James J. Gilchrist (United Kingdom)

University of Oxford Department of Paediatrics
I am a paediatric infectious diseases registrar in Oxford. I completed my DPhil with Adrian Hill’s infectious diseases genetics group (Wellcome Centre for Human Genetics, University of Oxford) in 2016. My PhD studies expanded on a long-standing interest in nontyphoidal Salmonella (NTS) disease in African children and HIV-infected adults, performing a genome-wide association study of NTS disease in Kenyan and Malawian children. I joined Ben Fairfax’s group (WIMM, Oxford) in 2018 supported by an NIHR clinical lectureship. My current work aims to understand how environmental exposures, in particular CMV infection, interact with genetic determinants of immune cell function and how this modifies health outcomes. I continue to have an active interest in the host genetic determinants of invasive infection in African children, with ongoing collaborative studies investigating the human genetic determinants of leprosy in African populations and rotavirus disease in Kenyan and Ugandan children.

Author Of 1 Presentation

 Conference Calendar

BIRC6 MODIFIES RISK OF INVASIVE BACTERIAL INFECTION IN KENYAN CHILDREN.

Date
Wed, 11.05.2022
Session Time
15:40 - 17:15
Session Type
Parallel Symposium
Session Name
0420 - PARALLEL SYMPOSIUM: Management of Fever (ID 64)
Room
DIMITRIS MITROPOULOS HALL
Presenter
Lecture Time
17:01 - 17:09

Abstract

Backgrounds:

Invasive bacterial disease is a major cause of morbidity and mortality in African children. Here we leverage cases of bacterial sepsis among children diagnosed with severe malaria to augment study power in a genome-wide association study (GWAS) of invasive bacterial disease in Kenyan children.

Methods

We performed a GWAS of invasive bacterial infection in Kenyan children (n=5,482: 1,445 bacteraemia cases, 1,143 severe malaria cases, 2,894 controls). To account for the varying probabilty of invasive bacterial disease among malaria cases, we used probabilistic models to identify children with a high probability of culture-negative bacterial sepsis, applying these probabilities as weights for malaria cases in our analysis. We replicated our findings in a second sample collection (n=1,692: 434 bacteraemia cases, 1,258 controls).

Results:

In children with a clinical diagnosis of severe malaria, 31.1% have a low (P(SM|Data)<0.5) probability of their disease being ‘true’ severe malaria. These children are critically unwell (case fatality=14.5%) and are enriched for bacteraemia (OR=3.06, p=1.07 x10-4). We thus hypothesised that a substantial proportion of these children have bacterial sepsis. By including these children in a weighted logistic regression GWAS, we identify and validate rs183868412 as a risk locus for invasive bacterial infection in Kenyan children: ORdisc=2.14, Pdisc=4.02x10-9; ORrep=2.77, Prep=1.29x10-3; ORmeta=2.22, Pmeta=1.66 x10-11. This locus is a determinant of BIRC6 splicing in stimulated monocytes (PPcoloc=0.94).

Conclusions/Learning Points:

Here we identify children with a high likelihood of invasive bacterial disease among critically unwell Kenyan children with malaria. By including these children in a GWAS of invasive bacterial infection we identify and validate a novel risk locus for invasive bacterial disease. The trait-associated variation modifies splicing of BIRC6 in stimulated monocytes, implicating the regulation of apoptosis and autophagy in the pathogenesis of sepsis in African children.

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Presenter of 1 Presentation

 Conference Calendar

BIRC6 MODIFIES RISK OF INVASIVE BACTERIAL INFECTION IN KENYAN CHILDREN.

Date
Wed, 11.05.2022
Session Time
15:40 - 17:15
Session Type
Parallel Symposium
Session Name
0420 - PARALLEL SYMPOSIUM: Management of Fever (ID 64)
Room
DIMITRIS MITROPOULOS HALL
Presenter
Lecture Time
17:01 - 17:09

Abstract

Backgrounds:

Invasive bacterial disease is a major cause of morbidity and mortality in African children. Here we leverage cases of bacterial sepsis among children diagnosed with severe malaria to augment study power in a genome-wide association study (GWAS) of invasive bacterial disease in Kenyan children.

Methods

We performed a GWAS of invasive bacterial infection in Kenyan children (n=5,482: 1,445 bacteraemia cases, 1,143 severe malaria cases, 2,894 controls). To account for the varying probabilty of invasive bacterial disease among malaria cases, we used probabilistic models to identify children with a high probability of culture-negative bacterial sepsis, applying these probabilities as weights for malaria cases in our analysis. We replicated our findings in a second sample collection (n=1,692: 434 bacteraemia cases, 1,258 controls).

Results:

In children with a clinical diagnosis of severe malaria, 31.1% have a low (P(SM|Data)<0.5) probability of their disease being ‘true’ severe malaria. These children are critically unwell (case fatality=14.5%) and are enriched for bacteraemia (OR=3.06, p=1.07 x10-4). We thus hypothesised that a substantial proportion of these children have bacterial sepsis. By including these children in a weighted logistic regression GWAS, we identify and validate rs183868412 as a risk locus for invasive bacterial infection in Kenyan children: ORdisc=2.14, Pdisc=4.02x10-9; ORrep=2.77, Prep=1.29x10-3; ORmeta=2.22, Pmeta=1.66 x10-11. This locus is a determinant of BIRC6 splicing in stimulated monocytes (PPcoloc=0.94).

Conclusions/Learning Points:

Here we identify children with a high likelihood of invasive bacterial disease among critically unwell Kenyan children with malaria. By including these children in a GWAS of invasive bacterial infection we identify and validate a novel risk locus for invasive bacterial disease. The trait-associated variation modifies splicing of BIRC6 in stimulated monocytes, implicating the regulation of apoptosis and autophagy in the pathogenesis of sepsis in African children.

Hide