title: Unveiling the interactions among BMPR-2, ALK-1 and 5-HTT genes in the pathophysiology of HAPE.
abstract: BACKGROUND
  Few potential candidate genes coding for type I and II receptors of transforming growth factor beta signaling pathway and the serotonin transporter have been associated with pulmonary hypertension (PH). The latter being a phenotype for high altitude pulmonary edema (HAPE), these genes are hypothesized to be crucial markers to investigate under the hypobaric hypoxic environment of high altitude.
  
  
  OBJECTIVE
  We hence aimed to investigate bone-morphogenetic protein-2 (BMP2), bone morphogenetic protein receptor type-II (BMPR-2), activin receptor-like kinase-1 (ALK-1), serotonin transporter (5-HTT) and serotonin (5-HT) for their contribution, individually/epistatically, to clinical endpoints by altering downstream signaling molecules.
  
  
  METHODS
  In a case-control design, interactions between/among polymorphisms of BMPR-2, ALK-1 and 5-HTT were screened in 200 HAPE-patients (HAPE-p) and 200 HAPE-free sojourners (HAPE-f). Plasma biomarker BMP-2 and 5-HT were estimated. The relative gene expression was also witnessed in 20 humans/10 rats followed by correlation analyses.
  
  
  RESULTS
  The genotype/allele models revealed the prevalence of BMPR-2 rs6717924A-rs4303700A-rs1048829A; ALK-1 rs11169953T-rs3759178C-rs706816C and 5-HTT rs6354C in HAPE (P≤0.05). Multifactor dimensionality reduction for interactions among genes revealed a 4-locus model of BMPR-2 rs6717924G/A; ALK-1 rs11169953C/T-rs706816T/C and 5-HTT rs6354A/C as the best disease predicting (P≤0.001); whereas HapEvolution analysis confirmed the alleles rs6717924A, rs4303700A and rs6354C as the best interacting (P≤0.01). Plasma levels of BMP-2 and 5-HT were elevated in HAPE (P≤0.0001). The expression of BMP-2, ALK-1, 5-HT, 5-HTT was elevated and of BMPR-2 decreased in humans and rats (P≤0.05). The risk alleles BMPR-2 rs6717924A-rs4303700G-rs1048829A; ALK-1 rs11169953T-rs706816C and 5-HTT rs6354C correlated inversely with arterial oxygen saturation (SaO2) and positively with mean arterial pressure (MAP), BMP-2 and 5-HT in HAPE. Likewise, haplotypes BMPR-2 GGGCGAAAA, AAATAGGGA and ALK-1 CCTCAAAG, CCTTAAAG correlated with clinical markers and biomarkers (P≤0.01). BMP-2 and 5-HT correlated positively with MAP and negatively with SaO2 (P≤0.01).
  
  
  CONCLUSIONS
  The genetic-interactions among BMPR-2, ALK-1, and 5-HTT polymorphisms, elevated BMP-2 and 5-HT levels and differential gene expression substantiated the strong genetic contribution in HAPE pathophysiology.
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Department of Biotechnology, University of Pune, Pune, India.
authors.forename: Zahara
authors.initials: Z
authors.lastname: Ali
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Waseem
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Pandey
authors.affiliation: Department of Medicine, SNM Hospital, Leh, Ladakh, Jammu and Kashmir, India.
authors.forename: Ghulam
authors.initials: G
authors.lastname: Mohammad
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Department of Biotechnology, University of Pune, Pune, India. Electronic address: qpasha@igib.res.in.
authors.forename: M A
authors.initials: MA
authors.lastname: Qadar Pasha
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000531:Altitude; D000532:Altitude Sickness / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D062186:Arterial Pressure; D055396:Bone Morphogenetic Protein 2 / Q000097:blood / Q000235:genetics*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D006239:Haplotypes; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008957:Models, Genetic; D058011:Multifactor Dimensionality Reduction; D011110:Polymorphism, Genetic; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000097:blood; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: 5-HT; 5-HTT; ALK-1; BMP-2; BMPR-2; Genetic-interactions; High altitude pulmonary edema; High-altitude; Pulmonary hypertension