Dataset Information

Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children.

ABSTRACT: Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10(-9); OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.

SUBMITTER: Kenyan Bacteraemia Study Group

PROVIDER: S-EPMC4908194 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children.

Rautanen Anna A Pirinen Matti M Mills Tara C TC Rockett Kirk A KA Strange Amy A Ndungu Anne W AW Naranbhai Vivek V Gilchrist James J JJ Bellenguez Céline C Freeman Colin C Band Gavin G Bumpstead Suzannah J SJ Edkins Sarah S Giannoulatou Eleni E Gray Emma E Dronov Serge S Hunt Sarah E SE Langford Cordelia C Pearson Richard D RD Su Zhan Z Vukcevic Damjan D Macharia Alex W AW Uyoga Sophie S Ndila Carolyne C Mturi Neema N Njuguna Patricia P Mohammed Shebe S Berkley James A JA Mwangi Isaiah I Mwarumba Salim S Kitsao Barnes S BS Lowe Brett S BS Morpeth Susan C SC Khandwalla Iqbal I Blackwell Jenefer M JM Bramon Elvira E Brown Matthew A MA Casas Juan P JP Corvin Aiden A Duncanson Audrey A Jankowski Janusz J Markus Hugh S HS Mathew Christopher G CG Palmer Colin N A CNA Plomin Robert R Sawcer Stephen J SJ Trembath Richard C RC Viswanathan Ananth C AC Wood Nicholas W NW Deloukas Panos P Peltonen Leena L Williams Thomas N TN Scott J Anthony G JAG Chapman Stephen J SJ Donnelly Peter P Hill Adrian V S AVS Spencer Chris C A CCA

American journal of human genetics 20160526 6

Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Strep ...[more]

PMID: 27236921

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Project description:BackgroundGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency state in humans. The clinical phenotype is variable and includes asymptomatic individuals, episodic hemolysis induced by oxidative stress, and chronic hemolysis. G6PD deficiency is common in malaria-endemic regions, an observation hypothesized to be due to balancing selection at the G6PD locus driven by malaria. G6PD deficiency increases risk of severe malarial anemia, a key determinant of invasive bacterial disease in malaria-endemic settings. The pneumococcus is a leading cause of invasive bacterial infection and death in African children. The effect of G6PD deficiency on risk of pneumococcal disease is undefined. We hypothesized that G6PD deficiency increases pneumococcal disease risk and that this effect is dependent upon malaria.MethodsWe performed a genetic case-control study of pneumococcal bacteremia in Kenyan children stratified across a period of falling malaria transmission between 1998 and 2010.ResultsFour hundred twenty-nine Kenyan children with pneumococcal bacteremia and 2677 control children were included in the study. Among control children, G6PD deficiency, secondary to the rs1050828 G>A mutation, was common, with 11.2% (n = 301 of 2677) being hemi- or homozygotes and 33.3% (n = 442 of 1329) of girls being heterozygotes. We found that G6PD deficiency increased the risk of pneumococcal bacteremia, but only during a period of high malaria transmission (P = 0.014; OR 2.33, 95% CI 1.19-4.57). We estimate that the population attributable fraction of G6PD deficiency on risk of pneumococcal bacteremia in areas under high malaria transmission is 0.129.ConclusionsOur data demonstrate that G6PD deficiency increases risk of pneumococcal bacteremia in a manner dependent on malaria. At the population level, the impact of G6PD deficiency on invasive pneumococcal disease risk in malaria-endemic regions is substantial. Our study highlights the infection-associated morbidity and mortality conferred by G6PD deficiency in malaria-endemic settings and adds to our understanding of the potential indirect health benefits of improved malaria control.

Project description:Objective:To investigate the prevalence, risk factors, clinical features, and neurobehavioral comorbidities of epilepsy and acute symptomatic seizures in school-aged children in Kilifi, Kenya. Methods:Randomly selected children (N = 11,223) were screened for epilepsy and other neurodevelopmental disorders. Those who screened positive were invited for further clinical, electroencephalographic (EEG), and neuropsychological evaluations. Prevalence was measured by dividing cases by screened population, providing Agresti-Coull confidence intervals (CIs). Prevalence ratios were computed using log binomial regression, and odds ratios (ORs) were computed using logistic regression; both were implemented with generalized linear models. Attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other neurodevelopmental impairments were assessed in cases and controls. Results:Prevalence of lifetime epilepsy was 20.9 per 1,000 (95% CI = 18.4-23.7), and that of active epilepsy was 11.5 per 1,000 (95% CI = 9.7-13.6). Prevalence of acute symptomatic seizures was 68.8 per 1,000 (95% CI = 64.2-73.6). Acute symptomatic seizures preceded a diagnosis of epilepsy in 8% of children. Of 98 children diagnosed with epilepsy, focal seizures were seen in 79%, abnormal EEG was seen in 39%, and 83% were not receiving antiepileptic drugs. Childhood absence epilepsy and Lennox-Gastaut epilepsy were the most easily identifiable epilepsy syndromes. Perinatal complications, previous hospitalization, geophagia, and snoring were risk factors for epilepsy. Family history of seizures, abnormal pregnancy, previous hospitalization, and snoring were risk factors for acute symptomatic seizures. Neurobehavioral comorbidities were present in 54% of subjects with lifetime epilepsy and in 3% of controls, with associations for individual comorbidities being statistically significant: ADHD (OR = 14.55, 95% CI = 7.54-28.06), ASD (OR = 36.83, 95% CI = 7.97-170.14), and cognitive impairments (OR = 14.55, 95% CI = 3.52-60.14). Significance:The burden of seizure disorders in this area is higher than in locations in high-income countries, and can be reduced by preventing risk factors. A comprehensive management plan for neurobehavioral comorbidities of epilepsy should be incorporated into standard epilepsy care.

Project description:The GAVI Alliance supported 10-valent pneumococcal conjugate vaccine (PCV10) introduction in Kenya. We estimated the cost-effectiveness of introducing either PCV10 or the 13-valent vaccine (PCV13) from a societal perspective and explored the incremental impact of including indirect vaccine effects.The costs and effects of pneumococcal vaccination among infants born in Kenya in 2010 were assessed using a decision analytic model comparing PCV10 or PCV13, in turn, with no vaccination. Direct vaccine effects were estimated as a reduction in the incidence of pneumococcal meningitis, sepsis, bacteraemic pneumonia and non-bacteraemic pneumonia. Pneumococcal disease incidence was extrapolated from a population-based hospital surveillance system in Kilifi and adjustments were made for variable access to care across Kenya. We used vaccine efficacy estimates from a trial in The Gambia and accounted for serotype distribution in Kilifi. We estimated indirect vaccine protection and serotype replacement by extrapolating from the USA. Multivariable sensitivity analysis was conducted using Monte Carlo simulation. We assumed a vaccine price of US$ 3.50 per dose.The annual cost of delivering PCV10 was approximately US$14 million. We projected a 42.7% reduction in pneumococcal disease episodes leading to a US$1.97 million reduction in treatment costs and a 6.1% reduction in childhood mortality annually. In the base case analysis, costs per discounted DALY and per death averted by PCV10, amounted to US$ 59 (95% CI 26-103) and US$ 1,958 (95% CI 866-3,425), respectively. PCV13 introduction improved the cost-effectiveness ratios by approximately 20% and inclusion of indirect effects improved cost-effectiveness ratios by 43-56%. The break-even prices for introduction of PCV10 and PCV13 are US$ 0.41 and 0.51, respectively.Introducing either PCV10 or PCV13 in Kenya is highly cost-effective from a societal perspective. Indirect effects, if they occur, would significantly improve the cost-effectiveness.

Dataset Information

Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children.

Publications

Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children.

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