Genetic Modifiers of Stroke in Patients with Sickle Cell Disease—A Scoping Review
Abstract
:1. Introduction
2. Methods
2.1. Article Selection
2.2. Data Extraction
3. Results
3.1. Search Results
3.2. Fetal Hemoglobin Induction
3.2.1. BCL11A
3.2.2. HBG2
3.2.3. Other Fetal Hemoglobin Inducers
3.3. Inflammation
3.3.1. TNF-α
3.3.2. TGFβR-3
3.3.3. LTC4S
3.3.4. IL4R
3.3.5. ADCY9
3.3.6. GOLGB1
3.4. Cellular Adhesion
3.4.1. TEK
3.4.2. VCAM-1
3.4.3. ITGA4
3.5. Endothelial Disruption
3.5.1. ANXA2
3.5.2. ENPP1
3.5.3. NOS3
3.5.4. CBS
3.5.5. MTHFR
3.6. Hemolysis
3.6.1. Alpha Thalassemia Trait
3.6.2. G6PD
4. Discussion
4.1. INHERENT
4.2. Limitations
5. Conclusions
Supplementary Materials
Funding
Conflicts of Interest
Appendix A
PubMed | (“anemia, sickle cell”[mesh] OR “sickle cell anemia” OR “sickle cell anaemia” OR “sickle anemia” OR “sickle anaemia” OR drepanocytosis OR “hemoglobin s disease” OR “sickle cell disorder” OR “sickling disorder” OR “hbs disease” OR “sickle cell disease”) AND (stroke[mesh] OR stroke OR strokes OR “Cerebrovascular Accident” OR “Cerebrovascular Accidents” OR Cerebrovascular Apoplexy OR CVA OR CVAs OR “Brain Vascular Accident” OR “Brain Vascular Accidents” OR “brain attacks” OR “brain accidents” OR “brain insult” OR “brain insults” OR “cerebral attack” OR “cerebral attacks” OR “cerebral accident” OR “cerebral accidents” OR “cerebral insult” OR “cerebral insults” OR “cerebral vascular insufficiency” OR “cerebrovascular attack” OR “cerebrovascular attacks” OR “cerebrovascular accident” OR “cerebrovascular accidents” OR “cerebrovascular insult” OR “cerebrovascular insults”) AND ((“genetic markers”[mesh] OR “genetic marker” OR “genetic markers” OR “genetic biomarker” OR “genetic biomarkers” OR “dna marker” OR “dna markers” OR “chromosome marker” OR “chromosome markers”) OR (BCL11A) OR (betaglycan[supplementary concept] OR TGFBR3 OR “beta-glycan” OR betaglycan OR “TGF-beta type III” OR “TGF-beta receptor type III” OR “transforming growth factor beta type III” OR VCAM1) OR (“adenylate cyclase 9”[supplementary concept] OR “adenylate cyclase 9” OR “adenylyl cyclase IX” OR ADCY9 OR “adenylyl cyclase type IX”) OR (“ANXA2 protein, human”[supplementary concept] OR ANXA2 OR “annexin A2 protein” OR “annexin 2”) OR (“TEK protein, human”[supplementary concept] OR TEK OR “TIE-2” OR tie OR “angiopoietin-1 receptor” OR “angiopoietin receptor”) OR (“adenylate cyclase 9”[Supplementary Concept] OR “adenylate cyclase 9” OR “adenylyl cyclase IX” OR “adenylyl cyclase type IX” OR ADCY9) OR (“Vascular Cell Adhesion Molecule-1”[mesh] OR “Vascular Cell Adhesion Molecule 1” OR “Inducible Cell Adhesion Molecule 110” OR “CD106 Antigens” OR “VCAM 1” OR “CD106 antigen” OR “Vascular Cell Adhesion Molecule” OR “INCAM 110”) OR (“ectonucleotide pyrophosphatase phosphodiesterase 1”[Supplementary Concept] OR “ectonucleotide pyrophosphatase phosphodiesterase 1” OR ENPP1 OR “ecto-nucleotide pyrophosphatase phosphodiesterase 1” OR “glycoprotein PC-1” OR “plasma cell membrane glycoprotein PC-1” OR “alkaline phosphodiesterase 1” OR NPP1 OR “major aFGF-stimulated phosphoprotein OR “PC-1 glycoprotein” OR “plasma-cell membrane glycoprotein 1”) OR (“Glucosephosphate Dehydrogenase”[mesh] OR “plasma-cell membrane glycoprotein 1” OR “Glucosephosphate Dehydrogenase” OR “6 phosphate dehydrogenase” OR “6 phosphoglucose dehydrogenase” OR “Glucose 6 Phosphate Dehydrogenase”) OR (“alpha-Thalassemia”[mesh] OR “alpha-Thalassemia” OR “alpha thalassaemia) OR “Thalassemia alpha” OR “a thalassemia” OR “Hemoglobin H Disease”) OR (hbg2) OR (“BCL11A protein, human”[Supplementary Concept] OR BCL11A OR “C2H2-type zinc finger protein” OR “B-cell CLL-lymphoma 11A”)) |
EMBASE | (“sickle cell anemia”/exp OR “sickle cell anemia” OR “sickle cell anaemia” OR “sickle anemia” OR “sickle anaemia” OR drepanocytosis OR “hemoglobin s disease” OR “sickle cell disorder” OR “sickling disorder” OR “hbs disease” OR “sickle cell disease”) AND (“cerebrovascular accident”/exp OR stroke OR strokes OR “Cerebrovascular Accident” OR “Cerebrovascular Accidents” OR Cerebrovascular Apoplexy OR CVA OR CVAs OR “Brain Vascular Accident” OR “Brain Vascular Accidents” OR “brain attacks” OR “brain accident” OR “brain blood flow disturbance” OR “brain blood flow disturbances” OR “brain accidents” OR “brain insult” OR “brain insults” OR “cerebral attack” OR “cerebral attacks” OR “cerebral accident” OR “cerebral accidents” OR “cerebral blood flow disturbance” OR “cerebral blood flow disturbances” OR “cerebral insult” OR “cerebral insults” OR “cerebral vascular insufficiency” OR “cerebrovascular attack” OR “cerebrovascular attacks” OR “cerebrovascular accident” OR “cerebrovascular accidents” OR “cerebrovascular blood flow disturbance” OR “cerebrovascular blood flow disturbances” OR “cerebrovascular insult” OR “cerebrovascular insults”) AND ((“genetic marker”/exp OR “genetic marker” OR “genetic markers” OR “genetic biomarker” OR “genetic biomarkers” OR “dna marker” OR “dna markers” OR “chromosome marker” OR “chromosome markers”) OR (BCL11A) OR (“transforming growth factor beta receptor 3”/exp OR TGFBR3 OR “beta-glycan” OR betaglycan OR “TGF-beta type III” OR “TGF-beta type 3” OR “TGF-beta receptor type III” OR “TGF-beta receptor type 3” OR “transforming growth factor beta type III” OR “transforming growth factor beta type 3” OR VCAM1) OR (“adenylate cyclase 9” OR “adenylyl cyclase IX” OR ADCY9 OR “adenylyl cyclase type IX”) OR (ANXA2 OR “annexin A2 protein” OR “annexin 2”) OR (“angiopoietin receptor”/exp OR TEK OR “TIE-2” OR tie2 OR “angiopoietin-1 receptor” OR “angiopoietin receptor”) OR (“adenylate cyclase 9” OR “adenylyl cyclase IX” OR “adenylyl cyclase type IX” OR ADCY9) OR (“Vascular Cell Adhesion Molecule 1”/exp OR “Vascular Cell Adhesion Molecule 1” OR “Inducible Cell Adhesion Molecule 110” OR “CD106 Antigens” OR “VCAM 1” OR “CD106 antigen” OR “Vascular Cell Adhesion Molecule” OR “INCAM 110”) OR (“ectonucleotide pyrophosphatase phosphodiesterase 1” OR ENPP1 OR “ecto-nucleotide pyrophosphatase phosphodiesterase 1” OR “glycoprotein PC-1” OR “plasma cell membrane glycoprotein PC-1” OR “alkaline phosphodiesterase 1” OR NPP1 OR “major aFGF-stimulated phosphoprotein” OR “PC-1 glycoprotein” OR “plasma-cell membrane glycoprotein 1” OR “MAPF protein” OR “major acidic fibroblast growth factor-stimulated phosphoprotein”) OR (“glucose 6 phosphate dehydrogenase”/exp OR “plasma-cell membrane glycoprotein 1” OR “Glucosephosphate Dehydrogenase” OR “6 phosphate dehydrogenase” OR “6 phosphoglucose dehydrogenase” OR “Glucose 6 Phosphate Dehydrogenase” OR “6 phosphoglucoside dehydrogenase”) OR (“alpha Thalassemia”/exp OR “alpha-Thalassemia” OR “alpha thalassaemia” OR “Thalassemia alpha” OR “a thalassemia” OR “Hemoglobin H Disease”) OR (hbg2) OR (BCL11A OR “C2H2-type zinc finger protein” OR “B-cell CLL-lymphoma 11A” OR “CTIP1 protein”)) |
CINAHL | (DE “anemia, sickle cell” OR “sickle cell anemia” OR “sickle cell anaemia” OR “sickle anemia” OR “sickle anaemia” OR drepanocytosis OR “hemoglobin s disease” OR “sickle cell disorder” OR “sickling disorder” OR “hbs disease” OR “sickle cell disease”) AND (DE stroke OR stroke OR strokes OR “Cerebrovascular Accident” OR “Cerebrovascular Accidents” OR Cerebrovascular Apoplexy OR CVA OR CVAs OR “Brain Vascular Accident” OR “Brain Vascular Accidents” OR “brain attacks” OR “brain accident” OR “brain blood flow disturbance” OR “brain blood flow disturbances” OR “brain accidents” OR “brain insult” OR “brain insults” OR “cerebral attack” OR “cerebral attacks” OR “cerebral accident” OR “cerebral accidents” OR “cerebral blood flow disturbance” OR “cerebral blood flow disturbances” OR “cerebral insult” OR “cerebral insults” OR “cerebral vascular insufficiency” OR “cerebrovascular attack” OR “cerebrovascular attacks” OR “cerebrovascular accident” OR “cerebrovascular accidents” OR “cerebrovascular blood flow disturbance” OR “cerebrovascular blood flow disturbances” OR “cerebrovascular insult” OR “cerebrovascular insults”) AND ((DE “genetic markers” OR “genetic marker” OR “genetic markers” OR “genetic biomarker” OR “genetic biomarkers” OR “dna marker” OR “dna markers” OR “chromosome marker” OR “chromosome markers”) OR (BCL11A) OR (“transforming growth factor beta receptor 3”/exp OR TGFBR3 OR “beta-glycan” OR betaglycan OR “TGF-beta type III” OR “TGF-beta type 3” OR “TGF-beta receptor type III” OR “TGF-beta receptor type 3” OR “transforming growth factor beta type III” OR “transforming growth factor beta type 3” OR VCAM1) OR (“adenylate cyclase 9” OR “adenylyl cyclase IX” OR ADCY9 OR “adenylyl cyclase type IX”) OR (ANXA2 OR “annexin A2 protein” OR “annexin 2”) OR (TEK OR “TIE-2” OR tie2 OR “angiopoietin-1 receptor” OR “angiopoietin receptor”) OR (“adenylate cyclase 9” OR “adenylyl cyclase IX” OR “adenylyl cyclase type IX” OR ADCY9) OR (“Vascular Cell Adhesion Molecule 1” OR “Inducible Cell Adhesion Molecule 110” OR “CD106 Antigens” OR “VCAM 1” OR “CD106 antigen” OR “Vascular Cell Adhesion Molecule” OR “INCAM 110”) OR (“ectonucleotide pyrophosphatase phosphodiesterase 1” OR ENPP1 OR “ecto-nucleotide pyrophosphatase phosphodiesterase 1” OR “glycoprotein PC-1” OR “plasma cell membrane glycoprotein PC-1” OR “alkaline phosphodiesterase 1” OR NPP1 OR “major aFGF-stimulated phosphoprotein” OR “PC-1 glycoprotein” OR “plasma-cell membrane glycoprotein 1” OR “MAPF protein” OR “major acidic fibroblast growth factor-stimulated phosphoprotein”) OR (“plasma-cell membrane glycoprotein 1” OR “Glucosephosphate Dehydrogenase” OR “6 phosphate dehydrogenase” OR “6 phosphoglucose dehydrogenase” OR “Glucose 6 Phosphate Dehydrogenase” OR “6 phosphoglucoside dehydrogenase”) OR (DE “alpha Thalassemia” OR “alpha-Thalassemia” OR “alpha thalassaemia” OR “Thalassemia alpha” OR “a thalassemia” OR “Hemoglobin H Disease”) OR (hbg2) OR (BCL11A OR “C2H2-type zinc finger protein” OR “B-cell CLL-lymphoma 11A” OR “CTIP1 protein”)) |
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Gene | SNP rsID/Common Name | Effect Allele | Allele Frequency | Effect Size | Observed Effect on Stroke Risk | Citation |
---|---|---|---|---|---|---|
Fetal Hemoglobin Induction | ||||||
BCL11A | rs1427407 | G | 0.74 * | IR = 74% | Increase | [8] |
BCL11A + Del −α3.7kb | rs1427407 | T | 0.25 * | OR = 2.0 | Decrease | [9] |
Inflammation | ||||||
ACDY9 | rs2238432 | A | 0.19 * | OR = 0.47 | Decrease | [10] |
GOLGB1 | rs3732410 | C | 0.07 * | OR = 0.17 | Decrease | [11] |
IL4R | rs1805015 | C | 0.37 * | OR = 2.5 OR = 1.6 | Increase | [12] [13] |
LTC4S | rs730012 | C | 0.05 * | OR = 0.39 | Decrease | [13] |
TNFa | rs1800629 | G | 0.88 * | OR = 2.7 OR = 0.52 OR = 3.3 | Increase | [14] [12] [13] |
TNFa | rs1800629 | A | 0.12 * | OR = 0.39 | Decrease | [13] |
TGFβR-3 | rs284875 | A | 0.01 | HR = 3.4 | Increase | [15] |
TGFβR-3 | rs284875 | T | 0.043 | OR = 2.5 | Increase | [10] |
Cellular Adhesion | ||||||
ITGA4 | rs113276800 | A | 0.06 * | OR = 7.6 | Increase | [16] |
ITGA4 | rs3770138 | T | 0.06 * | OR = 5.6 | Increase | [16] |
TEK | rs489347 | G | 0.42 | OR = 2.2 | Increase | [10] |
TEK | rs489347 | C | 0.75 * | OR = 3.1 | Increase | [15] |
VCAM1 | rs1041163 | C | 0.19 * | OR = 1.98 | Increase | [12] |
VCAM1 | Haplotype 7 | OR = 4.2 | Increase | [16] | ||
VCAM1 | rs1409419 | T | 0.40 * | OR = 4.2 OR = 4.7 | Increase | [16] |
VCAM1 | rs3783613 | C | 0.03 * | OR = 0.35 | Decrease | [17] |
Endothelial Disruption | ||||||
ANXA2 | rs11853426 | T | 0.37 * | OR = 2.7 | Increase | [10] |
CBS | rs5742905 | G | 0.02 * | OR = 0.32 | Decrease | [18] |
ENPP1 | rs1044498 | C | 0.74 * | OR = 0.49 | Decrease | [11] |
ENPP1 | rs1044498 | A | 0.26 * | OR = 4.0 | Increase | [16] |
MTHFR | rs1016843877 | T | 0.34 | OR = 3.5 | Increase | [19] |
NOS3 | VNTR ** | OR = 0.10 | Decrease | [16] | ||
NOS3 | rs2070744 | C | 0.15 * | OR = 0.18 | Decrease | [16] |
NOS3 | rs1799983 | T | 0.13 * | OR = 0.080 | Decrease | [16] |
Hemolysis | ||||||
Del −α3.7kb | N/A | N/A | 0.244 * | OR = 4.1 OR = 6.5 | Decrease | [20] [21] |
Del −α3.7kb + MCS-R2 | rs11865131 | A | 0.18 * | OR = 1.3 | Increase | [22] |
G6PD | rs503086 | T | N/A | OR = 2.5 OR = 2.8 OR = 0.25 OR = 12.6 | Increase | [20] [23] [24] [25] |
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Oni, M.O.; Brito, M.; Rotman, C.; Archer, N.M., on behalf of the International Hemoglobinopathy Research Network (INHERENT). Genetic Modifiers of Stroke in Patients with Sickle Cell Disease—A Scoping Review. Int. J. Mol. Sci. 2024, 25, 6317. https://doi.org/10.3390/ijms25126317
Oni MO, Brito M, Rotman C, Archer NM on behalf of the International Hemoglobinopathy Research Network (INHERENT). Genetic Modifiers of Stroke in Patients with Sickle Cell Disease—A Scoping Review. International Journal of Molecular Sciences. 2024; 25(12):6317. https://doi.org/10.3390/ijms25126317
Chicago/Turabian StyleOni, Morohuntodun O., Miguel Brito, Chloe Rotman, and Natasha M. Archer on behalf of the International Hemoglobinopathy Research Network (INHERENT). 2024. "Genetic Modifiers of Stroke in Patients with Sickle Cell Disease—A Scoping Review" International Journal of Molecular Sciences 25, no. 12: 6317. https://doi.org/10.3390/ijms25126317
APA StyleOni, M. O., Brito, M., Rotman, C., & Archer, N. M., on behalf of the International Hemoglobinopathy Research Network (INHERENT). (2024). Genetic Modifiers of Stroke in Patients with Sickle Cell Disease—A Scoping Review. International Journal of Molecular Sciences, 25(12), 6317. https://doi.org/10.3390/ijms25126317