HLA class I and II associations with common enteric pathogens in the first year of life

Abstract

Background: genetic susceptibility to infection is mediated by numerous host factors, including the highly diverse, classical human leukocyte antigen (HLA) genes, which are critical genetic determinants of immunity. We systematically evaluated the effect of HLA alleles and haplotypes on susceptibility to 12 common enteric infections in children during the first year of life in an urban slum of Dhaka, Bangladesh.

Methods: a birth cohort of 601 Bangladeshi infants was prospectively monitored for diarrhoeal disease. Each diarrhoeal stool sample was analyzed for enteric pathogens by multiplex TaqMan Array Card (TAC). High resolution genotyping of HLA class I (A and B) and II (DRB1, DQA1, and DQB1) genes was performed by next-generation sequencing. We compared the frequency of HLA alleles and haplotypes between infected and uninfected children.

Findings: we identified six individual allele associations and one five-locus haplotype association. One allele was associated with protection: A*24:02 - EAEC. Five alleles were associated with increased risk: A*24:17 - typical EPEC, B*15:01 - astrovirus, B*38:02 - astrovirus, B*38:02 - Cryptosporidium and DQA1*01:01 - Cryptosporidium. A single five-locus haplotype was associated with protection: A*11:01~B*15:02~DRB1*12:02~DQA1*06:01~DQB1*03:01- adenovirus 40/41.

Interpretation: our findings suggest a role for HLA in susceptibility to early enteric infection for five pathogens. Understanding the genetic contribution of HLA in susceptibility has important implications in vaccine design and understanding regional differences in incidence of enteric infection.

Funding: this research was supported by the National Institute of Health (NIH) and the Bill and Melinda Gates Foundation.

Keywords: Bangladesh; Children; Diarrhoea; HLA; Infection; Susceptibility.