A genome-wide association meta-analysis of diarrhoeal disease in young children identifiesFUT2locus and provides plausible biological pathways

Abstract

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.

Rotavirus infection beyond the gut

“…These HBGAs contain a carbohydrate structure, namely H type I antigen, whose synthesis is dependent on the FUT2 gene expression, which determines the secretor status. There is abundant evidence in the literature suggesting a strong association between the FUT2 gene and risk of infection with RV and other enteropathogens such as norovirus 5,49,50. Individuals with secretor phenotype have an increased susceptibility to RV, especially to P[8] genotype; conversely, severe RV gastroenteritis is virtually absent among children without FUT2 expression in the intestinal epithelium 51.…”

FUT2 secretor genotype and susceptibility to infections and chronic conditions in the ALSPAC cohort

“…Non-secretors have a lower risk of diarrheal illness 2 and ear infections in childhood 3 . The non-secretor phenotype also confers resistance to specific pathogens that require FUT2 -dependent antigens to infect host cells, including Norovirus 4 – 7 , Rotavirus 8 – 11 and Helicobacter pylori 12 , 13 .…”

Big Data’s Role in Precision Public Health

“…Big data is a component in studies that have shown new precision characteristics of such public health concerns as cholera ( 141 ), chikungunya ( 142 ), diabetes ( 143 , 144 ), diarrhea ( 145 ), heatwave ( 146 ), influenza ( 147 ), opioid epidemic ( 148 , 149 ), preterm birth ( 150 ), stunting ( 151 ), and Zika ( 152 ).…”