Iron Deficiency May Elevate Risk of Celiac Disease Development

Isabel A. Hujoel, MD

Credit: University of Washington

Iron deficiency may play a crucial role in the development of celiac disease, with genetically lower iron levels associated with an increased risk of having the immune-mediated condition, according to new research.¹

A team of investigators conducted a two-sample Mendelian randomization study to assess the correlation between single nucleotide polymorphisms (SNPs) associated with iron status and the presence of celiac disease, which can suggest causality under certain conditions.

Led by Isabel A. Hujoel, MD, of the division of gastroenterology at the University of Washington, the study team indicated these associations suggested a causal relationship between iron deficiency and the subsequent development of celiac disease if certain assumptions are able to hold.

“While iron deficiency is unlikely to be the only environmental trigger for celiac disease, iron deficiency is highly prevalent in celiac disease, and there are intriguing temporal and demographic associations between the two conditions and potential pathophysiological mechanisms,” Hujoel wrote.

The incidence of celiac disease, a genetic condition commonly linked to gluten intake, has been rising in recent decades, with a worldwide prevalence of 0.7% to 1.8%.² Better disease detection is an important factor, but the data seems to indicate an overall increase in disease prevalence. Although multiple environmental triggers are theorized, the evidence is not confirmatory for the development of celiac disease – one such environmental trigger is iron deficiency, a highly prevalent condition in cases of the disease.³

Hujoel and colleagues conducted a two-sample Mendelian randomization study to evaluate this potential causal relationship.¹ Given the use of random allocation and genetic variants, inherently non-modifiable instruments for modifiable exposures, the study may avoid confounding factors and suggest causality if certain assumptions hold. These assumptions indicate that the instrument must be associated with the exposure, does not impact the outcome outside of the exposure of interest, and does not influence other potential exposures which may have an impact on the outcome of interest.

“Crucially for this study, by relying on SNPs associated with iron status, and not on iron status itself, Mendelian randomization may avoid the confounding impact of coeliac disease-causing iron deficiency,” Hujoel added.

The team obtained the SNPs from a recent meta-analysis of three genome-wide association studies (GWAS). As the outcome of interest was celiac disease, investigators used publicly available GWAS summary statistics from the UK Biobank to determine the association between the genetic instruments for systemic iron status and celiac disease. These summary statistics restricted 336,638 White British individuals, including 1855 diagnosed with celiac disease, for analysis.

Altogether, there were four identified independent and strongly associated SNPs for systemic iron status: rs1800562 and rs1799945 in the HFE gene, rs855791 in the TMPRSS6 gene, and rs57659670 believed to affect the DUOX2 gene. An online database of SNP-phenotype associations revealed the genetic instruments were not significantly associated with known risk factors for celiac disease. Associations for all the genetic instruments for systemic iron status were all available in the UK Biobank summary statistics.

Upon analysis, investigators found higher iron status was negatively associated with the risk of celiac disease (odds ratio [OR] per 1 SD increase in serum iron: 0.65, 95% CI, 0.47 to 0.91). They observed little heterogeneity between SNP-specific associations of serum iron celiac disease (Cochran Q statistic = 4.8; P = .18).

According to the data, the leave-one-out analyses were generally consistent, and no single variant drove the association between iron status and celiac disease. Ultimately, all three assumptions of Mendelian randomization appeared plausible. Hujoel and colleagues indicated the relationship will need to be confirmed with further clinical trials and if confirmed, followed by prevention studies.

“More broadly, this study raises questions of the potential ties between iron deficiency and gluten-sensitivity, and the potential implications of dietary restrictions and avoidant restrictive food intake disorders which are common in celiac disease, inflammatory bowel disease, and irritable bowel syndrome,” they wrote.

References

1. _{Hujoel IA, Hujoel MLAInvestigating the role of iron status in the development of coeliac disease: a Mendelian randomisation study BMJ Open Gastroenterology 2024;11:e001236. doi: 10.1136/bmjgast-2023-001236}
2. _{Singh P, Arora A, Strand TA, et al. Global prevalence of celiac disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2018;16:823–36. doi:10.1016/j.cgh.2017.06.037}
3. _{Lebwohl B, Ludvigsson JF, Green PHR. Editorial: the unfolding story of celiac disease risk factors. Clin Gastroenterol Hepatol 2014;12:632–5. doi:10.1016/j.cgh.2013.10.031}