Folate Supplementation in People with Sickle Cell Disease

Dixit, Ramakant; Nettem, Sowmya; Singh, Simerjit; Soe, Htoo Htoo Kyaw; Abas, Adinegara BL; Vance, Leah D.

doi:10.2139/ssrn.3297902

Cited by 16 publications

(25 citation statements)

References 11 publications

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“…Subjects with SCD are at higher risk of cobalamin deficiency, justifying supplementation in clinical practice. 35 Identification of genes involved in mitotic check-point and DNA repair, starch, and sucrose metabolism, and solute carriers require further study to explore their roles in modifying the SCD phenotype. Similarly, future studies on heme pathways can explore if hemolysis metabolism or susceptibility are responsible for findings in this signaling hub in the replication samples.…”

Section: Discussionmentioning

confidence: 99%

Genetic modifiers of long‐term survival in sickle cell anemia

Wonkam

Chimusa

Mnika

et al. 2020

Clinical & Translational Med

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Background Sickle cell anemia (SCA) is a clinically heterogeneous, monogenic disorder. Medical care has less‐than‐optimal impact on clinical outcomes in SCA in Africa due to several factors, including patient accessibility, poor access to resources, and non‐availability of specific effective interventions for SCA. Methods Against this background, we investigated 192 African participants who underwent whole exome sequencing. Participants included 105 SCA patients spanning variable clinical expression: a “long survivor” group (age over 40 years), a “stroke” group (at least one episode of overt stroke), and a “random” group (patients younger than 40 years without overt cerebrovascular disease). Fifty‐eight ethnically matched homozygous hemoglobin A controls were also studied. Findings were validated in an independently recruited sample of 29 SCA patients. Statistical significance of the mutational burden of deleterious and loss‐of‐function variants per gene against a null model was estimated for each group, and gene‐set association tests were conducted to test differences between groups. Results In the “long survivor” group, deleterious/loss‐of‐function variants were enriched in genes including CLCN6 (a voltage‐dependent chloride channel for which rare deleterious variants have been associated with lower blood pressure) and OGHDL (important in arginine metabolism, which is a therapeutic target in SCA). In the “stroke” group, significant genes implicated were associated with increased activity of the blood coagulation cascade and increased complement activation, for example, SERPINC1, which encodes antithrombin. Oxidative stress and glutamate biosynthesis pathways were enriched in “long survivors” group. Published transcriptomic evidence provides functional support for the role of the identified pathways. Conclusions This study provides new gene sets that contribute to variability in clinical expression of SCA. Identified genes and pathways suggest new avenues for other interventions.

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Section: Discussionmentioning

confidence: 99%

Genetic modifiers of long‐term survival in sickle cell anemia

Wonkam

Chimusa

Mnika

et al. 2020

Clinical & Translational Med

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“…Although authors observed an increase in serum folate levels (concentrations below 11 nmol/L were evident in 15% (n = 6/39) of children in the placebo group versus none of the folic acid group, while concentrations above 40 nmol/L were evident in 81% (n = 33/41) of the folic acid group versus 15% in the placebo (n = 15/39) group) after one year in those treated with FA, no effect on hemoglobin, growth parameters, or other clinical events was observed (21). The quality of the evidence, however, was low due to the high risk of bias in random sequence generation and incomplete data, making it di cult to draw conclusions from this trial (7).…”

Section: Background and Rationale {6a}mentioning

confidence: 91%

“…While the severity of disease can vary among homozygous and heterozygous genotypes, hallmarks of the disease include: hemolytic anemia, vaso-occlusion, stroke, ischemic tissue damage, organ failure, and severe pain in the back, extremities, thorax, abdomen, and central nervous system (4)(5)(6). Chronic hemolytic anemia and increased red blood cell (RBC) production and turnover in SCD are thought to increase the requirements of folate, a water-soluble family of compounds that are essential for erythropoiesis (7,8). Naturally occurring folate is commonly found in foods such as leafy green vegetables, oranges, beans and legumes (9), while dietary supplements and folate-forti ed foods commonly contain folic acid (FA), the synthetic oxidized version of folate, due to its stability and higher bioavailability (10).…”

Section: Background and Rationale {6a}mentioning

confidence: 99%

Folic Acid Supplementation in Children with Sickle Cell Disease: Study Protocol for a Double-Blind Randomized Cross-Over Trial

Williams

McCartney

Adams

et al. 2020

Preprint

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Abstract • Background: Sickle cell disease (SCD) is a genetic disorder which causes dysfunctional red blood cells (RBC) and is thought to increase requirements for folate, an essential B-vitamin, due to increased RBC production and turn-over in the disease. High-dose supplementation with 1-5mg/d folic acid, synthetic folate, has been the standard recommendation for children with SCD. There is concern about whether children with SCD need such high doses of folic acid, following mandatory folic acid fortification of enriched grains in Canada, and advancements in medical therapies which extend the average lifespan of RBCs. In animal and human studies, high folic acid intakes (1 mg/d)have been associated with accelerated growth of some cancers, and the biological effects of circulating unmetabolized folic acid (UMFA), which can occur with doses of folic acid ≥0.2mg/d, are not fully understood. The objective of this study is to determine efficacy and alterations in folate metabolism of high-dose folic acid in children with SCD during periods of folic acid supplementation versus no supplementation• Methods: In this double-blind randomized controlled cross-over trial, children with SCD (n=36, aged 2-19 y)will be randomized to either receive 1 mg/d folic acid, the current standard of care, or a placebo for 12-weeks. After a 12-week washout period, treatments will be reversed. Total folate concentrations (serum and RBC), different folate forms (including UMFA), folate-related metabolites, and clinical outcomes will be measured at baseline and after treatment periods. The sum of the values measured in the two periods will be calculated for each subject and compared across the two sequence groups by means of a test for independent samples for the primary (RBC folate concentrations) and secondary (UMFA) outcomes. Dietary intake will be measured at the beginning of each study period. • Discussion:As the first rigorously designed clinical trial in children with SCD, this trial will inform and assess current clinical practice, with the ultimate goal of improving nutritional status of children with SCD.• Trial registration: This trial was registered July 8, 2019 at clinicaltrials.gov: NCT04011345. https://clinicaltrials.gov/ct2/show/NCT04011345

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“…While the severity of disease can vary among homozygous and heterozygous genotypes, hallmarks of the disease include hemolytic anemia, vaso-occlusion, stroke, ischemic tissue damage, organ failure, and severe pain in the back, extremities, thorax, abdomen, and central nervous system [4][5][6]. Chronic hemolytic anemia and increased red blood cell (RBC) production and turnover in SCD are thought to increase the requirements of folate, a water-soluble family of compounds that are essential for erythropoiesis [7,8]. Naturally occurring folate is commonly found in foods such as leafy green vegetables, oranges, beans, and legumes [9], while dietary supplements and folate-fortified foods commonly contain folic acid (FA), the synthetic oxidized version of folate, due to its stability and higher bioavailability [10].…”

Section: Background and Rationale {6a}mentioning

confidence: 99%

Folic acid supplementation in children with sickle cell disease: study protocol for a double-blind randomized cross-over trial

Williams

McCartney

Adams

et al. 2020

Trials

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Background: Sickle cell disease (SCD) is a genetic disorder which causes dysfunctional red blood cells (RBC) and is thought to increase requirements for folate, an essential B vitamin, due to increased RBC production and turnover in the disease. High-dose supplementation with 1-5 mg/d folic acid, synthetic folate, has been the standard recommendation for children with SCD. There is concern about whether children with SCD need such high doses of folic acid, following mandatory folic acid fortification of enriched grains in Canada, and advancements in medical therapies which extend the average lifespan of RBCs. In animal and human studies, high folic acid intakes (1 mg/d) have been associated with accelerated growth of some cancers, and the biological effects of circulating unmetabolized folic acid (UMFA), which can occur with doses of folic acid ≥ 0.2 mg/d, are not fully understood. The objective of this study is to determine efficacy of, and alterations in folate metabolism from high-dose folic acid in children with SCD during periods of folic acid supplementation versus no supplementation. Methods: In this double-blind randomized controlled cross-over trial, children with SCD (n = 36, aged 2-19 years) will be randomized to either receive 1 mg/d folic acid, the current standard of care, or a placebo for 12 weeks. After a 12-week washout period, treatments will be reversed. Total folate concentrations (serum and RBC), different folate forms (including UMFA), folate-related metabolites, and clinical outcomes will be measured at baseline and after treatment periods. The sum of the values measured in the two periods will be calculated for each subject and compared across the two sequence groups by means of a test for independent samples for the primary (RBC folate concentrations) and secondary (UMFA) outcomes. Dietary intake will be measured at the beginning of each study period. Discussion: As the first rigorously designed clinical trial in children with SCD, this trial will inform and assess current clinical practice, with the ultimate goal of improving nutritional status of children with SCD. Trial registration: ClinicalTrials.gov NCT04011345. Registered on

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Folate Supplementation in People with Sickle Cell Disease

Cited by 16 publications

References 11 publications

Genetic modifiers of long‐term survival in sickle cell anemia

Genetic modifiers of long‐term survival in sickle cell anemia

Folic Acid Supplementation in Children with Sickle Cell Disease: Study Protocol for a Double-Blind Randomized Cross-Over Trial

Folic acid supplementation in children with sickle cell disease: study protocol for a double-blind randomized cross-over trial

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