PMID- 30254217
OWN - NLM
STAT- MEDLINE
DCOM- 20190411
LR  - 20200309
IS  - 1476-5438 (Electronic)
IS  - 1018-4813 (Print)
IS  - 1018-4813 (Linking)
VI  - 27
IP  - 1
DP  - 2019 Jan
TI  - Novel insight into the genetic basis of high-altitude pulmonary hypertension in 
      Kyrgyz highlanders.
PG  - 150-159
LID - 10.1038/s41431-018-0270-8 [doi]
AB  - The Central Asian Kyrgyz highland population provides a unique opportunity to 
      address genetic diversity and understand the genetic mechanisms underlying 
      high-altitude pulmonary hypertension (HAPH). Although a significant fraction of 
      the population is unaffected, there are susceptible individuals who display HAPH 
      in the absence of any lung, cardiac or hematologic disease. We report herein the 
      analysis of the whole-genome sequencing of healthy individuals compared with HAPH 
      patients and other controls (total n = 33). Genome scans reveal selection signals 
      in various regions, encompassing multiple genes from the first whole-genome 
      sequences focusing on HAPH. We show here evidence of three candidate genes MTMR4, 
      TMOD3 and VCAM1 that are functionally associated with well-known molecular and 
      pathophysiological processes and which likely lead to HAPH in this population. 
      These processes are (a) dysfunctional BMP signaling, (b) disrupted tissue repair 
      processes and (c) abnormal endothelial cell function. Whole-genome sequence of 
      well-characterized patients and controls and using multiple statistical tools 
      uncovered novel candidate genes that belong to pathways central to the 
      pathogenesis of HAPH. These studies on high-altitude human populations are 
      pertinent to the understanding of sea level diseases involving hypoxia as a main 
      element of their pathophysiology.
FAU - Iranmehr, Arya
AU  - Iranmehr A
AD  - Department of Electrical & Computer Engineering, University of California, San 
      Diego, La Jolla, CA, 92093, USA.
FAU - Stobdan, Tsering
AU  - Stobdan T
AD  - Division of Respiratory Medicine, Department of Pediatrics, University of 
      California, San Diego, La Jolla, CA, 92093, USA.
FAU - Zhou, Dan
AU  - Zhou D
AD  - Division of Respiratory Medicine, Department of Pediatrics, University of 
      California, San Diego, La Jolla, CA, 92093, USA.
FAU - Poulsen, Orit
AU  - Poulsen O
AD  - Division of Respiratory Medicine, Department of Pediatrics, University of 
      California, San Diego, La Jolla, CA, 92093, USA.
FAU - Strohl, Kingman P
AU  - Strohl KP
AD  - Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, 
      OH, USA.
FAU - Aldashev, Almaz
AU  - Aldashev A
AD  - National Academy of Sciences, Bishkek, 720071, Kyrgyz Republic.
FAU - Telenti, Amalio
AU  - Telenti A
AD  - Department of Integrative Structural and Computational Biology, Scripps Research 
      Institute, La Jolla, CA, 92037, USA.
FAU - Wong, Emily H M
AU  - Wong EHM
AD  - Human Longevity Inc., San Diego, CA, 92121, USA.
FAU - Kirkness, Ewen F
AU  - Kirkness EF
AD  - Human Longevity Inc., San Diego, CA, 92121, USA.
FAU - Venter, J Craig
AU  - Venter JC
AD  - Human Longevity Inc., San Diego, CA, 92121, USA.
AD  - J. Craig Venter Institute, La Jolla, CA, 92037, USA.
FAU - Bafna, Vineet
AU  - Bafna V
AD  - Department of Computer Science & Engineering, University of California, San 
      Diego, La Jolla, CA, 92093, USA.
FAU - Haddad, Gabriel G
AU  - Haddad GG
AD  - Division of Respiratory Medicine, Department of Pediatrics, University of 
      California, San Diego, La Jolla, CA, 92093, USA. ghaddad@ucsd.edu.
AD  - Department of Pediatrics, Department of Neurosciences, University of California, 
      San Diego, La Jolla, CA, 92093, USA. ghaddad@ucsd.edu.
AD  - Rady Children's Hospital, San Diego, CA, 92123, USA. ghaddad@ucsd.edu.
LA  - eng
GR  - R01 GM114362/GM/NIGMS NIH HHS/United States
GR  - R01GM114362/GM/NIGMS NIH HHS/United States
GR  - R01 HL127403-02/HL/NHLBI NIH HHS/United States
GR  - R21 NS101652/NS/NINDS NIH HHS/United States
GR  - R01 HL127403/HL/NHLBI NIH HHS/United States
GR  - R21NS101652-01/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180925
PL  - England
TA  - Eur J Hum Genet
JT  - European journal of human genetics : EJHG
JID - 9302235
RN  - 0 (TMOD3 protein, human)
RN  - 0 (Tropomodulin)
RN  - 0 (Vascular Cell Adhesion Molecule-1)
RN  - EC 3.1.3.48 (MTMR4 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor)
SB  - IM
CIN - J Lung Health Dis. 2019;3(2):29-30. PMID: 31304480
MH  - Altitude
MH  - Genome-Wide Association Study
MH  - Humans
MH  - Hypertension, Pulmonary/*genetics
MH  - Kyrgyzstan
MH  - *Polymorphism, Genetic
MH  - Protein Tyrosine Phosphatases, Non-Receptor/genetics
MH  - Tropomodulin/genetics
MH  - Vascular Cell Adhesion Molecule-1/genetics
PMC - PMC6303266
COIS- VB is a co-founder, has an equity interest and receives income from Digital 
      Proteomics, LLC and Pretzel Genomics Ltd. The terms of this arrangement have been 
      reviewed and approved by the University of California, San Diego in accordance 
      with its conflict of interest policies. Digital Proteomics, LLC was not involved 
      in the research presented here. EHMW, EFK and JCV are employees of Human 
      Longevity Inc.
EDAT- 2018/09/27 06:00
MHDA- 2019/04/12 06:00
PMCR- 2020/01/01
CRDT- 2018/09/27 06:00
PHST- 2018/04/05 00:00 [received]
PHST- 2018/08/30 00:00 [accepted]
PHST- 2018/08/09 00:00 [revised]
PHST- 2018/09/27 06:00 [pubmed]
PHST- 2019/04/12 06:00 [medline]
PHST- 2018/09/27 06:00 [entrez]
PHST- 2020/01/01 00:00 [pmc-release]
AID - 10.1038/s41431-018-0270-8 [pii]
AID - 270 [pii]
AID - 10.1038/s41431-018-0270-8 [doi]
PST - ppublish
SO  - Eur J Hum Genet. 2019 Jan;27(1):150-159. doi: 10.1038/s41431-018-0270-8. Epub 
      2018 Sep 25.