title: Genome-Wide Analysis Identifies IL-18 and FUCA2 as Novel Genes Associated with Diastolic Function in African Americans with Sickle Cell Disease.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL, United States of America.
authors.forename: Julio D
authors.identifier: http://orcid.org/0000-0001-9766-4038
authors.initials: JD
authors.lastname: Duarte
authors.affiliation: Division of Cardiology, Sarver Heart Center, University of Arizona, Tucson, AZ, United States of America.
authors.forename: Ankit A
authors.initials: AA
authors.lastname: Desai
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States of America.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Sysol
authors.affiliation: Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL, United States of America.
authors.forename: Taimur
authors.initials: T
authors.lastname: Abbasi
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL United States of America.
authors.forename: Amit R
authors.initials: AR
authors.lastname: Patel
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL United States of America.
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Lang
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States of America.
authors.forename: Akash
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Medicine, University of Arizona, Tucson, AZ, United States of America.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States of America.
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States of America.
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
mesh_terms: D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000235:genetics* / Q000503:physiopathology*; D000818:Animals; D044383:Black People; D003971:Diastole / Q000502:physiology*; D055106:Genome-Wide Association Study; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D040641:Quantitative Trait Loci; D005644:alpha-L-Fucosidase / Q000235:genetics*; D001741:Black or African American
chemical_list: D020382:Interleukin-18; C000593240:FUCA2 protein, human; D005644:alpha-L-Fucosidase