title: Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia.
abstract: Stroke is a devastating complication of sickle cell anemia (SCA), occurring in 11% of patients before age 20 years. Previous studies of sibling pairs have demonstrated a genetic component to the development of cerebrovascular disease in SCA, but few candidate genetic modifiers have been validated as having a substantial effect on stroke risk. We performed an unbiased whole-genome search for genetic modifiers of stroke risk in SCA. Genome-wide association studies were performed using genotype data from single-nucleotide polymorphism arrays, whereas a pooled DNA approach was used to perform whole-exome sequencing. In combination, 22 nonsynonymous variants were identified and represent key candidates for further in-depth study. To validate the association of these mutations with the risk for stroke, the 22 candidate variants were genotyped in an independent cohort of control patients (n = 231) and patients with stroke (n = 57) with SCA. One mutation in GOLGB1 (Y1212C) and another mutation in ENPP1 (K173Q) were confirmed as having significant associations with a decreased risk for stroke. These mutations were discovered and validated by an unbiased whole-genome approach, and future studies will focus on how these functional mutations may lead to protection from stroke in the context of SCA.
authors: Texas Children's Hematology Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. jmflanag@bcm.edu
authors: Jonathan M
authors: JM
authors: Flanagan
authors: Vivien
authors: V
authors: Sheehan
authors: Heidi
authors: H
authors: Linder
authors: Thad A
authors: TA
authors: Howard
authors: Yong-Dong
authors: YD
authors: Wang
authors: Carolyn C
authors: CC
authors: Hoppe
authors: Banu
authors: B
authors: Aygun
authors: Robert J
authors: RJ
authors: Adams
authors: Geoffrey A
authors: GA
authors: Neale
authors: Russell E
authors: RE
authors: Ware
mesh_terms: D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D059472:Exome; D055106:Genome-Wide Association Study; D000077614:Golgi Matrix Proteins; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D012307:Risk Factors; D020521:Stroke / Q000209:etiology* / Q000235:genetics*
chemical_list: D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; C087574:macrogolgin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases