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Healthcare professional Resource for Gluten Related Disorders.

Dr. Schär Institute

Genetic and exogenous causes of celiac disease

Celiac disease has a complex pathology resulting from interaction between a number of genetic and exogenous factors.

Genetic factors

A high incidence of celiac disease within affected families (approximately 10% among first-degree relatives and 80% among twins) suggests a genetic involvement in the pathogenesis of celiac disease [5]. An important genetic factor is the human leukocyte antigen (HLA) system, a gene complex whose task is to recognise foreign molecules. 90% of celiac patients carry genes encoding HLA DQ2 whilst most of the remainder carry the HLA DQ8 haplotype [1]. Although these are necessary for the disease to develop, they are not solely responsible for it. It is known that these genes are also present in up to 40% of individuals in Western populations, however, the frequency is population dependent [2].

Exogenous factors

The presence of gluten in the diet is clearly a pre-requisite for the development of celiac disease. Recent weaning guidelines have recommended that it may be prudent to avoid both early (<4 months of age) and late (>7 months of age) introduction of gluten and to introduce gluten while infants are still being breastfed [3,4]. However, these recommendations were based largely on observational data and more recently a number of new randomised control studies have been published in this area. Data from such studies appears to indicate that exclusive or any breastfeeding, including breastfeeding at the time of gluten introduction does not reduce the risk of developing coeliac disease during childhood. Moreover, for infants at higher risk of developing celiac disease, gluten introduction at 4 months of age, or at 6-12 months of age results in similar rates of celiac disease diagnosis in early childhood [5].
  1. Fasano, A., Catassi, C. (2012). Clinical practice. Celiac disease. N Engl J Med.;     20; 367(25):2419-26. doi: 10.1056/NEJMcp1113994.
  2. Karrell K, Louka AS, Moodie SJ et al. HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) hererodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol 2003; 64:469-77
  3. Abadie V, Sollid LM, Barreiro LB et al. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol 2011; 29:493-525
  4. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific opinion on the appropriate age for introduction of complementary feeding of infants. Available at: (accessed 12/06/15)
  5. ESPGHAN Committee on Nutrition: Agostini C, Decsi T, Fewtrell M et al. Complementary feeding: a commentary by the ESPGHAN Committee on Nutrition. J Paediatric Gastroenterol Nutr 2008; 46:99-110
  6. Szajewska H, Shamir R, Chmielewska A et al. Systematic review with meta-analysis: early infant feeding and coeliac disease – update 2015. Alimentary Pharmacol & Ther 2015;41:1038-1054

Further information on this topic

Professional articles 1

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Studies 1

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The importance of the microbiota in the pathogenesis and treatment of celiac disease

The composition of the gut microbiome is influenced by many factors. The microbiota may also be a key influencer in overall health and disease outcomes.

>> Read more... <<<
Körner, U; Groeneveld, M;

Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients With Celiac Disease


Gluten ingestion leads to small intestinal mucosal injury in patients with celiac disease, necessitating strict life-long exclusion of dietary gluten. Despite adherence to a glutenfree diet, many patients remain symptomatic and still have small intestinal inflammation. In this case, nondietary therapies are needed. We investigated the ability of ALV003, a mixture of 2 recombinant gluten-specific proteases given orally, to protect patients with celiac disease from gluten-inducedmucosal injury in a phase 2 trial.

We established the optimal daily dose of gluten to be used in a 6-week challenge study. Then, in the intervention study, adults with biopsy-proven celiac disease were randomly assigned to groups given ALV003 (n ¼ 20) or placebo (n ¼ 21) together with the daily gluten challenge. Duodenal biopsies were collected at baseline and after gluten challenge. The ratio of villus height to crypt depth and densities of intraepithelial lymphocytes were the primary end points.

A daily dose of 2g gluten was selected for the intervention study. Sixteen patients given ALV003 and 18 given placebo were eligible for efficacy evaluation. Biopsies from subjects in the placebo group showed evidence of mucosal injury after gluten challenge (mean villus height to crypt depth ratio changed from 2.8 before challenge to 2.0 afterward; P ¼ .0007; density of CD3þ intraepithelial lymphocytes changed from 61 to 91 cells/mm after challenge; P ¼ .0003). However, no significant mucosal deterioration was observed in biopsies from the ALV003 group. Between groups, morphologic changes and CD3þ intraepithelial lymphocyte counts differed significantly from baseline to week 6 (P ¼ .0133 and P ¼ .0123, respectively). There were no statistically significant differences in symptoms between groups.

Based on a phase 2 trial, the glutenase ALV003 appears to attenuate gluten-induced small intestinal mucosal injury in patients with celiac disease in the context of an everyday gluten-free diet containing daily up to 2 g gluten.

Resource: Gastroenterology 2014;146:1649–1658

Marja-Leena Lähdeaho, Katri Kaukinen, Kaija Laurila, Pekka Vuotikka, Olli-Pekka Koivurova, Tiina Kärjä-Lahdensuu, Annette Marcantonio, Daniel C. Adelman, and Markku Mäki
2014 February