Genome-Wide Analysis Identifies IL-18 and FUCA2 as Novel Genes Associated with Diastolic Function in African Americans with Sickle Cell Disease.

TitleGenome-Wide Analysis Identifies IL-18 and FUCA2 as Novel Genes Associated with Diastolic Function in African Americans with Sickle Cell Disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsDuarte JD, Desai AA, Sysol JR, Abbasi T, Patel AR, Lang RM, Gupta A, Garcia JGN, Gordeuk VR, Machado RF
JournalPLoS One
Volume11
Issue9
Paginatione0163013
Date Published2016
ISSN Number1932-6203
KeywordsAdolescent, African Continental Ancestry Group, alpha-L-Fucosidase, Anemia, Sickle Cell, Animals, Diastole, Genome-Wide Association Study, Humans, Interleukin-18, Mice, Middle Aged, Quantitative Trait Loci
Abstract

<p><b>BACKGROUND: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>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.</p>

DOI10.1371/journal.pone.0163013
Alternate JournalPLoS ONE
PubMed ID27636371
PubMed Central IDPMC5026353
Grant ListK23 GM112014 / GM / NIGMS NIH HHS / United States
R01 HL111656 / HL / NHLBI NIH HHS / United States