Genome-Wide Analysis Identifies IL-18 and FUCA2 as Novel Genes Associated with Diastolic Function in African Americans with Sickle Cell Disease
AuthorDuarte, Julio D.
Desai, Ankit A.
Sysol, Justin R.
Patel, Amit R.
Lang, Roberto M.
Garcia, Joe G. N.
Gordeuk, Victor R.
Machado, Roberto F.
AffiliationUniv Arizona, Dept Med
Univ Arizona, Sarver Heart Ctr, Div Cardiol
MetadataShow full item record
PublisherPUBLIC LIBRARY SCIENCE
CitationGenome-Wide Analysis Identifies IL-18 and FUCA2 as Novel Genes Associated with Diastolic Function in African Americans with Sickle Cell Disease 2016, 11 (9):e0163013 PLOS ONE
Rights© 2016 Duarte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License
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AbstractBackground Diastolic dysfunction is common in sickle cell disease (SCD), and is associated with an increased risk of mortality. However, the molecular pathogenesis underlying this development is poorly understood. The aim of this study was to identify a gene expression profile that is associated with diastolic function in SCD, potentially elucidating molecular mechanisms behind diastolic dysfunction development. Methods Diastolic function was measured via echocardiography in 65 patients with SCD from two independent study populations. Gene expression microarray data was compared with diastolic function in both study cohorts. Candidate genes that associated in both analyses were tested for validation in a murine SCD model. Lastly, genotyping array data from the replication cohort was used to derive cis-expression quantitative trait loci (cis-eQTLs) and genetic associations within the candidate gene regions. Results Transcriptome data from both patient cohorts implicated 7 genes associated with diastolic function, and mouse SCD myocardial expression validated 3 of these genes. Genetic associations and eQTLs were detected in 2 of the 3 genes, FUCA2 and IL18. Conclusions FUCA2 and IL18 are associated with diastolic function in SCD patients, and may be involved in the pathogenesis of the disease. Genetic polymorphisms within the FUCA2 and IL18 gene regions are also associated with diastolic function in SCD, likely by affecting expression levels of the genes.
NoteOpen access journal.
VersionFinal published version
SponsorsNational Institute of General Medical Sciences [K23 GM112014]; American Heart Association [14CRP18910051]; PHA Research Fellowship /ATS Foundation; National Heart, Lung, and Blood Institute [F30 HL128034, R01 HL111656, R01 HL127342]