Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy

Saraf, Santosh L.; Zhang, Xu; Shah, Binal N.; Kanias, Tamir; Gudehithlu, Krishnamurthy P.; Kittles, Rick A.; Machado, Roberto F.; Arruda, José A.L.; Gladwin, Mark T.; Singh, Ashok K.; Gordeuk, Victor R.

doi:10.3324/haematol.2015.124875

Cited by 68 publications

(104 citation statements)

References 67 publications

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“…Eleven SNPs have been identified in MYH9 and APOL1 genes, associated with the development of FSGS and ESRD in African-American populations (Genovese et al, 2010;Kao et al, 2008;Kopp et al, 2008), and subsequently validated in an American SCD population (Ashley-Koch et al, 2011;Saraf et al, 2015). Furthermore, the relative association of APOL1 with renal dysfunction was reduced in the presence of MYH9 SNPs (Ashley-Koch et al, 2011) in contrast to the findings of previous studies (Kao et al, 2008;Kopp et al, 2008).…”

Section: Sickle Cell and Cardiovascular Disease Genetics 583contrasting

confidence: 54%

“…Longer repeats are further associated with reduced glomerular filtration rates in African-American SCD patients (Saraf et al, 2015). Another SNP in HMOX1, rs743811, has been associated with chronic kidney disease and ESRD in a group of African-American SCD patients (Saraf et al, 2015) ( Table 2).…”

Section: Sickle Cell and Cardiovascular Disease Genetics 583mentioning

confidence: 99%

“…SCD nephropathy includes papillary necrosis, hyposthenuria, impaired renal acidification, proteinuria, ischemia, and supranormal proximal tubular function as a result of the sickled erythrocytes (Pham et al, 2000;Stuart et al, 2004). Elevated levels of cell-free hemoglobin are characteristic of SCD due to the unstable nature of sickle hemoglobin (Nath and Katusic, 2012;Saraf et al, 2015). Subsequent increases in heme iron, a known proinflammatory molecule, are postulated to preclude vascular injury (Kanakiriya et al, 2003;Tracz et al, 2007).…”

Section: Sickle Cell and Cardiovascular Disease Genetics 583mentioning

confidence: 99%

“…Another SNP in HMOX1, rs743811, has been associated with chronic kidney disease and ESRD in a group of African-American SCD patients (Saraf et al, 2015) ( Table 2). HMOX1 therefore plays a functional role in modulating the development of kidney disease in SCD patients through insufficient protection from hemoglobinmediated toxicity (Bean et al, 2012).…”

Section: Sickle Cell and Cardiovascular Disease Genetics 583mentioning

confidence: 99%

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Genetics of Sickle Cell-Associated Cardiovascular Disease: An Expert Review with Lessons Learned in Africa

Geard

Pule

Chelo

et al. 2016

OMICS: A Journal of Integrative Biology

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Sickle cell disease (SCD) vastly impacts the African continent and is associated with cardiovascular diseases. Stroke, kidney disease, and pulmonary hypertension are considered as proxies of severity in SCD with several genomic loci implicated in their heritability. The present expert review examined the current data on epidemiology and genetic risk factors of stroke, pulmonary hypertension, and kidney disease associated with SCD, as indexed in PubMed Ò and Google Scholar Ò . Studies collectively show that stroke and kidney disease each affect *10% of SCD patients, with pulmonary hypertension displaying a higher prevalence of 30% among adults with SCD. There is some evidence that these epidemiology figures may be an underestimate in SCD patients living in Africa. A modest number of publications have identified genetic factors involved in pathways regulating inflammation, coagulation, cell adhesion, heme degradation, a-globin and c-globin production, and others, which contribute to the development risk of targeted cardiovascular phenotypes. However, in most cases, these studies have not been validated across populations. There is therefore an urgent need for large-scale genome-wide association, wholeexome and whole-genome studies, and multiomics research on cardiovascular diseases associated with SCD, particularly in Africa, to allow for proportional investment of global research funding on diseases that greatly impact the African continent. Ultimately, this will cultivate socially responsible research investments and identification of at-risk individuals with improved preventive medicine, which should be a cornerstone of global precision medicine.

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Section: Sickle Cell and Cardiovascular Disease Genetics 583contrasting

confidence: 54%

Section: Sickle Cell and Cardiovascular Disease Genetics 583mentioning

confidence: 99%

Section: Sickle Cell and Cardiovascular Disease Genetics 583mentioning

confidence: 99%

Section: Sickle Cell and Cardiovascular Disease Genetics 583mentioning

confidence: 99%

See 2 more Smart Citations

Genetics of Sickle Cell-Associated Cardiovascular Disease: An Expert Review with Lessons Learned in Africa

Geard

Pule

Chelo

et al. 2016

OMICS: A Journal of Integrative Biology

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“…A note of caution in this regard is that it will be important to consider the potential for renal toxicity with bisphosphonates given the high prevalence of chronic kidney disease in adult SCD patients. 10 Conflict-of-interest disclosure: V.R.G. has served as a consultant for Incyte Corporation and La Jolla Pharmaceuticals in the last year.…”

mentioning

confidence: 99%

Osteoclast activation and sickle bone disease

Gordeuk

2015

Blood

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Genetic Variation and Sickle Cell Disease Severity

Kirkham,

Estepp,

Weiss

et al. 2023

JAMA Netw Open

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ImportanceSickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.ObjectiveTo assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.Data SourcesPubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.Study SelectionAt least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.Data Extraction and SynthesisData relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.Main Outcomes and MeasuresOutcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.ResultsThe 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10−95 to 6.19 × 10−5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10−7 to 6.00 × 10−4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.Conclusions and RelevanceThe findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

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Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy

Cited by 68 publications

References 67 publications

Genetics of Sickle Cell-Associated Cardiovascular Disease: An Expert Review with Lessons Learned in Africa

Genetics of Sickle Cell-Associated Cardiovascular Disease: An Expert Review with Lessons Learned in Africa

Osteoclast activation and sickle bone disease

Genetic Variation and Sickle Cell Disease Severity

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