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Haptoglobin Polymorphism: A Novel Genetic Risk Factor for Celiac Disease Development and Its Clinical Manifestations

¹ Second Department of Medicine, University of Debrecen, Debrecen, Hungary; ² Department of Pediatrics, University of Debrecen, Debrecen, Hungary; ³ Clinical Research Center, University of Debrecen, Debrecen, Hungary; ⁴ First Department of Surgery, University of Debrecen, Debrecen, Hungary; ⁵ First Department of Medicine, University of Debrecen, Debrecen, Hungary; ⁶ Third Department of Medicine, University of Debrecen, Debrecen, Hungary; ⁷ First Department of Pediatrics, Semmelweis University, Budapest, Hungary; ⁸ First Department of Medicine, Semmelweis University, Budapest, Hungary; ⁹ Laboratory of Clinical Immunology, University of Debrecen, Debrecen, Hungary; ¹⁰ Department of Pathology, University of Debrecen, Debrecen, Hungary; ¹¹ Department of Pediatrics, Kenezy Gyula County Hospital, Debrecen, Hungary; ¹² Celiac Disease Center, Heim Pal Children’s Hospital, Budapest, Hungary.

^aAddress correspondence to this author at: Department of Gastroenterology, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. Fax 36-52-314-410; e-mail drpappm{at}yahoo.com.

Background: Haptoglobin (Hp) -chain alleles 1 and 2 account for 3 phenotypes that may influence the course of inflammatory diseases via biologically important differences in their antioxidant, scavenging, and immunomodulatory properties. Hp1-1 genotype results in the production of small dimeric, Hp2-1 linear, and Hp2-2 cyclic polymeric haptoglobin molecules. We investigated the haptoglobin polymorphism in patients with celiac disease and its possible association to the presenting symptoms.

Methods: We studied 712 unrelated, biopsy-proven Hungarian celiac patients (357 children, 355 adults; severe malabsorption 32.9%, minor gastrointestinal symptoms 22.8%, iron deficiency anemia 9.4%, dermatitis herpetiformis 15.6%, silent disease 7.2%, other 12.1%) and 384 healthy subjects. We determined haptoglobin phenotypes by gel electrophoresis and assigned corresponding genotypes.

Results: Hp2-1 was associated with a significant risk for celiac disease (P = 0.0006, odds ratio [OR] 1.54, 95% CI 1.20–1.98; prevalence 56.9% in patients vs 46.1% in controls). It was also overrepresented among patients with mild symptoms (69.2%) or silent disease (72.5%). Hp2-2 was less frequent in patients than in controls (P = 0.0023), but patients having this phenotype were at an increased risk for severe malabsorption (OR 2.21, 95% CI 1.60–3.07) and accounted for 45.3% of all malabsorption cases. Celiac and dermatitis herpetiformis patients showed similar haptoglobin phenotype distributions.

Conclusions: The haptoglobin polymorphism is associated with susceptibility to celiac disease and its clinical presentations. The predominant genotype in the celiac population was Hp2-1, but Hp2-2 predisposed to a more severe clinical course. The phenotype-dependent effect of haptoglobin may result from the molecule’s structural and functional properties.