title: Genetic Modifiers of White Blood Cell Count, Albuminuria and Glomerular Filtration Rate in Children with Sickle Cell Anemia.
abstract: Discovery and validation of genetic variants that influence disease severity in children with sickle cell anemia (SCA) could lead to early identification of high-risk patients, better screening strategies, and intervention with targeted and preventive therapy. We hypothesized that newly identified genetic risk factors for the general African American population could also impact laboratory biomarkers known to contribute to the clinical disease expression of SCA, including variants influencing the white blood cell count and the development of albuminuria and abnormal glomerular filtration rate. We first investigated candidate genetic polymorphisms in well-characterized SCA pediatric cohorts from three prospective NHLBI-supported clinical trials: HUSTLE, SWiTCH, and TWiTCH. We also performed whole exome sequencing to identify novel genetic variants, using both a discovery and a validation cohort. Among candidate genes, DARC rs2814778 polymorphism regulating Duffy antigen expression had a clear influence with significantly increased WBC and neutrophil counts, but did not affect the maximum tolerated dose of hydroxyurea therapy. The APOL1 G1 polymorphism, an identified risk factor for non-diabetic renal disease, was associated with albuminuria. Whole exome sequencing discovered several novel variants that maintained significance in the validation cohorts, including ZFHX4 polymorphisms affecting both the leukocyte and neutrophil counts, as well as AGGF1, CYP4B1, CUBN, TOR2A, PKD1L2, and CD163 variants affecting the glomerular filtration rate. The identification of robust, reliable, and reproducible genetic markers for disease severity in SCA remains elusive, but new genetic variants provide avenues for further validation and investigation.
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Beverly A
authors.identifier: http://orcid.org/0000-0001-5427-9666
authors.initials: BA
authors.lastname: Schaefer
authors.affiliation: Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Flanagan
authors.affiliation: University of Miami, Miami, FL, United States of America.
authors.forename: Ofelia A
authors.initials: OA
authors.lastname: Alvarez
authors.affiliation: Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Nelson
authors.affiliation: Cohen Children's Medical Center, New Hyde Park, NY, United States of America.
authors.forename: Banu
authors.initials: B
authors.lastname: Aygun
authors.affiliation: St. Jude Children's Research Hospital, Memphis, TN, United States of America.
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Nottage
authors.affiliation: Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: George
authors.affiliation: University of South Carolina, Columbia, SC, United States of America.
authors.forename: Carla W
authors.initials: CW
authors.lastname: Roberts
authors.affiliation: Case Western Reserve University, Cleveland, OH, United States of America.
authors.forename: Connie M
authors.initials: CM
authors.lastname: Piccone
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Thad A
authors.initials: TA
authors.lastname: Howard
authors.affiliation: University of Texas School of Public Health, Houston, TX, United States of America.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davis
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Ware
mesh_terms: D000293:Adolescent; D000419:Albuminuria / Q000150:complications / Q000175:diagnosis*; D000755:Anemia, Sickle Cell / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics; D002648:Child; D004375:Duffy Blood-Group System / Q000235:genetics / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005919:Glomerular Filtration Rate; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology; D008075:Lipoproteins, HDL / Q000235:genetics; D008297:Male; D009504:Neutrophils / Q000166:cytology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics
chemical_list: C473745:ACKR1 protein, human; C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D004375:Duffy Blood-Group System; D018398:Homeodomain Proteins; D008075:Lipoproteins, HDL; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C000591861:ZFHX4 protein, human; D006918:Hydroxyurea