Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates PRKCA.

Diarrhea is a major cause of both morbidity and mortality worldwide, especially among young children. Cryptosporidiosis is a leading cause of diarrhea in children, particularly in South Asia and sub-Saharan Africa, where it is responsible for over 200,000 deaths per year. Beyond the initial clinical presentation of diarrhea, it is associated with long-term sequelae such as malnutrition and neurocognitive developmental deficits. Risk factors include poverty and overcrowding, and yet not all children with these risk factors and exposure are infected, nor do all infected children develop symptomatic disease. One potential risk factor to explain these differences is their human genome. To identify genetic variants associated with symptomatic cryptosporidiosis, we conducted a genome-wide association study (GWAS) examining 6.5 million single nucleotide polymorphisms (SNPs) in 873 children from three independent cohorts in Dhaka, Bangladesh, namely, the Dhaka Birth Cohort (DBC), the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study, and the Cryptosporidiosis Birth Cohort (CBC). Associations were estimated separately for each cohort under an additive model, adjusting for length-for-age Z-score at 12 months of age, the first two principal components to account for population substructure, and genotyping batch. The strongest meta-analytic association was with rs58296998 (P = 3.73 × 10-8), an intronic SNP and expression quantitative trait locus (eQTL) of protein kinase C alpha (PRKCA). Each additional risk allele conferred 2.4 times the odds of Cryptosporidium-associated diarrhea in the first year of life. This genetic association suggests a role for protein kinase C alpha in pediatric cryptosporidiosis and warrants further investigation.IMPORTANCE Globally, diarrhea remains one of the major causes of pediatric morbidity and mortality. The initial symptoms of diarrhea can often lead to long-term consequences for the health of young children, such as malnutrition and neurocognitive developmental deficits. Despite many children having similar exposures to infectious causes of diarrhea, not all develop symptomatic disease, indicating a possible role for human genetic variation. Here, we conducted a genetic study of susceptibility to symptomatic disease associated with Cryptosporidium infection (a leading cause of diarrhea) in three independent cohorts of infants from Dhaka, Bangladesh. We identified a genetic variant within protein kinase C alpha (PRKCA) associated with higher risk of cryptosporidiosis in the first year of life. These results indicate a role for human genetics in susceptibility to cryptosporidiosis and warrant further research to elucidate the mechanism

Epidemiology and Risk Factors for Cryptosporidiosis in Children from 8 Low-income Sites : Results from the MAL-ED Study

Funding Information: The MAL-ED study is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health (NIH), and the NIH Fogarty International Center. This work was also supported by the National Institute of Allergy and Infectious Diseases of the NIH (grant numbers K23 AI087910 to P. K. and K23 AI087910 to W. A. P.) and by the Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases Discovery Program (to P. D.).Peer reviewedPublisher PD

Calcified Neurocysticercus, Perilesional Edema, and Histologic Inflammation

Here, we present the second report of the histopathology of a Taenia solium calcification giving rise to perilesional edema. This has important implications, because if perilesional edema lesions are inflammatory in character, immunosuppressive or anti-inflammatory medications, not just antiepileptic drugs alone, may be useful to prevent or treat recurring episodes in such patients

Total number of diarrheal episodes per month.

<p>The x-axis represents the child’s age in months, and the y-axis represents total number of diarrheal episodes per age-month. The dark blue segment represents number of total diarrheal episodes, and the light blue segment represents the proportion of diarrheal episodes per month that test positive for <i>Cryptosporidium species</i>. In each month, the total possible number of children included is 392. Cryptosporidium infection makes up a very small portion of the total burden of diarrhea in our cohort.</p

Natural History of Cryptosporidiosis in a Longitudinal Study of Slum-Dwelling Bangladeshi Children: Association with Severe Malnutrition

<div><p>Background</p><p>Cryptosporidiosis is a common cause of infectious diarrhea in young children worldwide, and is a significant contributor to under-five mortality. Current treatment options are limited in young children. In this study, we describe the natural history of <i>Cryptosporidium spp</i>. infection in a birth cohort of children in Bangladesh and evaluate for association with malnutrition.</p><p>Methodology/Principal Findings</p><p>This is a longitudinal birth cohort study of 392 slum-dwelling Bangladeshi children followed over the first two years of life from 2008 to 2014. Children were monitored for diarrheal disease, and stool was tested for intestinal protozoa. Anthropometric measurements were taken at 3-month intervals. A subset of <i>Cryptosporidium</i> positive stools were genotyped for species and revealed that <i>C</i>. <i>hominis</i> was isolated from over 90% of samples. In the first two years of life, 77% of children experienced at least one infection with <i>Cryptosporidium spp</i>. Non-diarrheal infection (67%) was more common than diarrheal infection (6.3%) although 27% of children had both types of infection. Extreme poverty was associated with higher rates of infection (chi-square, 49.7% vs 33.3%, <i>p</i> = 0.006). Malnutrition was common in this cohort, 56% of children had stunted growth by age two. Children with <i>Cryptosporidium spp</i>. infection had a greater than 2-fold increased risk of severe stunting at age two compared to uninfected children (odds ratio 2.69, 95% CI 1.17, 6.15, <i>p</i> = 0.019) independent of sex, income, maternal body-mass index, maternal education and weight for age adjusted <i>z</i> (WAZ) score at birth.</p><p>Conclusions/Significance</p><p><i>Cryptosporidium</i> infection is common (77%) in this cohort of slum-dwelling Bangladeshi children, and both non-diarrheal and diarrheal infections are significantly associated with a child’s growth at 2 years of age.</p></div

Box plot of mean height-for-age adjusted z-scores over first 24 months of life.

<p>In this cohort of 392 children, mean HAZ dropped continuously over the first two years of life, which was also consistently well below the W.H.O. reference population mean (indicated by red line).</p

Comparison of demographics of 392 children who completed two years of follow up.

<p>Comparison of demographics of 392 children who completed two years of follow up.</p