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

<div><p>Background</p><p>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>Methods</p><p>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>Results</p><p>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, <i>FUCA2</i> and <i>IL18</i>.</p><p>Conclusions</p><p><i>FUCA2</i> and <i>IL18</i> are associated with diastolic function in SCD patients, and may be involved in the pathogenesis of the disease. Genetic polymorphisms within the <i>FUCA2</i> and <i>IL18</i> gene regions are also associated with diastolic function in SCD, likely by affecting expression levels of the genes.</p></div

Patient characteristics within SCD discovery and replication cohorts.

<p>Patient characteristics within SCD discovery and replication cohorts.</p

Cis-eQTL and genetic associations with E/e′ within the <i>IL18</i> and <i>FUCA2</i> gene regions.

<p>Cis-eQTL and genetic associations with E/e′ within the <i>IL18</i> and <i>FUCA2</i> gene regions.</p

Comparison of candidate gene expression levels in myocardial tissue of mice with and without sickle cell disease.

<p>A: <i>Adam9</i>, B: <i>Fuca2</i>, C: <i>Il18</i>, D: <i>Olfr658</i>, E: <i>Prosc</i>, F: <i>Slc16a2</i>, G: <i>Sult2b1</i>. Error bars denote standard error of the mean. * ≤ 0.05; † ≤ 0.001.</p

Candidate genes associated with diastolic function in SCD discovery and replication cohorts.

<p>Candidate genes associated with diastolic function in SCD discovery and replication cohorts.</p

Comparison of E/e′ ratio between mice with and without sickle cell disease.

<p>Error bars denote standard error of the mean. * ≤ 0.05.</p

QTc, echocardiography, CMR, and laboratory characteristics of the UC Cohort.

<p>QTc, echocardiography, CMR, and laboratory characteristics of the UC Cohort.</p

Kaplan-Meier survival curve, QTc of 460ms.

<p>Kaplan-Meier survival curves from time of ECG acquisition at the 75^th percentile of QTc (460ms) in the UIC cohort.</p

Kaplan-Meier survival curve, QTc of 480ms.

<p>Kaplan-Meier survival curves from time of ECG acquisition at the 90^th percentile of QTc (480ms) in the UIC cohort.</p

Univariate and multivariate regression analysis for QTc in the UIC Cohort.

<p>Univariate and multivariate regression analysis for QTc in the UIC Cohort.</p