Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates <italic toggle="yes">PRKCA</italic>

ABSTRACT 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...

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Autores principales:	Genevieve L. Wojcik, Poonum Korpe, Chelsea Marie, Alexander J. Mentzer, Tommy Carstensen, Josyf Mychaleckyj, Beth D. Kirkpatrick, Stephen S. Rich, Patrick Concannon, A. S. G. Faruque, Rashidul Haque, William A. Petri, Priya Duggal
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Cryptosporidium genetics genome analysis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f3c1e733c46640059450c4c85e820484
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spelling	oai:doaj.org-article:f3c1e733c46640059450c4c85e8204842021-11-15T15:56:58ZGenome-Wide Association Study of Cryptosporidiosis in Infants Implicates <italic toggle="yes">PRKCA</italic>10.1128/mBio.03343-192150-7511https://doaj.org/article/f3c1e733c46640059450c4c85e8204842020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03343-19https://doaj.org/toc/2150-7511ABSTRACT 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.Genevieve L. WojcikPoonum KorpeChelsea MarieAlexander J. MentzerTommy CarstensenJosyf MychaleckyjBeth D. KirkpatrickStephen S. RichPatrick ConcannonA. S. G. FaruqueRashidul HaqueWilliam A. PetriPriya DuggalAmerican Society for MicrobiologyarticleCryptosporidiumgeneticsgenome analysisMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cryptosporidium genetics genome analysis Microbiology QR1-502
spellingShingle	Cryptosporidium genetics genome analysis Microbiology QR1-502 Genevieve L. Wojcik Poonum Korpe Chelsea Marie Alexander J. Mentzer Tommy Carstensen Josyf Mychaleckyj Beth D. Kirkpatrick Stephen S. Rich Patrick Concannon A. S. G. Faruque Rashidul Haque William A. Petri Priya Duggal Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates <italic toggle="yes">PRKCA</italic>
description	ABSTRACT 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.
format	article
author	Genevieve L. Wojcik Poonum Korpe Chelsea Marie Alexander J. Mentzer Tommy Carstensen Josyf Mychaleckyj Beth D. Kirkpatrick Stephen S. Rich Patrick Concannon A. S. G. Faruque Rashidul Haque William A. Petri Priya Duggal
author_facet	Genevieve L. Wojcik Poonum Korpe Chelsea Marie Alexander J. Mentzer Tommy Carstensen Josyf Mychaleckyj Beth D. Kirkpatrick Stephen S. Rich Patrick Concannon A. S. G. Faruque Rashidul Haque William A. Petri Priya Duggal
author_sort	Genevieve L. Wojcik
title	Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates <italic toggle="yes">PRKCA</italic>
title_short	Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates <italic toggle="yes">PRKCA</italic>
title_full	Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates <italic toggle="yes">PRKCA</italic>
title_fullStr	Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates <italic toggle="yes">PRKCA</italic>
title_full_unstemmed	Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates <italic toggle="yes">PRKCA</italic>
title_sort	genome-wide association study of cryptosporidiosis in infants implicates <italic toggle="yes">prkca</italic>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/f3c1e733c46640059450c4c85e820484
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Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates <italic toggle="yes">PRKCA</italic>

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