E0636 - Iron Deficiency and the Development of Celiac Disease

Award: Outstanding Research Award in the Small Intestine Category

Award: Presidential Poster Award

Isabel Hujoel, MD¹, Margaux Hujoel, PhD^2
1University of Washington, Seattle, WA; ²Brigham and Women’s Hospital and Harvard Medical School; Broad Institute of MIT and Harvard, Seattle, WA

Introduction: The prevalence of celiac disease is increasing; however, the cause for this increase is unknown. Iron deficiency is one suggested environmental trigger for celiac disease development. We aimed to evaluate this possible association through the use of Mendelian randomization (MR). MR capitalizes on the random allocation of single nucleotide polymorphisms (SNPs) at conception, and under certain assumptions can suggest causality.

Methods: We conducted a two-sample MR study examining the relationship between SNPs associated with iron status and the presence of celiac disease. The SNPs were drawn from a meta-analysis of three genome-wide association studies (GWAS). The GWAS summary statistics from the UK Biobank, consisting of 336,638 white British individuals of whom 1,855 participants had celiac disease, were used to assess the association between these SNPs and celiac disease. The assumptions of MR were tested to evaluate for possible causality. We also performed an MR Egger test for pleiotropy.

Results: There are four SNPs strongly associated with systemic iron status. Using PhenoScanner, we found that these SNPs were not significantly associated with known risk factors for celiac disease. All four were available in the UK Biobank summary statistics, and utilizing these SNPs, we harmonized exposure and outcome associations. We found that higher iron status was negatively associated with risk of celiac disease (odds ratio per 1 standard deviation increase in serum iron: 0.65, 95% CI 0.47-0.91). We performed leave-one-out analyses and had consistent results and did not find one single variant to be driving this association. All three assumptions of MR appeared plausible.

Discussion: We found that genetically lower iron levels were associated with an increased risk of having celiac disease. If the assumptions of MR hold, this association suggests a causal role of iron deficiency in celiac disease development. While unlikely to be the only environmental trigger, iron deficiency is prevalent in both the general and celiac population. One possible mechanism for this pathogenic role is that the transferrin receptor 1, which is upregulated in the setting of iron deficiency, directly transports gliadin peptides across enterocytes – a key step in celiac disease development. Our findings highlight a potential opportunity for celiac disease prevention.


Disclosures:


Isabel Hujoel, MD¹, Margaux Hujoel, PhD². E0636 - Iron Deficiency and the Development of Celiac Disease, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.