Silvia Kariuki (Kenya)
KEMRI-Wellcome Trust Research Programme Centre for Geographic Medicine Research-CoastAuthor Of 1 Presentation
BIRC6 MODIFIES RISK OF INVASIVE BACTERIAL INFECTION IN KENYAN CHILDREN.
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.