent was obtained from each participant. "
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    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 beta2 chain, 2% was alpha5 positive, and four were DQ2/DQ8/beta2/alpha5 negative. Only the presence of alpha5 resulted negatively associated to disease (p = 2 x 10(-4)), whereas we confirmed the effect of the beta half of DQ2 dimer on CD predisposition (p = 4 x 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 x 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.
    Human Immunology 12/2008; 70(1):55-9. DOI:10.1016/j.humimm.2008.10.018 · 2.14 Impact Factor
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    ABSTRACT: HLA-linked genes are relevant to celiac disease (CD); the potential genetic differences present worldwide are not fully understood. Previous results suggest that the distribution of HLA-DQ2/DQ7/DQ8 in Chile may differ from that in Europe and North America. In celiac patients and their first-degree relatives (FDRS), we assessed their clinical, serological and histological characteristics, determined HLA-DQ2, HLA-DQ7 and HLA-DQ8 alleles and genotypes, and evaluated the relations between them. A total of 222 individuals were assessed (56 cases, 166 FDRs). 16.9% of FDRs were tTG positive; 53.6% of them showed overweight/obesity and 3% undernourishment; they spontaneously declared being asymptomatic, but detailed questioning revealed that 60.7% experienced symptoms, which had not been investigated. DQ2 was present in 53.9% and 43.9.0% of cases and FDRs (p < 0.05). The most frequent genotype distribution was DQ2/DQ7 (fr 0.392 (cases) and 0.248 (FDRs), respectively, p < 0.02). The next most common genotypes were HLA-DQ2/DQ8 (fr 0.236 in FDRs and 0.176 in cases, p < 0.05). 3.92% cases were not HLA-DQ2/DQ8 carriers. Among tTG positive FDRs, 57.4%, 22.3% and 20.2% carried DQ2, DQ7 and DQ8, respectively. In cases, 72.7% of the biopsies classified Marsh ≥3 carried at least one DQ2; 91.7% of DQ2/DQ2 and 88.3% of DQ2/DQ7 were Marsh ≥3. Thus, DQ2 frequency is lower than reported; the higher frequency found for DQ8 and DQ7 concur with recent publications from Argentine and Brazil. These results suggest that although CD may manifest clinically in ways similar to those described in other populations, some genetic peculiarities in this region deserve further study.
    Nutrients 06/2015; 7(6):4955-4965. DOI:10.3390/nu7064955 · 3.27 Impact Factor
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