Variation at HLA-DRB1 is associated with resistance to enteric fever

Abstract

Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C1. We conducted a genome-wide association study of 432 individuals with blood culture–confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10−10), a marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1* 04:05 allele (OR = 0.14, P = 2.60 × 10−11) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.

Genetic susceptibility to invasive Salmonella disease

“…Patients with enteric fever and the protective haplotype were shown to produce statistically significantly less TNF ex vivo on whole blood stimulation with LPS on day four of disease 59 . However, this finding should be interpreted with caution, as this effect was not seen in a better-powered GWAS of enteric fever in the same population 6 .…”

Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections

“…Further analysis of the Vietnamese population again suggested that a haplotype in the TNF region gives protection against enteric fever, but the causative disease locus remains to be determined (32). In a recent genome-wide association study of patients in Vietnam and Nepal with blood culture-confirmed enteric fever, a strong association was found for HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation (33).…”

Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) evolution after silicone implants. Who is at risk?

“…More importantly, the co-occurrence of type-1 diabetes and celiac disease [53] in the same patients was linked to HLA-C exemplifying both genetic predisposition as well as coexistence of two immunologic phenomena. Taken together, these associations between HLA subgroups and autoimmunity are believed to represent a hyperactive immune system with the disadvantage of autoimmunity risk in one hand and an evolutionary advantage in fighting infections, such as enteric fever [54]. In addition to the genetic predisposition, environmental factors have also been linked to autoimmunity.…”