Genetic Modifiers of White Blood Cell Count, Albuminuria and Glomerular Filtration Rate in Children with Sickle Cell Anemia

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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.

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Most cited references 47

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Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

Mark Gladwin, Vandana Sachdev, Maria Jison … (2004)

The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated. Copyright 2004 Massachusetts Medical Society

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How I use hydroxyurea to treat young patients with sickle cell anemia.

Matthew Ware (2010)

Hydroxyurea has many characteristics of an ideal drug for sickle cell anemia (SCA) and provides therapeutic benefit through multiple mechanisms of action. Over the past 25 years, substantial experience has accumulated regarding its safety and efficacy for patients with SCA. Early proof-of-principle studies were followed by prospective phase 1/2 trials demonstrating efficacy in affected adults, then adolescents and children, and more recently infants and toddlers. The phase 3 National Heart, Lung and Blood Institute-sponsored Multicenter Study of Hydroxyurea trial proved clinical efficacy for preventing acute vaso-occlusive events in severely affected adults. Based on this cumulative experience, hydroxyurea has emerged as an important therapeutic option for children and adolescents with recurrent vaso-occlusive events; recent evidence documents sustained long-term benefits with prevention or reversal of chronic organ damage. Despite abundant evidence for its efficacy, however, hydroxyurea has not yet translated into effective therapy for SCA. Because many healthcare providers have inadequate knowledge about hydroxyurea, patients and families are not offered treatment or decline because of unrealistic fears. Limited support for hydroxyurea by lay organizations and inconsistent medical delivery systems also contribute to underuse. Although questions remain regarding its long-term risks and benefits, current evidence suggests that many young patients with SCA should receive hydroxyurea treatment.

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APOL1 kidney risk alleles: population genetics and disease associations.

Sophie Limou, George Nelson, Jeffrey B Kopp … (2014)

APOL1 kidney disease is a unique case in the field of the genetics of common disease: 2 variants (termed G1 and G2) with high population frequency have been repeatedly associated with nondiabetic CKDs, with very strong effect size (odds ratios 3-29) in populations of sub-Saharan African descent. This review provides an update on the spectrum of APOL1 kidney disease and on the worldwide distribution of these kidney risk variants. We also summarize the proper way to run a recessive analysis on joint and independent effects of APOL1 G1 and G2 kidney risk variants.

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Author and article information

Contributors

Philippe Connes: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 6 October 2016

Publication date Collection: 2016

Volume: 11

Issue: 10

Electronic Location Identifier: e0164364

Affiliations

[1 ]Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States of America

[2 ]Baylor College of Medicine, Houston, TX, United States of America

[3 ]University of Miami, Miami, FL, United States of America

[4 ]Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, United States of America

[5 ]Cohen Children’s Medical Center, New Hyde Park, NY, United States of America

[6 ]St. Jude Children’s Research Hospital, Memphis, TN, United States of America

[7 ]University of South Carolina, Columbia, SC, United States of America

[8 ]Case Western Reserve University, Cleveland, OH, United States of America

[9 ]University of Texas School of Public Health, Houston, TX, United States of America

Université Claude Bernard Lyon 1, FRANCE

Author notes

Competing Interests: KN is now employed by Janssen Pharmaceuticals, Inc.; RW is a consultant for Bayer Pharmaceuticals, Nova Laboratories and Global Blood Therapeutics; receives research support from Bristol-Myers Squibb, Addmedica, and Biomedomics Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Conceptualization: RW JF BD.
Data curation: BS JF TH BD RW.
Formal analysis: JF BD.
Funding acquisition: RW BD.
Investigation: BS JF OA SN BA KN AG CR CP TH BD RW.
Methodology: BS JF TH RW.
Project administration: BD RW.
Supervision: TH RW.
Writing – original draft: BS JF RW.
Writing – review & editing: TH OA SN BA KN AG CR CP BD.

* E-mail: beverly.schaefer@ 123456cchmc.org

Author information

Beverly A. Schaefer http://orcid.org/0000-0001-5427-9666

Article

Publisher ID: PONE-D-16-26300

DOI: 10.1371/journal.pone.0164364

PMC ID: 5053442

PubMed ID: 27711207

SO-VID: 34a87aa9-f894-4b71-bf8a-a524766609ef

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 30 June 2016

Date accepted : 24 September 2016

Page count

Figures: 0, Tables: 4, Pages: 14