Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approachReportar como inadecuado




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Journal of Translational Medicine

, 13:184

First Online: 06 June 2015Received: 15 May 2015Accepted: 18 May 2015DOI: 10.1186-s12967-015-0542-9

Cite this article as: Aggarwal, S., Gheware, A., Agrawal, A. et al. J Transl Med 2015 13: 184. doi:10.1186-s12967-015-0542-9

Abstract

BackgroundExtreme 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.

MethodsGenotyping 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.

ResultSignificant 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. 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.

ConclusionWe 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.

KeywordsEndophenotypes Prakriti High altitude Deep vein thrombosis Ayurveda Bleeding rs1063856 rs480902 PHD2 Predictive medicine Shilpi Aggarwal and Atish Gheware contributed equally to this work

Electronic supplementary materialThe 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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Autor: Shilpi Aggarwal - Atish Gheware - Anurag Agrawal - Saurabh Ghosh - Indian Genome Variation Consortium - Bhavana Prasher - Mit

Fuente: https://link.springer.com/







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