Abstract
The factors determining the presentation of celiac disease are unclear. We investigated the phenotypic concordance and the distribution of human leukocyte antigen (HLA) risk haplotypes in affected siblings. One hundred sibling pairs were included. Clinical and histological parameters and HLA haplotypes were compared between the first diagnosed indexes and their siblings. The phenotype was categorized into gastrointestinal, extra-intestinal, malabsorption/anemia, and asymptomatic. The phenotype was fully concordant in 21 pairs. The most common concordant phenotype was gastrointestinal (14 pairs). Indexes had more anemia/malabsorption and extra-intestinal symptoms than siblings (45% vs. 20%, p < 0.001 and 33% vs. 12%, p < 0.001, respectively). Twenty siblings and none of the indexes were asymptomatic. The indexes were more often women (81% vs. 63%, p = 0.008). They were also more often seronegative (11% vs. 0%, p = 0.03) and younger (37 vs. 43 year, p < 0.001), and had more severe histopathology (total/subtotal atrophy 79% vs. 58%, p = 0.047) at diagnosis. The indexes and siblings were comparable in other disease features. Pairs with discordant presentation had similar HLA haplotypes more often than the concordant pairs. The phenotype was observed to vary markedly between siblings, with the indexes generally having a more severe presentation. HLA did not explain the differences, suggesting that non-HLA genes and environmental factors play significant roles.
Highlights
Celiac disease is an immune-mediated condition with an estimated prevalence of 1–2% in Western countries [1,2,3]
Gastrointestinal symptoms were the most common and distributed presentation was observed in both groups, but the indexes had malabsorption/anemia and extra-intestinal symptoms significantly more often (Table 1)
Familial phenotype concordance has not been previously studied using a similar approach, but some studies have shown that the intestinal form of celiac disease and dermatitis herpetiformis can occur within the same family [24,25]
Summary
Celiac disease is an immune-mediated condition with an estimated prevalence of 1–2% in Western countries [1,2,3]. Patients often have different gastrointestinal or extra-intestinal symptoms that may appear at any age, or they can even be completely asymptomatic [10,11,12] The reason for this phenotypic diversity remains obscure [13,14,15,16,17], but the observed variability even between identical twins suggests that it is not solely determined by genetics [5,18]. The concordance of the clinical picture between affected relatives has been scarcely studied This information could improve our understanding of the complex interactions between genetic and environmental factors in celiac disease, and possibly increase the diagnostic yield of this markedly under-recognized condition [3]
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