FOXO3 Variants Are Associated With Lower Fetal Hemoglobin Levels In Children With Sickle Cell Disease

Abstract Although they ostensibly have a monogenetic disease, individuals with sickle cell anemia (SCA) exhibit wide variability in their degree of clinical severity. One of the most powerful and reproducible predictors of disease severity is the level of endogenous fetal hemoglobin (HbF). Several genetic modifiers of HbF levels have previously been identified, by association with beta globin haplotypes, or by genome wide association studies. These methods are only able to detect common variants, with a minor allele frequency (MAF) greater than 5%. We have applied whole exome sequencing (WES) to find new genetic variants associated with baseline HbF in SCA, using 171 pediatric SCA genomes from participants in two clinical trials, HUSTLE (NCT NCT00305175) and SWiTCH (NCT 00122980). WES allows identification of both common and rare exonic variants, and use of burden analysis testing. In order to capture the association between the phenotype variants with a MAF below 1%, burden tests maximize power by grouping low frequency variants together by gene. This allows us to transition from a single variant theory, in which a variant is associated with a phenotype, to a gene-based theory, in which a collection of rare variants within a single gene are associated with the phenotype. Burden analysis (T1), found seven unique non-synonymous variations in a Forkhead box O transcription factor, FOXO3, to be significantly associated with lower HbF (p=5.6x10-4, b-value ln HbF -0.66). All variants produced the same effect, a lowering of HbF. HbF values were normalized using natural log transformation to permit analysis, and adjusted for age, BCL11A, and XmnI variant status. The box-plot below shows the overall effect of any of the non-synonymous exonic variants in FOXO3 on baseline HbF compared to wild-type. Each individual was heterozygous for a variant. FOXO3 is involved in multiple cellular processes, including cell cycle arrest, removal of reactive oxygen species, and regulation of erythroid differentiation. Erythroid maturation is altered by changes in post-translational maturation (PTM) such as removal of a phosphorylation site, as the in Ser553Phe variant identified in our analysis (Bakker, et al, JCB 2004). Changes in erythroid maturation kinetics may affect the amount of HbF produced. Variations in FOXO3 may represent another contributor to the heritability of HbF in patients with SCA. Further functional genomics analysis of FOXO3 may add to our understanding of gamma globin induction.Table 1Description of FOXO3 variants found to be associated with lower HbF in a cohort of pediatric sickle cell patients by WES and burden testing (T1).Chr 6LocationAmino Acid ChangeAltered PTMPolyPhen2 prediction%MAF108882607Asp66Asnnone knownPossibly damaging0.3108882830Ala140Valnone knownBenign0.6108984883Asp283Asnnone knownDamaging0.3108985057Ala121Thrnone knownBenign0.3108985280Pro415Leunone knownDamaging0.6108985679Arg548HismethylationDamaging0.3108985694Ser553PhephosphorylationBenign0.3Figure 1Boxplot demonstrating effect of any FOXO3 variants on endogenous %HbF compared to wild-type individuals.Figure 1. Boxplot demonstrating effect of any FOXO3 variants on endogenous %HbF compared to wild-type individuals. Disclosures: Off Label Use: Hydroxyurea is not FDA approved for use in pediatric sickle cell patients.

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Identification of Genetic Modifiers Associated with Risk of Stroke in Children with Sickle Cell Anemia

Blood ◽

10.1182/blood.v120.21.3228.3228 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3228-3228

Author(s):

Jonathan Michael Flanagan ◽

Heidi Linder ◽

Vivien Sheehan ◽

Thad A Howard ◽

Banu Aygun ◽

...

Keyword(s):

Cerebrovascular Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Conflicts Of Interest ◽

Association Studies ◽

Snp Markers ◽

Genome Wide Association Studies ◽

Genetic Modifiers ◽

Sibling Pairs ◽

Synonymous Mutations

Abstract Abstract 3228 Introduction: Stroke is one of the most catastrophic acute complications of sickle cell anemia (SCA), occurring in 11% of patients before 20 years of age. A further 20 to 30% of children with SCA will develop less clinically overt cerebrovascular disease events such as transient ischemic attacks (TIA) and silent infarcts. There is a definite need for biomarkers that could determine the cause of these irreversible cerebrovascular events and which might predict children at greatest risk. Previous studies of sibling pairs have shown that there is a genetic component to cerebrovascular disease development but few genetic modifiers have been validated as having a substantial effect on risk of stroke. The aim of this study was to perform an unbiased whole genome search for genetic modifiers of stroke risk in SCA. Methods: Pediatric patients with SCA and documented primary stroke (n=177) were compared to a pediatric control non-stroke group with SCA (n=335). All control patients were over 5 years old and without previous clinical stroke prior to beginning any clinical treatment. Genome wide association studies (GWAS) were performed using genotype data obtained from Affymetrix SNP6.0 arrays. A pooled DNA approach was used to perform whole exome sequencing (WES) by Illumina next generation sequencing of pooled control (n=104) and pooled stroke (n=120) groups. Results: From the Affymetrix SNP6.0 GWAS data, 139 single nucleotide polymorphisms (SNP) were identified with stroke association. From the WES, 294 non-synonymous mutations were found to be significantly associated with stroke. In combination, 11 mutations identified by WES were located within 250kb of a SNP identified by GWAS (Table 1). These 11 mutations represent key areas of the genome that are targets for further in depth study. To next validate the genetic variants identified by WES with association with risk of stroke, 21 candidate mutations were genotyped in an independent cohort of control (n=231) and stroke (n=57) patients with SCA. One mutation in GOLGB1 (Y1212C) was corroborated as having significant association with lower risk of stroke (p=0.02). Conclusion: This mutation in GOLGB1 is predicted to effect the golgi associated function of the encoded protein and future studies will focus on how this functional mutation may protect against development of cerebrovascular disease in the context of SCA. For all variants with significant association with stroke, the chromosomal position of each variant identified by WES (n=300, p<0.001) was compared to the location of all SNP markers (n=139, p<0.0001). We identified 11 variants by WES where there was at least one SNP marker within 250kb. These variants all represent excellent regions of the genome for future study. The four variants highlighted with a asterisk (*) are variants predicted by PolyPhen2 or SIFT to be deleterious. Disclosures: No relevant conflicts of interest to declare.

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Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5′ olfactory receptor gene cluster

Blood ◽

10.1182/blood-2009-08-239517 ◽

2010 ◽

Vol 115 (9) ◽

pp. 1815-1822 ◽

Cited By ~ 96

Author(s):

Nadia Solovieff ◽

Jacqueline N. Milton ◽

Stephen W. Hartley ◽

Richard Sherva ◽

Paola Sebastiani ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Olfactory Receptor ◽

Association Studies ◽

Receptor Gene ◽

Fetal Hemoglobin ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Olfactory Receptor Gene ◽

Genome Wide

Abstract In a genome-wide association study of 848 blacks with sickle cell anemia, we identified single nucleotide polymorphisms (SNPs) associated with fetal hemoglobin concentration. The most significant SNPs in a discovery sample were tested in a replication set of 305 blacks with sickle cell anemia and in subjects with hemoglobin E or β thalassemia trait from Thailand and Hong Kong. A novel region on chromosome 11 containing olfactory receptor genes OR51B5 and OR51B6 was identified by 6 SNPs (lowest P = 4.7E−08) and validated in the replication set. An additional olfactory receptor gene, OR51B2, was identified by a novel SNP set enrichment analysis. Genome-wide association studies also validated a previously identified SNP (rs766432) in BCL11A, a gene known to affect fetal hemoglobin levels (P = 2.6E−21) and in Thailand and Hong Kong subjects. Elements within the olfactory receptor gene cluster might play a regulatory role in γ-globin gene expression.

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Genetic association studies in β-hemoglobinopathies

Hematology ◽

10.1182/asheducation-2013.1.354 ◽

2013 ◽

Vol 2013 (1) ◽

pp. 354-361 ◽

Cited By ~ 31

Author(s):

Swee Lay Thein

Keyword(s):

Association Studies ◽

Globin Gene ◽

Genetic Association Studies ◽

Fetal Hemoglobin ◽

Clinical Severity ◽

Genetic Modifiers ◽

Genetic Studies ◽

Globin Gene Regulation ◽

Innate Ability

Abstract Characterization of the molecular basis of the β-thalassemias and sickle cell disease (SCD) clearly showed that individuals with the same β-globin genotypes can have extremely diverse clinical severity. Two key modifiers, an innate ability to produce fetal hemoglobin and coinheritance of α-thalassemia, both derived from family and population studies, affect the pathophysiology of both disorders at the primary level. In the past 2 decades, scientific research had applied genetic approaches to identify additional genetic modifiers. The review summarizes recent genetic studies and key genetic modifiers identified and traces the story of fetal hemoglobin genetics, which has led to an emerging network of globin gene regulation. The discoveries have provided insights on new targets for therapeutic intervention and raise possibilities of developing fetal hemoglobin predictive diagnostics for predicting disease severity in the newborn and for integration into prenatal diagnosis to better inform genetic counseling.

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Effect Of Genetic Modifiers Of Baseline Fetal Hemoglobin On Hydroxyurea Response In Children With Sickle Cell Disease

Blood ◽

10.1182/blood.v122.21.2216.2216 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2216-2216

Author(s):

Vivien A Sheehan ◽

Jacy R Crosby ◽

Jonathan Michael Flanagan ◽

Thad A Howard ◽

Nicole A. Mortier ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Fetal Hemoglobin ◽

Dose Effect ◽

Genome Wide Association Studies ◽

Genetic Modifiers ◽

Cell Disease ◽

Hydroxyurea Treatment ◽

Significant Difference ◽

Negative Effect

Abstract Hydroxyurea is a safe and effective therapy for sickle cell disease (SCD), with the majority of its benefit correlating with the amount of fetal hemoglobin (HbF) produced at maximum tolerated dose, or MTD. There is substantial individual variability in HbF response to hydroxyurea, with baseline HbF levels accounting for approximately 40% of the observed variability in final HbF at MTD. Several genetic modifiers of baseline, or endogenous, HbF levels have previously been identified by genome wide association studies. These include certain beta-globin haplotypes, and polymorphisms at the BCL11A and HBS1L-MYB gene loci. The effect of these known genetic modifiers of baseline HbF on drug response has been investigated in a small (n=38) cohort of pediatric patients treated with hydroxyurea in several centers with different treatment guidelines. In this limited group, no association was found between the BCL11A or HBS1L-MYB variants and the change in HbF at MTD (ΔHbF; final HbF minus baseline HbF). Co-inheritance of alpha thalassemia has been reported to have a negative effect on HbF response to hydroxyurea. To independently verify these findings in a larger sample size, we tested the effect of four BCL11A single nucleotide polymorphisms (SNPs), three HBS1L-MYB SNPs, the XmnI polymorphism, and co-inheritance of α-thalassemia on ΔHbF at MTD in a cohort of 171 pediatric SCA patients, treated prospectively and uniformly on HUSTLE (NCT NCT00305175) and SWiTCH (NCT 00122980) protocols. These patients represent the most accurate hydroxyurea phenotypes available, as all were meticulously titrated to MTD, and had complete laboratory data demonstrating compliance, such as absolute neutrophil count and absolute reticulocyte count within the therapeutic range. In our cohort, the BCL11A SNPs rs1427407, rs4671393 and rs11886868 were significantly associated with baseline HbF (Table 1). We saw no association between baseline HbF and any of the HBS1L-MYB SNPs, XmnI, α-thalassemia or BCL11A SNP rs7599488. In contrast to other reports, we found that coinheritance of α-thalassemia did not affect hydroxyurea treatment response (p=0.088). We found that BCL11A SNPs rs1427407, rs4671393 and rs11886868 were significantly associated with reduced ΔHbF following hydroxyurea treatment (Table 1), where individuals with the BCL11A SNPs had a smaller ΔHbF compared to individuals without the polymorphisms, as shown by the negative baseline β-value. For example, one BCL11A rs1427407 SNP is associated with a ΔHbF 3.46 percentage points lower than individuals without the SNP at MTD, with an additive, dose effect of the SNP at the second allele; homozygous individuals have higher baseline HbF, lower ΔHbF compared to heterozygotes or wild-type individuals (Figure 1). The other variants HBS1L-MYB SNPs, XmnI, α-thalassemia or BCL11A SNP rs7599488 did not significantly impact ΔHbF. None of the tested polymorphisms, including the BCL11A SNPs, were associated with a significant difference in final HbF levels. Individuals with higher baseline HbF due to BCL11A polymorphisms demonstrate a statistically significant lower rise in HbF in response to hydroxyurea than individuals without these polymorphisms. Identification of more variants associated with baseline and ΔHbF through next generation sequencing will help elucidate whether the negative effect of high baseline on ΔHbF is a BCL11A specific effect, or a manifestation of a general threshold effect, that there is a maximum amount of HbF an individual is able to achieve through hydroxyurea induction.Table 1Association between BCL11A SNPs and response to hydroxyurea.GeneSNP IDBaseline β-value (lnHbF)Baseline p-valueΔHbF β-value (%HbF)ΔHbF p-valueBCL11Ars14274070.3569.05x10-5-3.461.02x10-3BCL11Ars46713930.272.17x10-3-2.627.21x10-3BCL11Ars118868680.131.61x10-4-3.007.86x10-4BCL11Ars75994880.080.30-0.780.33Figure 1Effect of BCL11A rs1427407 on Hydroxyurea Response. Average baseline and ΔHbF values are shown for a sample BCL11A variant.Figure 1. Effect of BCL11A rs1427407 on Hydroxyurea Response. Average baseline and ΔHbF values are shown for a sample BCL11A variant. Disclosures: Off Label Use: Hydroxyurea is not FDA approved for use in pediatric sickle cell patients.

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Sickle cell disease and stroke

Blood ◽

10.1182/blood-2009-05-220921 ◽

2009 ◽

Vol 114 (25) ◽

pp. 5117-5125 ◽

Cited By ~ 87

Author(s):

Luis A. Verduzco ◽

David G. Nathan

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Oxygen Transport ◽

Transcranial Doppler ◽

Stroke Risk ◽

Association Studies ◽

Fetal Hemoglobin ◽

Genome Wide Association Studies ◽

Cell Disease ◽

Transport Efficiency

Abstract Twenty-four percent of sickle cell disease (SCD) patients have a stroke by the age of 45 years. Blood transfusions decrease stroke risk in patients deemed high risk by transcranial Doppler. However, transcranial Doppler has poor specificity, and transfusions are limited by alloimmunization and iron overload. Transfusion withdrawal may be associated with an increased rebound stroke risk. Extended blood typing decreases alloimmunization in SCD but is not universally adopted. Transfusions for thalassemia begun in early childhood are associated with lower rates of alloimmunization than are seen in SCD, suggesting immune tolerance. Optimal oxygen transport efficiency occurs at a relatively low hematocrit for SCD patients because of hyperviscosity. Consequently, exchange rather than simple transfusions are more effective in improving oxygen transport efficiency, but the former are technically more demanding and require more blood units. Although viscosity is of importance in the noncerebral manifestations of SCD, inflammation may play a larger role than viscosity in the development of large-vessel stroke. The future of SCD stroke management lies in the avoidance of transfusion. Hydroxyurea and anti-inflammatory measures may reduce the need for transfusion. Recent genome-wide association studies may provide methods for modulating fetal hemoglobin production enough to attenuate stroke risk and other complications of SCD.

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Genetics of fetal hemoglobin in Tanzanian and British patients with sickle cell anemia

Blood ◽

10.1182/blood-2010-08-302703 ◽

2011 ◽

Vol 117 (4) ◽

pp. 1390-1392 ◽

Cited By ~ 68

Author(s):

Julie Makani ◽

Stephan Menzel ◽

Siana Nkya ◽

Sharon E. Cox ◽

Emma Drasar ◽

...

Keyword(s):

African Diaspora ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Association Studies ◽

Fetal Hemoglobin ◽

Genome Wide Association Studies ◽

Genome Wide ◽

African Populations ◽

Patient Groups ◽

Chromosome 11P

Abstract Fetal hemoglobin (HbF, α2γ2) is a major contributor to the remarkable phenotypic heterogeneity of sickle cell anemia (SCA). Genetic variation at 3 principal loci (HBB cluster on chromosome 11p, HBS1L-MYB region on chromosome 6q, and BCL11A on chromosome 2p) have been shown to influence HbF levels and disease severity in β-thalassemia and SCA. Previous studies in SCA, however, have been restricted to populations from the African diaspora, which include multiple genealogies. We have investigated the influence of these 3 loci on HbF levels in sickle cell patients from Tanzania and in a small group of African British sickle patients. All 3 loci have a significant impact on the trait in both patient groups. The results suggest the presence of HBS1L-MYB variants affecting HbF in patients who are not tracked well by European-derived markers, such as rs9399137. Additional loci may be identified through independent genome-wide association studies in African populations.

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A gene co-association network regulating gut microbial communities in a Duroc pig population

Microbiome ◽

10.1186/s40168-020-00994-8 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Antonio Reverter ◽

Maria Ballester ◽

Pamela A. Alexandre ◽

Emilio Mármol-Sánchez ◽

Antoni Dalmau ◽

...

Keyword(s):

Microbial Communities ◽

Candidate Genes ◽

Relative Abundance ◽

Association Studies ◽

Single Gene ◽

Host Genome ◽

Genome Wide Association Studies ◽

Vaccine Response ◽

Microbiome Composition ◽

Host Genetic

Abstract Background Analyses of gut microbiome composition in livestock species have shown its potential to contribute to the regulation of complex phenotypes. However, little is known about the host genetic control over the gut microbial communities. In pigs, previous studies are based on classical “single-gene-single-trait” approaches and have evaluated the role of host genome controlling gut prokaryote and eukaryote communities separately. Results In order to determine the ability of the host genome to control the diversity and composition of microbial communities in healthy pigs, we undertook genome-wide association studies (GWAS) for 39 microbial phenotypes that included 2 diversity indexes, and the relative abundance of 31 bacterial and six commensal protist genera in 390 pigs genotyped for 70 K SNPs. The GWAS results were processed through a 3-step analytical pipeline comprised of (1) association weight matrix; (2) regulatory impact factor; and (3) partial correlation and information theory. The inferred gene regulatory network comprised 3561 genes (within a 5 kb distance from a relevant SNP–P < 0.05) and 738,913 connections (SNP-to-SNP co-associations). Our findings highlight the complexity and polygenic nature of the pig gut microbial ecosystem. Prominent within the network were 5 regulators, PRDM15, STAT1, ssc-mir-371, SOX9 and RUNX2 which gathered 942, 607, 588, 284 and 273 connections, respectively. PRDM15 modulates the transcription of upstream regulators of WNT and MAPK-ERK signaling to safeguard naive pluripotency and regulates the production of Th1- and Th2-type immune response. The signal transducer STAT1 has long been associated with immune processes and was recently identified as a potential regulator of vaccine response to porcine reproductive and respiratory syndrome. The list of regulators was enriched for immune-related pathways, and the list of predicted targets includes candidate genes previously reported as associated with microbiota profile in pigs, mice and human, such as SLIT3, SLC39A8, NOS1, IL1R2, DAB1, TOX3, SPP1, THSD7B, ELF2, PIANP, A2ML1, and IFNAR1. Moreover, we show the existence of host-genetic variants jointly associated with the relative abundance of butyrate producer bacteria and host performance. Conclusions Taken together, our results identified regulators, candidate genes, and mechanisms linked with microbiome modulation by the host. They further highlight the value of the proposed analytical pipeline to exploit pleiotropy and the crosstalk between bacteria and protists as significant contributors to host-microbiome interactions and identify genetic markers and candidate genes that can be incorporated in breeding program to improve host-performance and microbial traits.

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Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rate

Blood ◽

10.1182/blood.2020008345 ◽

2021 ◽

Author(s):

Gaia Zirka ◽

Philippe Robert ◽

Julia Tilburg ◽

Victoria Tishkova ◽

Chrissta X Maracle ◽

...

Keyword(s):

Transmembrane Protein ◽

Association Studies ◽

Genome Wide Association Studies ◽

Wild Type ◽

Shear Rates ◽

Extracellular Traps ◽

Genome Wide ◽

Healthy Donors ◽

Von Willebrand ◽

Willebrand Factor

Genome wide association studies linked expression of the human neutrophil antigen 3b (HNA-3b) epitope on the Slc44a2 protein with a 30% decreased risk of venous thrombosis (VT) in humans. Slc44a2 is a ubiquitous transmembrane protein identified as a receptor for Von Willebrand factor (VWF). To explain the link between Slc44a2 and VT we wanted to determine how Slc44a2 expressing either HNA-3a or HNA-3b on neutrophils could modulate their adhesion and activation on VWF under flow. Transfected HEK293T cells or neutrophils homozygous for the HNA-3a- or the HNA-3b-coding allele were purified from healthy donors and perfused in flow chambers coated with VWF at venous shear rates (100s-1). HNA-3a expression was required for Slc44a2-mediated neutrophil adhesion to VWF at 100s-1. This adhesion could occur independently of β2 integrin and was enhanced when neutrophils are preactivated with lipopolysaccharide (LPS). Moreover, specific shear conditions with high neutrophil concentration could act as a "second hit", inducing the formation of neutrophil extracellular traps. Neutrophil mobilization was also measured by intravital microscopy in venules from SLC44A2-knockout and wild-type mice after histamine-induced endothelial degranulation. Mice lacking Slc44a2 showed a massive reduction in neutrophil recruitment in inflamed mesenteric venules. Our results show that Slc44a2/HNA-3a is important for the adhesion and activation of neutrophils in veins under inflammation and when submitted to specific shears. Neutrophils expressing Slc44a2/HNA-3b not being associated with these observations, these results could thus explain the association between HNA-3b and a reduced risk for VT in humans.

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Abstract 15673: CRISPR-Cas9 Gene Editing in Mice Reveals Novel Thrombotic Function of a Human SNP in STXBP5

Circulation ◽

10.1161/circ.132.suppl_3.15673 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Qiuyu Zhu ◽

Kyung Ae Ko ◽

Sara Ture ◽

Craig N Morrell ◽

Joseph M Miano ◽

...

Keyword(s):

Endothelial Cells ◽

Gene Editing ◽

Association Studies ◽

Blood Stream ◽

Genome Wide Association Studies ◽

Wild Type ◽

Human Endothelial Cells ◽

Mesenteric Vessel ◽

Prolonged Bleeding Time ◽

Bleeding Score

Introduction: Endothelial cells responds to vascular injury by exocytosis, releasing von Willebrand factor (vWF) into the blood stream. However, the regulation of endothelial vWF release remains poorly understood. Recent genome-wide association studies (GWAS) have identified syntaxin-binding protein 5 (STXBP5) as a candidate gene linked to changes in vWF plasma levels. One top nonsynonymous single nucleotide polymorphism (SNP), rs1039084 (hg19 chr6:g.147635413A>G), encodes p. Asn436Ser substitution (STXBP5-N436S), and is associated with lower plasma vWF, higher bleeding score, and decreased venous thrombosis in humans. We recently discovered that STXBP5 inhibits endothelial vWF exocytosis and regulates thrombosis. However, the role of the STXBP5 genetic variants linked to vWF levels are not completely understood. Hypothesis: We hypothesized that STXBP5-N436S further inhibits endothelial exocytosis than wild type (STXBP5-WT). Methods: We overexpressed STXBP5-WT and STXBP5-N436S in cultured human endothelial cells and measured VWF release changes. Using CRISPR-Cas9 technique, we generated mice carrying the human rs1039084 SNP in Stxbp5 locus (Stxbp5-N437S mice). We conducted phenotypic analyses including endothelial exocytosis, hemostasis, and thrombosis in wild-type and Stxbp5-N437S mice. Results: In human endothelial cells, overexpression of STXBP5-N436S inhibits vWF exocytosis more potently than STXBP5-WT. Germline CRISPR-Cas9 gene editing efficiently and precisely knocked-in the human rs1039084 SNP in murine Stxbp5 locus, without causing detectable off-target genome cleavage. The baseline plasma vWF levels of Stxbp5-N437S mice are similar to WT mice, but Stxbp5-N437S mice showed impaired vWF exocytosis in response to epinephrine challenge. Moreover, Stxbp5-N437S mice have severe hemostasis defects displayed as prolonged bleeding time. Finally, Stxbp5-N437S mice have impaired mesenteric vessel thrombosis and carotid artery thrombosis. We are now studying the effects of the SNP upon STXBP5 structure and function. Conclusions: Our study validates the functional relevance of a candidate SNP identified by GWAS, and suggests that genetic variations within STXBP5 is a risk factor for thromboembolic disease.

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Genetic Data Analysis

Handbook of Research on Disease Prediction Through Data Analytics and Machine Learning - Advances in Medical Diagnosis, Treatment, and Care ◽

10.4018/978-1-7998-2742-9.ch017 ◽

2021 ◽

pp. 358-372

Author(s):

M. Shamila ◽

Amit Kumar Tyagi

Keyword(s):

Data Analysis ◽

Association Studies ◽

Single Gene ◽

Genetic Data ◽

Building Blocks ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Human Beings ◽

Genome Wide ◽

Genetic Data Analysis

Genome-wide association studies (GWAS) or genetic data analysis is used to discover common genetic factors which influence the health of human beings and become a part of a disease. The concept of using genomics has increased in recent years, especially in e-healthcare. Today there is huge improvement required in this field or genomics. Note that the terms genomics and genetics are not similar terms here. Basically, the human genome is made up of DNA, which consists of four different chemical building blocks (called bases and abbreviated A, T, C, and G). Based on this, we differentiate each and every human being living on earth. The term ‘genetics' originated from the Greek word ‘genetikos'. It means ‘origin'. In simple terms, genetics can be defined as a branch of biology, which deals with the study of the functionalities and composition of a single gene in an organism. There are mainly three branches of genetics, which include classical genetics, molecular genetics, and population genetics.

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