Influence of UGT1A1 promoter polymorphism, α-thalassemia and βs haplotype in bilirubin levels and cholelithiasis in a large sickle cell anemia cohort

Batista, Jéssica V G F; Arcanjo, Gabriela da Silva; Batista, Thais Helena Chaves; Sobreira, Marcondes J; Santana, Rodrigo Marcionilo; Domingos, Igor F.; Hatzlhofer, Betânia Lucena Domingues; Falcão, Daniela; Pereira-Martins, Diego A; Oliveira, Jéssica Maria; Araújo, Amanda Souza; Laranjeira, Luana P M; Medeiros, Fernanda; Albuquerque, Flávia Peixoto; Albuquerque, Dulcinéia Martins; Santos, Magnun Nueldo Nunes; Hazin, Manuela F; Anjos, Ana Claudia; Costa, Fernando Ferreira; Araújo, Aderson S; Lucena-Araújo, Antonio R.; Bezerra, Marcos André Cavalcanti

doi:10.1007/s00277-021-04422-1

Cited by 13 publications

(8 citation statements)

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“…We identified 571 manuscripts published before May 16, 2023, reporting genotype-phenotype associations across 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries (eMethods, eFigures 1 and 2, and eTable 5 in Supplement 1 ; eTable 1 in Supplement 2 ). 8 , 11 , 12 , 13 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ,…”

Section: Resultsmentioning

confidence: 99%

“…A total of 571 publications passed this screening (eFigure 1 in Supplement 1 , eTable 1 in Supplement 2 ). 8 , 11 , 12 , 13 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ...…”

Section: Methodsunclassified

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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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Section: Resultsmentioning

confidence: 99%

Section: Methodsunclassified

Genetic Variation and Sickle Cell Disease Severity

Kirkham,

Estepp,

Weiss

et al. 2023

JAMA Netw Open

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show abstract

“…The CCK level has been reported to be higher in cirrhotic patients than in noncirrhotic patients, which indicates that the gallbladder may be stimulated to contract once a patient starts to eat, especially with a greasy diet. We speculate that the increased level of CCK combined with the large burden of UCB and bile stasis may contribute to the development of common bile duct stones 18,19 . This study had some limitations.…”

Section: Discussionmentioning

confidence: 96%

Minimally invasive treatment of cirrhotic secondary hypersplenism with high-intensity focused ultrasound

Zhang

Tang

Huang

et al. 2022

Sci Rep

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High-intensity focused ultrasound (HIFU) has been reported to be a minimally invasive effective method for the treatment of secondary hypersplenism. However, neither the short-term efficacy nor the indications and/or contraindications have been described in patients with cirrhosis. From October 2019 to May 2021, eleven cases of patients with cirrhotic secondary hypersplenism were enrolled. The blood counts, liver function tests and abdominal ultrasound and/or MRI scans of all patients were closely evaluated. Among these 11 patients, eight (72.7%) patients were classified as Child–Pugh A, and the other 3 (27.3%) patients were Child–Pugh B; Five (45%) patients were diagnosed with gallstone, including multiple small stones in 2 patients and single stone in 3 patients. HIFU was performed successfully in all 11 patients. After HIFU, hematologic parameters and liver function were significantly improved in all 11 patients (p < 0.05). The HIFU ablated volume to spleen volume rate was 35–61%. Complications were ecchymosis of the waist in 7 (63.3%) patients, ablated area pain in 3 (27.3%) patients, and choledocholithiasis in 2 (18.2%) patients with multiple small gallstones. All of them recovered smoothly without additional treatment except for 2 patients with choledocholithiasis recovered with risky endoscopic retrograde cholangiopancreatography (ERCP) treatment. This series suggested that HIFU is an effective and safe treatment for cirrhotic secondary hypersplenism in patients classified as Child–Pugh A or B. However, multiple small gallstones could be a relative contraindication for it.

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Section: Discussionmentioning

confidence: 97%

Minimally invasive treatment of cirrhotic secondary hypersplenism with high-intensity focused ultrasound

Zhang

Huang

et al. 2022

Preprint

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High-intensity focused ultrasound (HIFU) has been reported to be a minimally invasive effective method for the treatment of secondary hypersplenism. However, neither the short-term efficacy nor the indications and/or contraindications have been described in patients with cirrhosis. From October 2019 to May 2021, eleven cases of patients with cirrhotic secondary hypersplenism were enrolled. The blood counts, liver function tests and abdominal ultrasound and/or MRI scans of all patients were closely evaluated. Among these 11 patients, eight (72.7%) patients were classified as Child-Pugh A, and the other 3 (27.3%) patients were Child-Pugh B; Five (45%) patients were diagnosed with gallstone, including multiple small stones in 2 patients and single stone in 3 patients. HIFU was performed successfully in all 11 patients. After HIFU, hematologic parameters and liver function were significantly improved in all 11 patients (p < 0.05). The HIFU ablated volume to spleen volume rate was 35%-61%. Complications were ecchymosis of the waist in 7 (63.3%) patients, ablated area pain in 3 (27.3%) patients, and choledocholithiasis in 2 (18.2%) patients with multiple small gallstones. All of them recovered smoothly without additional treatment except for 2 patients with choledocholithiasis recovered with risky endoscopic retrograde cholangiopancreatography (ERCP) treatment. This series suggested that HIFU is an effective and safe treatment for cirrhotic secondary hypersplenism in patients classified as Child-Pugh A or B. However, multiple small gallstones could be a relative contraindication for it.

show abstract

Influence of UGT1A1 promoter polymorphism, α-thalassemia and βs haplotype in bilirubin levels and cholelithiasis in a large sickle cell anemia cohort

Cited by 13 publications

References 50 publications

Genetic Variation and Sickle Cell Disease Severity

Genetic Variation and Sickle Cell Disease Severity

Minimally invasive treatment of cirrhotic secondary hypersplenism with high-intensity focused ultrasound

Minimally invasive treatment of cirrhotic secondary hypersplenism with high-intensity focused ultrasound

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