The DMT1 IVS4+44C>A polymorphism and the risk of iron deficiency anemia in children with celiac disease

<div><p>Background</p><p>Iron deficiency anemia in celiac disease is related to impaired duodenal mucosal uptake, due to villous atrophy. Iron enters the enterocytes through an apical divalent metal transporter, DMT1. Different DMT1 transcripts have been identified, depending on the presence of an iron-responsive element that allows DMT1 up-regulation during iron starvation. An intronic DMT1 polymorphism, IVS4+44C>A, has been associated with metal toxicity, and the CC-carriers show high iron levels.</p><p>Aims</p><p>This study investigates the association between DMT1 IVS4+44C>A and anemia in a cohort of 387 Italian celiac children, and the functional role of the polymorphism.</p><p>Methods and results</p><p>By association analysis, we found that DMT1 IVS4+44-AA genotype confers a four-fold risk of developing anemia, despite of atrophy degree. By analysis of mRNA from gastroesophageal biopsies, we found that total DMT1 is significantly upregulated in presence of mild, but not severe, atrophy, independently from IVS4+44C>A variant, and in normal but not in atrophic CC-biopsies. Moreover, we found that A-allele is associated to preferential expression of the DMT1 transcripts lacking the iron-responsive element, thus limiting the DMT1 overexpression that normally occurs to respond to iron starvation.</p><p>Discussion</p><p>Possibly, the IVS4+44-AA-related dysregulation of the iron-induced changes in DMT1 expression is not able to impair iron absorption in physiological condition. However, if exacerbated by the concomitant massive loss of functional absorbing tissue paralleling worsened stages of villus atrophy, it might be ineffective in counteracting iron deficiency, despite of DMT1 overexpression.</p><p>Conclusion</p><p>We suggest, for the first time, that celiac disease may unmask the contribution of the DMT1 IVS4+44C>A polymorphism to the risk of anemia.</p></div

Clinical features of 387 Italian children with Celiac Disease stratified according to IDA.

<p>Clinical features of 387 Italian children with Celiac Disease stratified according to IDA.</p

Total DMT1 expression in gastroesophageal biopsies from potential celiac children.

<p><b>A)</b> Expression of total DMT1 mRNA from 27 gastroesophageal biopsies resulted into significant up-regulation of the iron transporter in the subgroup showing T3a degree of villous atrophy (n = 3) with respect to the subgroups with normal mucosa (T0 = 11). No significant difference in DMT1 expression was found in T3b (n = 6) and in T3c (n = 7) biopsies. On the right the result of the t-test between the ΔCt values for DMT1 expression (ΔCt = Ct _DMT1- Ct _β-actin) of T0 and T3a biopsies. <b>B)</b> Significant overexpression of total DMT1 transcript in null atrophy (T0) biopsies from CC-carriers with respect to those from AA-carriers, as shown by the t-test on the right between their ΔCt values for DMT1 expression. Data are represented as mean ± standard deviation of the fold change from at least three different assays performed in duplicate. The t-test has been used to determine the statistical significance between groups by using the ΔCt values of the DMT1 target and the β-actin reference, due to the small size number. A <i>p</i>-value less than 0.05 has been considered significant.</p

Villous atrophy degree of 27 consecutive duodenal biopsies stratified according to DMT1 IVS+44C>A polymorphism.

<p>Villous atrophy degree of 27 consecutive duodenal biopsies stratified according to DMT1 IVS+44C>A polymorphism.</p

Logistic regression analysis for 387 celiac patients presenting (134) or not (253) IDA (Hb less than 3° percentile).

<p>Logistic regression analysis for 387 celiac patients presenting (134) or not (253) IDA (Hb less than 3° percentile).</p

DMT1 IVS+44C>A polymorphism is associated to DMT1 +IRE/–IRE transcript ratio.

<p>DMT1 IVS+44C>A polymorphism is associated to DMT1 +IRE/–IRE transcript ratio.</p