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Genome-wide Association Study Links HLA Allele to Typhoid Fever Resistance

NEW YORK (GenomeWeb) – Through a genome-wide association study, an international team of researchers has identified a variant linked with resistance to typhoid fever.

By examining the genomes of some 430 people with enteric fever and more than 2,000 controls, Chiea Chuen Khor from the Genome Institute of Singapore and his colleagues homed in on a marker mapping to the HLA class II region. Then using imputation-based fine-mapping, they found that an HLA-DRB1 allele contributed to resistance to typhoid, as they reported in Nature Genetics today.

"The interface between the human host and the pathogen likely has a critical role in determining outcome during an enteric fever infection," Khor and his colleagues wrote in their paper.

There are nearly 27 million cases of enteric fever each year, leading to some 200,000 deaths. The disease is caused by eating food contaminated with feces harboring either Salmonella enterica Typhi or S. enterica Paratyphi. While the genetic variability of the bacteria has been studied, the researchers noted that human host factors influencing susceptibility to typhoid fever have really not been examined.

To perform their GWAS, Khor and his colleagues turned to a Vietnamese cohort of 432 people with S. enterica Typhi infections, as determined through blood cultures, and 2,011 controls. They genotyped the cohort using the Illumina OmniExpress BeadChip or the Illumina 660W BeadChip as well as the Ilumina Human Exome BeadChip.

They found that the strongest association signal mapped to the SNP rs7765379, which is located in the class II human leukocyte antigen region near both the HLA-DQB1 and HLA-DRB1 genes. Another significant signal mapped to near the GUCY1A3 gene.

In an independent Nepalese cohort of 595 cases of enteric fever and 386 controls, Khor and his colleagues were able to replicate the association they found with the rs7765379 SNP, but not the other one near the GUCY1A3 gene. They further confirmed this association between rs7765379 and enteric fever in an additional 151 people with disease and 668 healthy people from Vietnam.

A meta-analysis of these discovery and replication cohorts also confirmed a significant association at rs7765379, and the researchers calculated that the minor allele at that spot was associated with a 4.55-fold increase in resistance to enteric fever.

Using a combined reference panel of East Asian and European individuals, the researchers also performed a statistical imputation of the classical HLA alleles and corresponding amino acids. Through this approach, they traced the strongest association to the classical HLA-DRB1*04:05 allele, which they noted was in tight linkage disequilibrium with rs7765379.

None of the omnibus test P values they calculated for each amino acid position encoded by the eight HLA genes was more significant than the HLA-DRB1*04:05 allele. Indeed, after Khor and his colleagues controlled for the effect of rs7765379, they still found a significant association with the HLA-DRB1*04:05 allele, suggesting that that allele is a driving factor for the signal they picked up.

To verify their imputation results, the researchers performed HLA typing on 140 people from their GWAS discovery cohort, finding a concordance of 99.3 percent between the typed and imputed alleles.

HLA-DRB1 encodes the β chain of HLA-DR and is an HLA class II molecule that presents antigens to CD4 + T lymphocytes. The researchers speculate that variations within HLA-DR could alter the ability of the HLA class II molecules to present antigens and, in turn, affect immune response.

"Presence of the HLA- DRB1*04:05 allele might tip the poise of pathogenicity between the invading pathogen and host immune response toward the human host, resulting in as much as fivefold greater protection from enteric fever," Khor and his colleagues said.