Connexin 26 (GJB2) is one of the major factors in human deafness worldwide. On average 1/1000 children is born deaf and the most common GJB2 variant (c.35delG) causes ∼40% of cases in Southern Europe. Carriers’ frequency for different loss-of-function GJB2 mutations is very high worldwide (up to 3%),1 suggesting a heterozygous advantage for a global condition or a founder effect.2 In this light, epidermal thickening in GJB2 carriers3, 4 has been proposed as a possible advantage reducing infections and bacterial invasion through skin.5, 6 Moreover, in vitro functional studies demonstrated that the loss-of-functional GJB2 expression provides improved protection against gastrointestinal bacterial pathogens.7 In particular, enteropathogenic Escherichia coli and Shigella flexneri may induce a strong selective effect, being the most common causes of diarrhoea. Thus, GJB2 carriers might have an increased resistance to gastrointestinal infectious diseases, as already proposed by Simpson et al.7

To test this hypothesis, a cross-sectional study involving 203 subjects aged 19–65 years (63% women) was carried out. Subjects (170) were wildtype for the GJB2 gene, whereas 33 carried one or more variants. The information about diarrhoea episodes and frequency, medical history and covariates (sex and age) was collected. People self-reporting diarrhoea episodes at least once a year were set as cases, whereas the remaining ones were controls (all the subject had similar level of education) (Table 1; Figure 1). Subjects affected by pertinent chronic diseases (Crohn’s disease, Intestinal bowel disease and so on) were excluded from the study. Fisher’s exact test was performed for case/control proportion in relation to genotype, giving a significant result (P=0.007), with an odds ratio (OR) of 3.21 (95% confidence interval (CI): 1.27–9.24). Although our sample was sex and age homogeneous (Wilcoxon test P>0.05), performing the same analysis separated by sex revealed that females mainly contributed to the finding (P=0.0016). In particular, in our data set women had higher incidence of diarrhoea than men (46% and 36% respectively), and for female GJB2 carriers this proportion dropped to 12.5%, with an OR=8.33 (95% CI: 1.82–78.03). As regards to the reported frequency per die (range: 0–3), linear regression was applied, including covariates, and a significant effect for genotype was detected (P=0.006/0.017 for females/total sample) indicating lower diarrhoea frequency for GJB2 carriers.

Table 1 Summary of the analysed sample
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Figure 1
figure 1

Frequency of diarrhoea episodes per year. The figure shows a bar plot of reported frequencies of diarrhoea episodes per year by cases and controls separately.

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In conclusion, present clinical results provide new insights on GJB2 heterozygote advantage, further suggesting that it might consist in an increased resistance to gastrointestinal infections as already demonstrated by in vitro studies. Future research activities should be carried out to further confirm the present finding (eg, increasing the sample size) and to investigate whether GJB2 carriers have a different gut microbiota composition.