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Year : 2018  |  Volume : 2  |  Issue : 4  |  Page : 269-275

Using postgenome-wide association study analysis; Vars2-Pic3ca-AKT is novel putative interactive pathway associated with conotruncal heart defects

Department of Molecular Genetics and Enzymology, Division of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt

Date of Submission10-Jul-2018
Date of Decision22-Jul-2018
Date of Acceptance01-Sep-2018
Date of Web Publication11-Dec-2018

Correspondence Address:
Dr. Alaaeldin Fayez
Department of Molecular Genetics and Enzymology, Division of Human Genetics and Genome Research, National Research Centre, Cairo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_106_18

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Background: Genome-wide association studies (GWASs) have identified 43-associated variants with conotruncal heart defects (CTD) at P ≤ 5E-7, P ≤ 5E-6, and P ≤ 5E-5 till January 2018. Despite the GWASs still provide a growing number of associated genetic variants, the identification of their pathogenic mechanisms remains a major challenge in human genetics requiring data mining efforts and predictive models for accurate interpretation of noncoding variants especially. Hence, I applied a post-GWAS analysis approach to identify the possible mechanism of action of noncoding variants associated with CTD according to the latest update of the GWAS catalog. Method: I aimed in this study to conduct a post-GWAS analysis of the most associated noncoding variants with CTD to elucidate its probable pathogenic mechanisms. Through three GWAS traits belong to CTDs, it was used in a variety of integrated and computational algorithms to collect the available information about the selected noncoding variants and its associated partners. Results: It was found differential histone modification, motif binding, and gene expression among the CTD-associated single nucleotide polymorphisms. Through intensive analysis, it was also found that both the linked rs2517582 and rs17189763 haplotype might lead to alteration in the Pic3ca-AKT signal pathway due to a change of CTCF-binding affinity and upregulation of VARS2 gene. Conclusion: It was concluded that the indirect effect of the upregulation VARS2 gene might associates with CTD. Consequently, phosphoinositide 3-kinases/AKT (pic3ca/AKT) pathway has a pivotal role in the signal system of heart morphogenesis.

Keywords: Bioinformatic algorithms, conotruncal heart defects, genome-wide association study, interactive pathway, noncoding variants

How to cite this article:
Fayez A. Using postgenome-wide association study analysis; Vars2-Pic3ca-AKT is novel putative interactive pathway associated with conotruncal heart defects. Biomed Biotechnol Res J 2018;2:269-75

How to cite this URL:
Fayez A. Using postgenome-wide association study analysis; Vars2-Pic3ca-AKT is novel putative interactive pathway associated with conotruncal heart defects. Biomed Biotechnol Res J [serial online] 2018 [cited 2022 Jan 25];2:269-75. Available from: https://www.bmbtrj.org/text.asp?2018/2/4/269/247235

  Introduction Top

The most common birth defects are congenital heart defects (CHDs), which account for 40% of birth defect-related deaths;[1] one-third of all CHDs is due to conotruncal and related malformations conotruncal heart defects (CTDs) because that CTDs are highly heritable.[2],[3],[4] Responsible genetic elements of CTDs are shared; hence, it is thought that these genetic elements originated from the connected biological pathway.[5],[6]

Although the majority of efforts on functional annotation of variants were mainly limited to exons and their immediate surrounding areas,[7] but based on genome-wide association study (GWAS) results, there are varieties of the noncoding variants that are associated with the human genetic diseases such as CTDs at strongest P significant level. Moreover, data from the encyclopedia of DNA element (ENCODE) project suggest that 37% of the human genome probably affects regulation and tissue-specific expression patterns.[8]

From the above findings, a modern key component of the CHD etiology is prone to identification of regulatory elements controlling a cell's transcription and translation process, and it is worth to exert more research about variants that alter the regulatory elements of genes rather than by directly affecting gene and protein function. Hence, the current study focused on annotations and computational-based tools to predict the functional impact and pathway included noncoding variants inclusion from the GWAS database.

Based on the GWAS traits belong to CTDs, out of the selected 43 noncoding variants, both the rs2517582 and rs17189763 are strongly associated with CTD at P ≤ 5E-7 and P ≤ 5E-6, respectively, and colocated at chromosome 6. I conducted a further investigation around rs2517582 and rs17189763 to predict how and why these variants associate with CTD. The results indicate to a probable novel interactive pathway including Vars2, Pic3ca, and AKT dosage components associated with CTD.

  Methods Top

Eligibility criteria

  • GWAS database: All highly significant associated single nucleotide polymorphisms (SNPs) with CTDs, either CTDs (inherited effects) or CTDs (maternal effects), at P ≤ 5E-8, P ≤ 5E-7, P ≤ 5E-6, and P ≤ 5E-5 were included. Details of all defined associated single-nucleotide polymorphisms (SNPs) are listed in [APPENDIX 1]
  • All full-paper studies describing related noncoding variants in CTD using MEDLINE (PubMed) database (last updated January 2018) were included, and language restrictions were not applied
  • Usage reservoir, annotation, and computational-based tools concern with regulatory element specifications, including GWAVA, HaploReg v4. 1, RegulomeDB, ENCODE Project, and genotype-tissue expression (GTEx) project V7.

Online tools

  • GWAS Catalog: The GWAS Catalog concerns with published SNP-trait associations which extracted from the literature. Extracted information includes study cohort information such as cohort size, country of recruitment, and subject ancestry, and SNP-disease association information including SNP identifier (i.e., RSID), P value, gene, and risk allele[9]
  • GWAVA: GWAVA is a tool which aims to predict the functional impact of noncoding genetic variants based on a wide range of annotations of noncoding elements (largely from ENCODE/GENCODE), along with genome-wide properties such as evolutionary conservation and guanine–cytosine content. This web server provides precomputed annotations and GWAVA scores for all known variants from the Ensembl Variation database (release 70, including over 50 million variants)[10]
  • HaploReg v4.1: HaploReg is a tool for exploring annotations and builds the mechanistic hypotheses of the impact of noncoding variants on clinical phenotypes and normal variation. The annotations parameters include the following:

    • Haplotype blocks
    • Regulatory SNPs at disease-associated loci
    • LD information from the 1000 genomes project
    • Chromatin state and protein-binding annotation from the roadmap epigenomics and ENCODE projects
    • Sequence conservation
    • Effect of SNPs on regulatory motifs
    • Effect of SNPs on expression from expression quantitative trait loci (eQTL) studies.

  • ENCODE project: The ENCODE consortium aims to build a comprehensive list of functional elements in the human genome, including elements that act at the protein and RNA levels and regulatory elements that control cells and circumstances in which a gene is active[11]
  • GTEx project V7: The aim of the GTEx project is to increase our understanding of how changes in our genes affect human health and disease with the ultimate goal of improving health care for future generations. GTEx will create a database that researchers can use to study how inherited changes in genes lead to common diseases. GTEx researchers are studying genes in different tissues obtained from many different people[12]
  • String: STRING is a database of known and predicted protein–protein interactions (PPIs). The interactions include direct (physical) and indirect (functional) associations[13]
  • Uniprot (protein knowledgebase; UniProtKB): The Universal Protein Resource (UniProt) is a comprehensive resource for protein sequence and annotation. The UniProt Knowledgebase (UniProtKB) is the central hub for the collection of functional information on proteins and its sequence with accurate, consistent, and rich annotation[14]
  • Reactome: Reactome is a pathway database which provides intuitive bioinformatic tools for the visualization, interpretation, and analysis of pathway knowledge[15]
  • The GeneCards human gene database v4.6.1 Build 19: GeneCards is a searchable, integrated database providing comprehensive information on all annotated and predicted human genes. It automatically integrates gene-centric data from ~125 web sources, including genomic, transcriptomic, proteomic, genetic, clinical, and functional informations[16]
  • MEDLINE (PubMed): MEDLINE is a bibliographic database that contains more than selected 23 million references to journal articles in life sciences with a concentration on biomedicine. It provides comprehensive view to the latest knowledge in the life science field.[17]

The proposal was reviewed and approved by Research and Ethical committee of Department of Molecular Genetics and Enzymology, Division of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt The Ethics Committee Approval number was Cairo, Egypt. and date was 2017-2018.

  Results Top

According to the retrieve of associated GWAS SNPs with CTDs that carried out from the NHGRI-EBI Catalog, till January 2018, it was not found associated CTD-SNPs at P ≤ 5E-8, so a total of 43 SNPs [Appendix 1] at P ≤ 5E-7 (5 SNPs), P ≤ 5E-6 (22 SNPs), and P ≤ 5E-5 (16 SNPs) were analysis approach giving the following results:

  • In the heart tissues; Increased modifi ed H3K4 me1_Enh for P ≤ 5E-7 SNPs against highly percentage of altered regulatory motifs for P ≤ 5E-5.

Modified methylation of the lysine residue located N-terminal of core histone H3 was predominant in highly associated CTD SNPs at P ≤ 5E-7; H3K4 me1 is well known to increase the transcription activity through binding it with activator proteins. Three out of five SNPs listed at P ≤ 5E-7 led to regulatory motif alterations in three transcription factors (TFs); NF-kappa-B, DMRT3, and NRSF. CTD SNPs at P ≤ 5E-5 are prone to alter of regulatory motifs.

Through scattering plot of regulatory motifs change scores between the reference and alternative alleles, it was observed that most of these changes are prone to decrease affinity of specific TFs [Figure 1]. List of these TFs is illustrated in [Figure 2] that indicates that most of these TFs are CTCF (CCCTC-binding factor), SPIB (Spi-B transcription factor) and GR (glucocorticoid receptor).
Figure 1: Scattering plot of regulatory motifs change scores between the reference and alternative alleles

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Figure 2: List of altered transcription factors that due to differential histone modification. The black bold number represents the frequency change score of a corresponding TF and that red bold number represents scale of the frequency

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  • P ≤ 5E-7 SNPs more conserved than P ≤ 5E-6 and P ≤ 5E-5 ones might be more functionality evidence.

According to the computed average derived allele frequency (DAF) and heterozygosity (het) scores by GWAVA, it was found that P ≤ 5E-7 SNPs are less frequency difference between populations and allelic heterozygosity than P ≤ 5E-6 and P ≤ 5E-5 ones [Figure 3].
Figure 3: Mean derived allele frequency and heterozygosity (het) of variants in 1 kb flanking region for selected 43 conotruncal heart defect-associated single-nucleotide polymorphism

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  • Exponentional percentage decreasing of histone modifications, selected eQTL in the heart tissue and TSS score through P ≤ 5E-7, P ≤ 5E-6, and P ≤ 5E-5 SNPs.

As shown in [Figure 4], it was observed that the bigger percentage of histone modification was found in P ≤ 5E-7 SNPs, like this percentage of expressed genes (eQTL) inside the heart tissues and predicted promoter segment too. Those results support that different activation/repression traits resulting from histone modification might lead to increase the differential gene expression profiles.
Figure 4: Differential percentage of histone gene expression alteration (expression quantitative trait loci) combined with score of predicted promoter sequence

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  • Elevated VARS2 gene expression resulting from two linkage SNPs on chromosome 6; predictive mechanism of action.

Among all studied 43 SNPs, it was found two linked SNPs, rs17189763 and rs2517582, with r2 = 0.81 and LD (D') = 0.98. Heterozygous and homozygous state of both alternative alleles of rs17189763 and rs2517582 were led to elevated VARS2 gene expression inside the heart tissues, as shown in [Figure 5]. Postbioinformatics analysis pointed to the difference in binding of transcriptional repressor CTCF between rs2517582 reference with + 9.5 and alternative ones with + 1.8 by 7.7 [ref 9.5-alt 1.8] lower affinity degrees, CTCF acts as chromatin-binding factor prevents interaction between the promoter and nearby enhancers. Therefore, the lower affinity of CTCF in rs2517582 could lead to loss of enhancer-blocking activity and increase the neighbored VARS2 gene as shown in [Figure 6].
Figure 5: Differential Vars2 expression between wild and mutant rs2517582 and 17189763 variants. Adopted from retrieved expression quantitative trait loci data

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Figure 6: Diagrammatic shape shows the differential CTCF binding affinity between reference and altered form of rs2517582 variant and localization of the surrounded enhancers

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  • Upregulation Vars2-Pic3ca-AKT might be novel predicted interactive pathway associated with CTDs.

Vars2 was expressed normally in the heart, but it is highly expressed in the presence TT/TT and CT/CT haplotypes for rs2517582 and rs17189763, respectively. Depend on naturally activation PPI between Vars2 and Pic3ca, both the TT/TT and CT/CT haplotypes led to increase the activity of Pic3ca producing more amount of PIP3 (phosphatidylinositol 3, 4, 5 tri-phosphate), which recruits the protein kinase AKT to the plasma membrane. Elevated recruiting of AKT protein has increased negative effect on down target proteins contributed in cell proliferation, survival, and heart development such as RAF, MEK, ERK, and mitogen-activated protein kinase (MAPK), the detailed predicted pathway illustrated in [Figure 7].
Figure 7: Putative predicted altered Vars2-phosphoinositide 3-kinases-AKT pathway due to rs2517582 variant. The non arrowed truncated line represents repressive action

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  Discussion Top

Through results published by Wang et al., of a protein interaction network around the known components of human Ras-MAPK/Phosphoinositide 3-kinases (PI3K) pathways, it was found that there is a positive activation relationship between VARS2 and PI3k proteins, and both of Ras-MAPK/PI3K and PI3K-AKT are conserved signaling cascade pathways in multicellular organisms playing crucial roles during the development and proliferation.[18]

Cell proliferation, survival, and differentiation are responded cell processes to Ras-MAPK/PI3K pathways through a series of overlapping set of cellular responses and gene expression; increased AKT activity has been shown to suppress the p38/JNK pathway.[19],[20],[21],[22]

In the current study, it was found that the both rs2517582 and rs17189763 are highly linked intronic variants (r2 = 0.81 and LD [D'] =0.98) with significant CTDs association, located faraway of VARS2 gene with 73222 and 41543 bps, respectively, according to the hg38 genome assembly, and both of them led to the increase level of VARS2 expression by mean 0.665 and 0.775 beta values, respectively, in the heart-left ventricle and atrial appendage tissues according to the multitissue eQTL findings. Hence, I looked for the relationship between the VARS2 gene and the cardiogenesis.

Pic3ca (phosphatidylinositol 3-kinase) is an effector enzyme of Ras proteins and encodes the p110α catalytic subunit of class IA PI3K, which signal downstream of multiple cell-surface receptor types and control of endothelial cell lineages migration.[23],[24],[25] There is activation synergism between PIK3CA and VARS2 genes according to Wang et al.[18]

PIP3 (phosphatidylinositol 3, 4, 5 tri-phosphate) generates by PI3K recruiting the protein kinase AKT to the plasma membrane where it is activated by 3-phosphoinositide-dependent kinase 1 and the second mTOR complex, mTORC2,[26] subsequently upregulated VARS2 transcript by both rs2517582 and rs17189763 variants will lead to activate excessive amount of PI3K and PIP3 recruiting excessive amount of AKT else. This putative expectation was confirmed by immunocytochemistry study using a PIP3-specific monoclonal antibody which referred to that AKT activation-reflected alterations in PIP3 levels in the cell,[27] and PI3K-dependent phosphorylation of AKT was absent in the mutant p110α embryos.[23]

AKT's inhibitory phosphorylations on Raf and MAPK was detected over multiple experimental analysis.[28],[29],[30],[31],[32],[33],[34] MAPK/PI3K pathways are essential extracellular signal transmitter from the surface receptors to a series cascade of downstream signaling kinases and TFs,[18] from these TFs that dependant on MAPK/PI3K signals are whose contribute in human embryo cardiogenesis. Therefore, the deletion of ERK2 (alias for MAPK1) associated with a variety of cardiac outflow tract anomalies,[35] also inside the RAS-MAPK signaling pathway was found six genes related to syndromic CHD such as PTPN11, SOS1, KRAS, NRAS, RAF1, and BRAF genes.[36]

Tidyman and Rauen pointed that isolated pulmonary valve dysplasia of Noonan syndrome due to mutations in the intracellular phosphatase PTPN11 which lead to constitutive activation of MAPK signal transduction pathways;[37] also, Sadoshima and Izumopointed and Matsui et al. pointed that LV hypertrophy and heart failure associated with time-based activation of AKT pathway.[38],[39] Hence, Schirone et al. mentioned that the PI3K/AKT pathway mediates many cellular response states through its effector AKT, which is a core kinase whose downstream targets.[40]

From the above findings, and the postanalysis CTD-related SNP GWAS, the current study exposed that Vars2-Pic3ca-AKT is a novel putative interactive pathway associated with CTDs, especially that both Raf1 and Mek2 included in my suggestive Vars2-Pic3ca-AKT pathway and reported as essential signal transduction for cardiac formation.[41]

  Conclusion Top

Finally, it was concluded that (1) Vars2 gene might have indirect causing of CTD, (2) PI3K/ACT pathway has a pivotal role in the signal system of heart morphogenesis, and (3) it was worth to study the functionality of trait-associated noncoding variants.

Financial support and sponsorship

Personnel funding.

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]


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