Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease

Ashley-Koch, Allison E.; Elliott, Laine E.; Kail, Melanie E.; Castro, Laura M. De; Jonassaint, Jude; Jackson, Terry L.; Price, Jennifer L.; Ataga, Kenneth I.; Levesque, Marc C.; Weinberg, J. Brice; Orringer, Eugene P.; Collins, Andrew; Vance, Jeffery M.; Telen, Marilyn J.

doi:10.1182/blood-2007-02-074849

Cited by 66 publications

(50 citation statements)

References 28 publications

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“…5,6 Several retrospective studies have identified specific single nucleotide polymorphisms (SNPs) associated with stroke in pediatric patients with SCA, using candidate gene approaches. [7][8][9][10][11][12][13][14] However, the majority of these potential modifiers did not have a replicated association with stroke using independent validation cohorts. 15 Only a few genetic modifiers have confirmed association with stroke, such as a-thalassemia trait being protective against stroke, but these do not explain the entire genetic contribution to stroke risk.…”

Section: Introductionmentioning

confidence: 96%

Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia

Flanagan

Sheehan

Linder

et al. 2013

Blood

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• The complication of stroke is common in patients with SCA, and there is a genetic component.• We have performed a largeassociation study to identify 2 genetic variants that protect patients with SCA from stroke.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 5 231) and patients with stroke (n 5 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. (Blood. 2013;121(16):3237-3245)

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Section: Introductionmentioning

confidence: 96%

Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia

Flanagan

Sheehan

Linder

et al. 2013

Blood

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“…Both conditions are associated with elevated plasma level of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide (NO) synthase [34,35]. Genomics analyses have shown an association in both conditions with genetic polymorphisms in the BMP6, TGFBR3 and Klotho genes, important in vascular biology, including regulation of NO production [29,36]. There has been evidence of severely impaired red cell deformability, increased density and altered rheology [22,33,37].…”

Section: Pathophysiologymentioning

confidence: 99%

Critical Reviews: How we treat sickle cell patients with leg ulcers

Minniti

Kato

2015

American J Hematol

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The past five decades have seen an improvement in the mortality and morbidity of sickle cell disease (SCD) because of prophylaxis against infectious complications, improved and expanded red cell transfusions, implementation of hydroxyurea therapy, and advances in supportive care. Now that the majority of patients in the western hemisphere reaches adulthood, end organ diseases are frequent, which include vasculopathic complications such as chronic leg ulcers. The management of patients with leg ulcers requires the hematologist to lead a team of health care professionals, and investigates the presence of associated, but potentially still occult signs of vasculopathy, such as pulmonary hypertension, renal disease, priapism and retinopathy. These complications may be asynchronous, and long term careful screening is indicated, in order to ensure early diagnosis and intervention. It is crucial to address both the immediate consequences of pain, infection and disability, and long term effects on quality of life, employment and stigma associated with chronic ulceration. Recent insights into their pathophysiology may have practical implications. We propose a holistic approach to the management of patients' physical and emotional problems and mechanisms of ulcers formation and delayed healing. An overview of topical and systemic therapies for chronic ulcers is given, with the understanding that wound care therapy is best left to the wound specialists, medical and surgical, with whom the hematologist must keep an open line of communication. In the absence of evidence-based guidelines, our opinion is based on both a critical review of the literature and our personal clinical and research experience. Am. J. Hematol. 91:22-30, 2016. V C 2015 Wiley Periodicals, Inc. Clinical CasesCase 1. A 49 year old African American woman with sickle cell anemia, bilateral hip replacements for avascular necrosis of the femoral head, pulmonary arterial hypertension documented by pulmonary artery catheterization, and history of laser treatment and vitrectomy for proliferative retinopathy and vitreous hemorrhage, presented with a very painful ulcer at the right malleolus. She has had three previous ulcers, on both legs, the first at age 32 years, attributed to excessive standing at her job, no trauma, which had responded to topical care and healed within few months of presentation. At that time she was not taking hydroxyurea, but has been taking it now for longer than 10 years with good fetal hemoglobin response: 17%. This current ulcer developed while she was experiencing high personal stress but no physical trauma. She rarely experiences vaso-occlusive pain crisis and has very infrequent hospitalizations. She was referred to the wound care service and after 7 months of unfruitful therapies, including surgical debridement, MIST ultrasound therapy, antibiotics, and compressions, she was started on monthly transfusions and her ulcer healed 5 months later. She has had consistently elevated serum lactate dehydrogenase (LDH) (>600 IU/L), serum dire...

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“…Ashley-Koch and colleagues recently published evidence that genetic polymorphisms identified in the TGβ superfamily are associated with PH risk in SCD, including activin A receptor, type II-like 1 (ACVRL1) and bone morphogenic protein receptor 2 (BMPR2), single nucleotide polymorphisms found to also be associated with primary PH. 66 Priapism and cutaneous leg ulcers have been reported in patients with thalassemia intermedia and other hemolytic anemias in addition to SCD. 52 In a recurring theme, this complication was found to be most prevalent in patients with SCD with the highest rates of hemolysis, 7,67 and reported by Nolan and colleagues to be associated with a genetic polymorphism in Klotho, a gene that regulates NO bioavailability.…”

Section: Vascular Phenotypes Of Sickle Cell Diseasementioning

confidence: 99%

Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia

Morris¹

2008

Hematology

162

214

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Many mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD), with dysfunction of the vascular endothelium as a unifying theme. Specifically, hemolysis-associated low arginine and nitric oxide (NO) bioavailability, amplified by NO synthase uncoupling, elevated arginase activity, superoxide production, oxidative stress, accumulation of arginine analogs such as asymmetric dimethylarginine, ischemia-reperfusion injury, inflammation, apolipoprotein A-1 depletion, and a hypercoagulable state are significant mechanisms contributing to endothelial dysfunction. Genetic polymorphisms also influence disease severity. Clearly the variable spectrum of disease is the consequence of multiple events and genetic susceptibility that go beyond the occurrence of a single amino acid substitution in the beta globin chain of hemoglobin. Recent studies begin to demonstrate overlap among these seemingly unrelated processes. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a common denominator in the pathogenesis of vasculopathy in SCD. The consequences of decreased NO bioavailability include endothelial cell activation, upregulation of the potent vasoconstrictor endothelin-1, vasoconstriction, platelet activation, increased tissue factor, and activation of coagulation, all of which ultimately translate into the clinical manifestations of SCD. Evidence supporting vasculopathy subphenotypes in SCD, including pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke, will be reviewed and relevance to other hemolytic disorders including the thalassemia syndromes will be considered.

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Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease

Cited by 66 publications

References 28 publications

Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia

Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia

Critical Reviews: How we treat sickle cell patients with leg ulcers

Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia

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