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.
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 October 2016.
All research outputs
#22,759,270
of 31,849,655 outputs
Outputs from PLOS ONE
#146,939
of 213,612 outputs
Outputs of similar age
#219,649
of 324,818 outputs
Outputs of similar age from PLOS ONE
#2,965
of 4,245 outputs
Altmetric has tracked 31,849,655 research outputs across all sources so far. This one is in the 19th percentile – i.e., 19% of other outputs scored the same or lower than it.
So far Altmetric has tracked 213,612 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 17.1. This one is in the 21st percentile – i.e., 21% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 324,818 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 25th percentile – i.e., 25% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 4,245 others from the same source and published within six weeks on either side of this one. This one is in the 21st percentile – i.e., 21% of its contemporaries scored the same or lower than it.
