title: Gene-centric association study of acute chest syndrome and painful crisis in sickle cell disease patients.
abstract: Patients with sickle cell disease (SCD) present with a wide range of clinical complications. Understanding this clinical heterogeneity offers the prospects to tailor the right treatments to the right patients and also guide the development of novel therapies. Several environmental (eg, nutrition) and nonenvironmental (eg, fetal hemoglobin levels, α-thalassemia status) factors are known to modify SCD severity. To find new genetic modifiers of SCD severity, we performed a gene-centric association study in 1514 African American participants from the Cooperative Study of Sickle Cell Disease (CSSCD) for acute chest syndrome (ACS) and painful crisis. From the initial results, we selected 36 single nucleotide polymorphism (SNPs) and genotyped them for replication in 387 independent patients from the CSSCD, 318 SCD patients recruited at Georgia Health Sciences University, and 449 patients from the Duke SCD cohort. In the combined analysis, an association between ACS and rs6141803 reached array-wide significance (P = 4.1 × 10(-7)). This SNP is located 8.2 kilobases upstream of COMMD7, a gene highly expressed in the lung that interacts with nuclear factor-κB signaling. Our results provide new leads to gaining a better understanding of clinical variability in SCD, a "simple" monogenic disease.
authors.affiliation: Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Galarneau
authors.forename: Sean
authors.initials: S
authors.lastname: Coady
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Garrett
authors.forename: Neal
authors.initials: N
authors.lastname: Jeffries
authors.forename: Mona
authors.initials: M
authors.lastname: Puggal
authors.forename: Dina
authors.initials: D
authors.lastname: Paltoo
authors.forename: Karen
authors.initials: K
authors.lastname: Soldano
authors.forename: Antonio
authors.initials: A
authors.lastname: Guasch
authors.forename: Allison E
authors.initials: AE
authors.lastname: Ashley-Koch
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Telen
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
authors.forename: George J
authors.initials: GJ
authors.lastname: Papanicolaou
mesh_terms: D056586:Acute Chest Syndrome / Q000150:complications* / Q000235:genetics*; D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D010146:Pain / Q000150:complications* / Q000235:genetics