Alimentary Tract
Sex differences in coeliac disease risk: A Swedish sibling design study

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Abstract

Background

For unknown reasons girls are at an increased risk of coeliac disease compared to boys. However, the observed association might be confounded, since maternal coeliac disease is associated with both an increased risk of the disease in first-degree relatives as well as an increased ratio of girls to boys in offspring.

Aims

We investigate the effect of sex on the risk of coeliac disease before the age of two years using sibling design.

Methods

We identified all singleton children (n = 792,401) born between 1987 and 1993 in Sweden using the Swedish Medical Birth Registry. Coeliac disease cases (2264) were identified using the Swedish National Inpatient Registry. We applied both conventional population-based Cox regression models and sibling designs modelling the association in sex discordant siblings.

Results

We observed a conclusively increased risk of coeliac disease in girls compared to boys, using both sibling design (hazard ratio 1.67, 95% confidence interval 1.44–1.93) and conventional Cox regression analysis (hazard ratio 1.75, 95% confidence interval 1.61–1.91) that could not be explained by perinatal factors previously associated with the disease.

Conclusions

We confirm that female sex is causally associated with childhood coeliac disease, but the reasons remains unknown.

Introduction

Coeliac disease (CD) is an autoimmune chronic gastrointestinal disease affecting approximately 1% of the population [1]. The disease may result in clinically overt disease with symptoms such as diarrhoea, failure to thrive, and abdominal bloating, but the disease might also be asymtomatic [2]. It is a multifactorial disorder precipitated by ingestion of gluten and other related proteins present in wheat, rye, and barley [2]. The human leucocyte antigen (HLA) molecules −DQ2 and −DQ8 predispose for CD [3], but environmental factors such as breastfeeding and being born small for gestational age (SGA) are also considered to be of importance [4], [5], [6].

Females are at an almost two-fold increased risk for CD as compared to males in some previous studies which have used a population-based approach [7], [8], [9], [10], [11], one of those from our research group [11]. Although some studies have not been able to reproduce this increased risk of CD in girls [12], [13], [14]. In any case, the association previously observed might be due to confounding. Maternal CD is associated with an increased risk of the disease in offspring, estimated prevalence in first-degree relatives is about 5–20% [12], [15]. Also, maternal CD has been implied in an increased ratio of girls to boys in offspring [16], [17], [18]. Hence, the association between female sex and CD in children might be confounded by maternal CD.

We investigated the association between sex and CD risk before age two years using both conventional population-based approaches and sibling design [19], [20]. In the sibling design model we investigated the association within sex discordant siblings. This model is more appropriate for investigating causality [27], [28] compared to the conventional population-based models, as it by design adjusts for shared genetics and shared environmental exposures such as maternal disease.

Section snippets

Study population

Using the Swedish Medical Birth Registry, we identified all children in singleton pregnancies (n = 792,401) born in Sweden between December 31, 1986, and January 1, 1994. We excluded 1.2% (9528/792,401) of the children due to missing information about maternal identification number. We followed the selected 782,873 children from birth until two years of age, a diagnosis of CD, death, or emigration from Sweden. The age interval was chosen since previous research [8] indicates that sex is more

Characteristics of the population

CD was more prevalent before age two years in girls (0.4%; 1413/380,652) compared to boys 0.2% (851/402,221) (Table 1). Boys compared to girls had a higher rate of unfavourable birth outcomes such as caesarean deliveries (10.8% versus 10.2%) and congenital malformations (1.9% versus 1.5%) (Table 1). Maternal age, maternal smoking early in pregnancy and maternal primiparity were approximately equally distributed between boys and girls.

A total of 241,291 children born to 110,495 mothers during

Discussion

We observed that girls had a 1.7 times higher risk of CD compared to boys, using sibling design as well as conventional population-based Cox regression models. In the sibling design model we are able to control for known and unknown confounders such as maternal disease and shared genetics, which otherwise might confound the association. Our results suggest a causal association between female sex and CD, confirming previous observational reports [7], [8], [9], [10], [27]. We also confirmed,

Conflicts of interest

The authors have no conflicts of interests to declare.

Source of funding

This work was supported by the Centre for Economic Demography at Lund University, the Swedish Council for Working Life and Social Research (FAS) [Dnr: 2010-0402, PI Juan Merlo], and the Swedish Research Council (VR) [Dnr K2011-69X-15377-07-6, PI Juan Merlo].

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