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

Abstract

Background: Haptoglobin (Hp) α-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.

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

“…The authors found that the phenotype HP2-1 was associated with a significant risk of CD. Conversely, HP2-2 was less frequent in CD patients than in controls, but patients having this phenotype were at an increased risk for severe malabsorption (127). Therefore, it is tempting to hypothesize that one copy of the zonulin gene increases the risk of CD because of its permeating effect on the intestinal barrier, while two copies of this gene, causing a severe malabsorption secondary to a more profound intestinal barrier dysfunction, led to high mortality and, therefore, was negatively selected during evolution.…”

“…10). Interestingly, Papp et al (127) have recently reported that HP polymorphism represents a novel genetic risk factor for CD development and its clinical manifestations. The authors found that the phenotype HP2-1 was associated with a significant risk of CD.…”

Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2

“…The enhanced expression of zonulin correlated with disease activity, because CD patients who were on a GFD showed mean values for zonulin expression that were intermediate to those of patients with active CD and normal controls. Interestingly, Papp et al (35) recently reported that a polymorphism in the HP gene represents a previously undescribed genetic risk factor for CD development and its clinical manifestations.…”

Zonulin and Iron Metabolism in Heart Transplant Recipients

“…Zonulin is a prehaptoglobin (HP) 2 [4], a molecule that, to date, has been regarded as only the inactive precursor for HP2, 1 of the 2 genetic variants (together with HP1) of human HPs. Several studies have suggested that the presence of the HP2 allele correlates with higher risk of developing immune-mediated diseases [13] and that HP2 homozygosis is associated with poor prognosis [13] and decreased longevity [14]. The only function assigned to HPs to date has been to bind hemoglobin to form stable complexes and thereby prevent hemoglobin-induced oxidative tissue damage [15].…”