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FUT2 non-secretor status is associated with altered susceptibility to symptomatic enterotoxigenic Escherichia coli infection in Bangladeshis.

ABSTRACT: Polymorphisms of the FUT2 gene alters glycan ABO(H) blood group and Lewis antigen expression (commonly known as non-secretor status) in the small intestinal mucosa. Whilst non-secretor status affects 20% of the population worldwide, it has been reported to be present in up to 40% of all Bangladeshis. Furthermore, Bangladeshi children are reportedly more susceptible to symptomatic enterotoxigenic Escherichia coli (ETEC) infection if they are non-secretors. Therefore, in an attempt to identify a non-secretor status genotypic biomarker of altered susceptibility to ETEC infection, we used the 1000 Genomes Project to identify three population related non-synonymous FUT2 single nucleotide polymorphisms (SNPs). We then assessed the genotypic frequency of these SNPs in Bangladeshi children who had been clinically monitored for ETEC infection. One novel missense FUT2 SNP, rs200157007-TT and the earlier established rs601338-AA SNP were shown to be causing non-secretor status, with these SNPs being associated with symptomatic but not asymptomatic ETEC infection. Moreover, rs200157007-TT and rs601338-AA were associated with symptomatic but not asymptomatic ETEC infection irrespective of the child's Lewis secretor status, suggesting FUT2, the regulator of Lewis and ABO(H) antigens in the intestinal mucosa, could be a host genotypic feature affecting susceptibility to ETEC infection.

SUBMITTER: Mottram L

PROVIDER: S-EPMC5587594 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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FUT2 non-secretor status is associated with altered susceptibility to symptomatic enterotoxigenic Escherichia coli infection in Bangladeshis.

Mottram Lynda L Wiklund Gudrun G Larson Göran G Qadri Firdausi F Svennerholm Ann-Mari AM

Scientific reports 20170906 1

Polymorphisms of the FUT2 gene alters glycan ABO(H) blood group and Lewis antigen expression (commonly known as non-secretor status) in the small intestinal mucosa. Whilst non-secretor status affects 20% of the population worldwide, it has been reported to be present in up to 40% of all Bangladeshis. Furthermore, Bangladeshi children are reportedly more susceptible to symptomatic enterotoxigenic Escherichia coli (ETEC) infection if they are non-secretors. Therefore, in an attempt to identify a n ...[more]

PMID: 28878367

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Project description:Background: The FUT2 (fucosyltransferase-2) gene determines blood group secretor status. Being homozygous for the inactive "non-secretor" rs601338(A) allele confers resistance to certain infections (e.g. Norovirus, Rotavirus) and susceptibility to others (e.g. Haemophilus influenza, Streptococcus pneumonia). Non-secretors also have an increased risk of type 1 diabetes and inflammatory bowel disease. We examined FUT2 genotype, infections and chronic conditions in a population-based cohort. Methods: We studied 7,582 pregnant women from the ALSPAC pregnancy cohort. Infections (measles, mumps, chicken pox, whooping cough, meningitis, herpes, gonorrhea and urinary infections) and chronic conditions (kidney disease, hypertension, diabetes, rheumatism, arthritis, psoriasis, hay fever, asthma, eczema and allergies) were self-reported. FUT2 secretor status was determined from the rs601338 genotype. ABO blood type was obtained from clinical records. Results: Overall, 1920 women (25.3%) were homozygous for the non-secretor allele (AA). Secretor status was associated with mumps, with 68% of non-secretors experiencing this infection, compared to 48% of secretors (RR, 1.40; 95% CI, 1.34-1.46). A weaker association was observed for measles infection (76% vs. 72%; RR, 1.05; 95% CI, 1.02-1.09). Non-secretors also experienced an increased risk of kidney disease (5.4% vs. 3.9%; RR, 1.39; 95% CI, 1.11-1.75). Independent of secretor status, AB blood type was a risk factor for mumps (RR 1.15; 95%CI, 1.03, 1.28 compared to type O). We found no evidence of interaction between secretor status and blood type. For some conditions, including asthma and arthritis, FUT2 heterozygosity (GA) appeared to confer an intermediate phenotype. There was no strong evidence of association between secretor status and other infections or chronic conditions, although statistical power was limited for rare outcomes. Conclusion: Our results identify an association between FUT2 secretor status and self-reported kidney disease, and confirm a recently reported association with susceptibility to mumps infection. The clinical implications of these associations warrant further investigation.

Project description:ImportanceA genetic polymorphism affecting FUT2 secretor status in approximately one-quarter of humans of European descent affects the expression of histo-blood group antigens on the mucosal epithelia of human respiratory, genitourinary, and digestive tracts. These histo-blood group antigens serve as host receptor sites necessary for attachment and infection of some pathogens, including norovirus.ObjectiveWe investigated whether an association exists between FUT2 secretor status and laboratory-confirmed rotavirus infections in US children.Design, setting, and participantsMulticenter case-control observational study involving active surveillance at 6 US pediatric medical institutions in the inpatient and emergency department clinical settings. We enrolled 1564 children younger than 5 years with acute gastroenteritis (diarrhea and/or vomiting) and 818 healthy controls frequency matched by age and month, from December 1, 2011, through March 31, 2013.Main outcomes and measuresPaired fecal-saliva specimens were tested for rotavirus and for secretor status. Comparisons were made between rotavirus test-positive cases and healthy controls stratified by ethnicity and vaccination status. Adjusted multivariable analyses assessed the preventive association of secretor status against severe rotavirus gastroenteritis.ResultsOne (0.5%) of 189 rotavirus test-positive cases was a nonsecretor, compared with 188 (23%) of 818 healthy control participants (P < .001). Healthy control participants of Hispanic ethnicity were significantly less likely to be nonsecretors (13%) compared with healthy children who were not of Hispanic ethnicity (25%) (P < .001). After controlling for vaccination and other factors, children with the nonsecretor FUT2 polymorphism appeared statistically protected (98% [95% CI, 84%-100%]) against severe rotavirus gastroenteritis.Conclusions and relevanceSevere rotavirus gastroenteritis was virtually absent among US children who had a genetic polymorphism that inactivates FUT2 expression on the intestinal epithelium. We observed a strong epidemiologic association among children with rotavirus gastroenteritis compared with healthy control participants. The exact cellular mechanism behind this epidemiologic association remains unclear, but evidence suggests that it may be rotavirus genotype specific. The lower prevalence of nonsecretors among Hispanic children may translate to an enhanced burden of rotavirus gastroenteritis among this group. Our findings may have bearing on our full understanding of rotavirus infections and the effects of vaccination in diverse populations.

Project description:Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrhea in children in low- and middle-income countries (LMICs). However, large-scale pathogen burden studies in children have identified ETEC in the guts of both symptomatic patients and controls. The factors that influence this balance are poorly understood, but it is postulated that the gut microbiome may play a role in either resistance or progression to disease. In this study, we profiled the microbiomes of children and adults from Bangladesh who were asymptomatically or symptomatically infected with ETEC. Symptomatic patients had significantly higher numbers of sequenced reads mapping to both E. coli and two ETEC toxins, suggesting higher bacterial burden. They were also significantly more likely to be coinfected with enteroaggregative E. coli (EAEC) and had higher proportions of other Gammaproteobacteria, including Klebsiella, Salmonella, and Haemophilus. Colonization with ETEC was also associated with increased prevalence of antimicrobial resistance (AMR) genes, most notably those of the β-lactamase class. Taxonomic profiles were distinctly different between all groups in both species richness and composition, although the direction of these changes was different in adults and children. As seen previously, children with high E. coli burdens also had higher proportions of Streptococcus spp., while healthy children were more heavily colonized by Bifidobacterium spp. Our study provides insight into the microbiome changes that occur upon infection with ETEC in an endemic setting and provides rationale for future studies investigating how the microbiome may protect or predispose individuals to symptomatic infections with gastrointestinal pathogens. IMPORTANCE Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrhea in children in low- and middle-income countries. However, these bacteria are often identified in both patients and healthy controls. We do not yet understand why only some people get sick, but it has been suggested that the gut microbiome might play a role. In this study, we used metagenomic sequencing to profile the gut microbiomes of individuals in Bangladesh, with or without a symptomatic ETEC infection. In general, individuals with high levels of ETEC also harbored other pathogenic E. coli strains, higher proportions of Gammaproteobacteria such as Salmonella and Klebsiella, and a higher burden of antimicrobial resistance genes in their guts. Healthy children, in contrast, had higher levels of bifidobacteria. These data confirm that the composition of the gut microbiome is different between symptomatic and asymptomatic people and provides important preliminary information on the impact of the gut microbiome in intestinal infections.

Dataset Information

FUT2 non-secretor status is associated with altered susceptibility to symptomatic enterotoxigenic Escherichia coli infection in Bangladeshis.

Publications

FUT2 non-secretor status is associated with altered susceptibility to symptomatic enterotoxigenic Escherichia coli infection in Bangladeshis.

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