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Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach

BACKGROUND: Extreme constitution “Prakriti” types of Ayurveda exhibit systemic physiological attributes. Our earlier genetic study has revealed differences in EGLN1, key modulator of hypoxia axis between Prakriti types. This was associated with differences in high altitude adaptation and susceptibil...

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Autores principales: Aggarwal, Shilpi, Gheware, Atish, Agrawal, Anurag, Ghosh, Saurabh, Prasher, Bhavana, Mukerji, Mitali
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457985/
https://www.ncbi.nlm.nih.gov/pubmed/26047609
http://dx.doi.org/10.1186/s12967-015-0542-9
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author Aggarwal, Shilpi
Gheware, Atish
Agrawal, Anurag
Ghosh, Saurabh
Prasher, Bhavana
Mukerji, Mitali
author_facet Aggarwal, Shilpi
Gheware, Atish
Agrawal, Anurag
Ghosh, Saurabh
Prasher, Bhavana
Mukerji, Mitali
author_sort Aggarwal, Shilpi
collection PubMed
description BACKGROUND: Extreme constitution “Prakriti” types of Ayurveda exhibit systemic physiological attributes. Our earlier genetic study has revealed differences in EGLN1, key modulator of hypoxia axis between Prakriti types. This was associated with differences in high altitude adaptation and susceptibility to high altitude pulmonary edema (HAPE). In this study we investigate other molecular differences that contribute to systemic attributes of Prakriti that would be relevant in predictive marker discovery. METHODS: Genotyping of 96 individuals of the earlier cohort was carried out in a panel of 2,800 common genic SNPs represented in Indian Genomic Variation Consortium (IGVC) panel from 24 diverse populations. Frequency distribution patterns of Prakriti differentiating variations (FDR correction P < 0.05) was studied in IGVC and 55 global populations (HGDP–CEPH) panels. Genotypic interactions between VWF, identified from the present analysis, and EGLN1 was analyzed using multinomial logistic regression in Prakriti and Indian populations from contrasting altitudes. Spearman’s Rank correlation was used to study this genotypic interaction with respect to altitude in HGDP–CEPH panel. Validation of functional link between EGLN1 and VWF was carried out in a mouse model using chemical inhibition and siRNA studies. RESULT: Significant differences in allele frequencies were observed in seven genes (SPTA1, VWF, OLR1, UCP2, OR6K3, LEPR, and OR10Z1) after FDR correction (P < 0.05). A non synonymous variation (C/T, rs1063856) associated with thrombosis/bleeding susceptibility respectively, differed significantly between Kapha (C-allele) and Pitta (T-allele) constitution types. A combination of derived EGLN1 allele (HAPE associated) and ancestral VWF allele (thrombosis associated) was significantly high in Kapha group compared to Pitta (p < 10(–5)). The combination of risk-associated Kapha alleles was nearly absent in natives of high altitude. Inhibition of EGLN1 using (DHB) and an EGLN1 specific siRNA in a mouse model lead to a marked increase in vWF levels as well as pro-thrombotic phenotype viz. reduced bleeding time and enhanced platelet count and activation. CONCLUSION: We demonstrate for the first time a genetic link between EGLN1 and VWF in a constitution specific manner which could modulate thrombosis/bleeding susceptibility and outcomes of hypoxia. Integration of Prakriti in population stratification may help assemble common variations in key physiological axes that confers differences in disease occurrence and patho-phenotypic outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-015-0542-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-44579852015-06-07 Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach Aggarwal, Shilpi Gheware, Atish Agrawal, Anurag Ghosh, Saurabh Prasher, Bhavana Mukerji, Mitali J Transl Med Research BACKGROUND: Extreme constitution “Prakriti” types of Ayurveda exhibit systemic physiological attributes. Our earlier genetic study has revealed differences in EGLN1, key modulator of hypoxia axis between Prakriti types. This was associated with differences in high altitude adaptation and susceptibility to high altitude pulmonary edema (HAPE). In this study we investigate other molecular differences that contribute to systemic attributes of Prakriti that would be relevant in predictive marker discovery. METHODS: Genotyping of 96 individuals of the earlier cohort was carried out in a panel of 2,800 common genic SNPs represented in Indian Genomic Variation Consortium (IGVC) panel from 24 diverse populations. Frequency distribution patterns of Prakriti differentiating variations (FDR correction P < 0.05) was studied in IGVC and 55 global populations (HGDP–CEPH) panels. Genotypic interactions between VWF, identified from the present analysis, and EGLN1 was analyzed using multinomial logistic regression in Prakriti and Indian populations from contrasting altitudes. Spearman’s Rank correlation was used to study this genotypic interaction with respect to altitude in HGDP–CEPH panel. Validation of functional link between EGLN1 and VWF was carried out in a mouse model using chemical inhibition and siRNA studies. RESULT: Significant differences in allele frequencies were observed in seven genes (SPTA1, VWF, OLR1, UCP2, OR6K3, LEPR, and OR10Z1) after FDR correction (P < 0.05). A non synonymous variation (C/T, rs1063856) associated with thrombosis/bleeding susceptibility respectively, differed significantly between Kapha (C-allele) and Pitta (T-allele) constitution types. A combination of derived EGLN1 allele (HAPE associated) and ancestral VWF allele (thrombosis associated) was significantly high in Kapha group compared to Pitta (p < 10(–5)). The combination of risk-associated Kapha alleles was nearly absent in natives of high altitude. Inhibition of EGLN1 using (DHB) and an EGLN1 specific siRNA in a mouse model lead to a marked increase in vWF levels as well as pro-thrombotic phenotype viz. reduced bleeding time and enhanced platelet count and activation. CONCLUSION: We demonstrate for the first time a genetic link between EGLN1 and VWF in a constitution specific manner which could modulate thrombosis/bleeding susceptibility and outcomes of hypoxia. Integration of Prakriti in population stratification may help assemble common variations in key physiological axes that confers differences in disease occurrence and patho-phenotypic outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-015-0542-9) contains supplementary material, which is available to authorized users. BioMed Central 2015-06-06 /pmc/articles/PMC4457985/ /pubmed/26047609 http://dx.doi.org/10.1186/s12967-015-0542-9 Text en © Aggarwal et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Aggarwal, Shilpi
Gheware, Atish
Agrawal, Anurag
Ghosh, Saurabh
Prasher, Bhavana
Mukerji, Mitali
Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach
title Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach
title_full Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach
title_fullStr Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach
title_full_unstemmed Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach
title_short Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach
title_sort combined genetic effects of egln1 and vwf modulate thrombotic outcome in hypoxia revealed by ayurgenomics approach
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457985/
https://www.ncbi.nlm.nih.gov/pubmed/26047609
http://dx.doi.org/10.1186/s12967-015-0542-9
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