TY - JOUR
T1 - Genetic modifiers of white blood cell count, albuminuria and glomerular filtration rate in children with sickle cell anemia
AU - Schaefer, Beverly A.
AU - Flanagan, Jonathan M.
AU - Alvarez, Ofelia A.
AU - Nelson, Stephen C.
AU - Aygun, Banu
AU - Nottage, Kerri A.
AU - George, Alex
AU - Roberts, Carla W.
AU - Piccone, Connie M.
AU - Howard, Thad A.
AU - Davis, Barry R.
AU - Ware, Russell E.
N1 - Funding Information:
This work was supported by grants from the Doris Duke Charitable Foundation (http://www. ddcf.org/) 2015132 and 2010036, the National Institutes of Health Center Cores P30 Grant (http:// grants.nih.gov/grants/funding) (DK090971) and National Institutes of Health National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov) R01- HL-090941, R01-HL-078787, and R01-HL-095647 (RW). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
PY - 2016/10
Y1 - 2016/10
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0164364
DO - 10.1371/journal.pone.0164364
M3 - Article
C2 - 27711207
AN - SCOPUS:84991225047
VL - 11
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 10
M1 - e0164364
ER -