Letter by Lagro et al Regarding Article, “Nationwide Cohort Study of Risk of Ischemic Heart Disease in Patients With Celiac Disease”

We read with interest the article by Ludvigsson et al,¹ which provides observational evidence that individuals with celiac disease or small intestinal inflammation are at increased risk of ischemic heart disease. Their study was based on a large number a subjects from a nationwide population-based study. The authors suggested that the mechanism underlying the positive associations between celiac disease and ischemic heart disease is the chronic inflammation that is a major risk factor for ischemic heart disease in the general population.¹

A major limitation of their study is the lack of information about potential confounders. Both chronic lifestyle habits related to celiac disease and nutritional, metabolic (eg, hypovitaminose D), and hormonal changes as a consequence of celiac disease might be involved in pathways leading from celiac disease to ischemic heart disease. As acknowledged by the authors, information about known risk factors of ischemic heart disease, including blood pressure, body mass index, lipids, exercise, and, especially, smoking, would be important. It has been suggested that active smoking has a protective effect for the development of celiac disease.^2–4 Ludvigsson et al performed a sensitivity analysis on a smaller subset with limited data on smoking.¹ After adjusting for smoking, body mass index, and nationality, the hazard ratio indeed increased, but was not statistically significant, probably because of the low event rate in this relatively young and selective subgroup. It would be interesting to explore whether the prevalence of smoking in this subset of pregnant women with celiac disease was lower than that in pregnant women without celiac disease. Similarly, the information about the role of other risk factors for ischemic heart disease in this subgroup would be of interest.

Before any conclusions can be drawn about potential underlying causal mechanisms, further studies with information about potential confounders are needed. However, as always, residual confounding might be an issue, Other approaches, such as mendelian randomization, might also be informative.⁵ If the association between celiac disease and ischemic heart disease is truly causal, common genetic variants related to celiac disease should also be associated with ischemic heart disease. Therefore, large-scale consortia focused on genome-wide association studies may enable such approaches.

Ludvigsson et al¹ proposed a very intriguing hypothesis for the mechanisms underlying the associations between celiac disease and ischemic heart disease. However, studies focused on the causality of these associations are needed before cardiovascular risk assessment will be part of the clinical guidelines for treatment of celiac disease.