Identification of non-coding genetic variants in samples from hypoxemic respiratory disease patients that affect the transcriptional response to hypoxia

A wide range of diseases course with an unbalance between the consumption of oxygen by tissues and its supply. This situation triggers a transcriptional response, mediated by the hypoxia inducible factors (HIFs), that aims to restore oxygen homeostasis. Little is known about the inter-individual variation in this response and its role in the progression of disease. Herein, we sought to identify common genetic variants mapping to hypoxia response elements (HREs) and characterize their effect on transcription. To this end, we constructed a list of genome-wide HIF-binding regions from publicly available experimental datasets and studied the genetic variability in these regions by targeted re-sequencing of genomic samples from 96 chronic obstructive pulmonary disease and 144 obstructive sleep apnea patients. This study identified 14 frequent variants disrupting potential HREs. The analysis of the genomic regions containing these variants by means of reporter assays revealed that variants rs1009329, rs6593210 and rs150921338 impaired the transcriptional response to hypoxia. Finally, using genome editing we confirmed the functional role of rs6593210 in the transcriptional regulation of EGFR. In summary, we found that inter-individual variability in non-coding regions affect the response to hypoxia and could potentially impact on the progression of pulmonary diseases.Ministerio de Ciencia e Innovación (Spanish Ministry of Science and Innovation, MICINN) [SAF2011 24225 to LdelP, SAF2014-53819-R to L.delP., B.J.]; Comunidad Autónoma de Madrid [S2010/BMD-2542 to L.delP., F.G.R., J.A.], Sociedad Española de Neumología y Cirugía Torácica (SEPAR) [34/2013 to LdelP, F.G.R.]; Fondo de Investigación Sanitaria/Instituto de Salud Carlos III [PI13-01512 to F.G.R.]; Fundación Caja Madrid (Beca de Movilidad para Profesores de las Universidades Públicas de Madrid 2011–2012 to L.delP); Canadian Institutes of Health Research (CIHR) [MOP-82875 to W.W.W.]; Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN355532-10 to W.W.W.]; National Institutes of Health [1R01GM084875 toW.W.W.]; CSIC (Spanish National Research Council) [JAE-Doc grant-2010 to O.R., in part by the European Social Fund]. Spanish science, technology and innovation contract [University of Castilla-LaMancha-2014 to O.R., in part by the European Social Fund]. Funding for open access charge: MICINN [SAF2011 24225 to L.delP., SAF2014-53819-R to L.delP., B.J.

Identification of non-coding genetic variants in samples from hypoxemic respiratory disease patients that affect the transcriptional response to hypoxia

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al.A wide range of diseases course with an unbalance between the consumption of oxygen by tissues and its supply. This situation triggers a transcriptional response, mediated by the hypoxia inducible factors (HIFs), that aims to restore oxygen homeostasis. Little is known about the inter-individual variation in this response and its role in the progression of disease. Herein, we sought to identify common genetic variants mapping to hypoxia response elements (HREs) and characterize their effect on transcription. To this end, we constructed a list of genome-wide HIF-binding regions from publicly available experimental datasets and studied the genetic variability in these regions by targeted re-sequencing of genomic samples from 96 chronic obstructive pulmonary disease and 144 obstructive sleep apnea patients. This study identified 14 frequent variants disrupting potential HREs. The analysis of the genomic regions containing these variants by means of reporter assays revealed that variants rs1009329, rs6593210 and rs150921338 impaired the transcriptional response to hypoxia. Finally, using genome editing we confirmed the functional role of rs6593210 in the transcriptional regulation of EGFR. In summary, we found that inter-individual variability in non-coding regions affect the response to hypoxia and could potentially impact on the progression of pulmonary diseases.Ministerio de Ciencia e Innovacion (Spanish Ministry of Science and Innovation, MICINN) [SAF2011 24225 to LdelP, SAF2014-53819-R to L.delP., B.J.]; Comunidad Autonoma de Madrid [S2010/BMD-2542 to L.delP., F.G.R., J.A.], Sociedad Española de Neumologia y Cirugia Toracica (SEPAR) [34/2013 to LdelP, F.G.R.]; Fondo de Investigacion Sanitaria/Instituto de Salud Carlos III [PI13-01512 to F.G.R.]; Fundacion Caja Madrid (Beca de Movilidad para Profesores de las Universidades Publicas de Madrid 2011–2012 to L.delP); Canadian Institutes of Health Research (CIHR) [MOP-82875 to W.W.W.]; Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN355532-10 to W.W.W.]; National Institutes of Health [1R01GM084875 to W.W.W.]; CSIC (Spanish National Research Council) [JAE-Doc grant-2010 to O.R., in part by the European Social Fund]. Spanish science, technology and innovation contract [University of Castilla-La Mancha-2014 to O.R., in part by the European Social Fund]. Funding for open access charge: MICINN [SAF2011 24225 to L.delP., SAF2014-53819-R to L.delP., B.J.].Peer Reviewe