Genome-Wide Association Study of Campylobacter-Positive Diarrhea Identifies Genes Involved in Toxin Processing and Inflammatory Response

Abstract

Diarrhea is responsible for the deaths of more than 500,000 children each year, many of whom reside in low-to-middle-income countries (LMICs). Additionally, children with multiple diarrheal infections early in life have increased growth stunting and malnutrition and decreased vaccine efficacy. Two bacteria that contribute to the burden of diarrhea are Campylobacter jejuni and Campylobacter coli, both are endemic in Bangladesh. However, not all children that are exposed to these pathogens, including Campylobacter, will experience diarrhea. We hypothesized that host genetics may influence susceptibility to Campylobacter infections and performed a genome-wide association study in 534 children from two independent birth cohorts in Dhaka, Bangladesh. Infants were monitored for diarrhea for the first 2 years of life and only defined as controls if all diarrheal samples in the first year were negative for Campylobacter jejuni/C. coli. Each cohort was analyzed separately under an additive model and adjusted for length-for-age z-scores at birth and 12 months, sex, water treatment, and ancestry. In a fixed effect inverse-variance weighted meta-analysis of these two cohorts, we identified a genome-wide significant region on chromosome 8 in intron 4 of the rho guanine nucleotide exchange factor 10 gene (ARHGEF10). Individuals with the G allele (rs13281104) had a 2-fold lower risk of having a Campylobacter-associated diarrheal episode than individuals with the A allele (OR 0.41, 95% CI 0.29 to 0.58, P = 3.6 1027). This SNP is associated with decreased expression of the neighboring gene, CLN8, which may be involved in the transport of the cytolethal distending toxin produced by Campylobacter.