An Investigation into the Genetic Determinants of
Maternal Physiology and Birth Weight at High Altitude
D. Aryal4, D. Bruce-Hickman1, G. Cavalleri, S. Cox1, M. Ishak1, C. Malcolm-Browne5, H.
Montgomery1, M. Peters*1, J. Randall*2, P. Robbins3, C. Tomlinson1
*Main Grant Holders
1 The Institute for Human Health and Performance, UCL 2 Department of Anthropology, UCL 3 University of
Oxford, Royal College Surgeons Ireland 4 Paropakar Maternity and Women’s Hospital, Kathmandu 5 The
Mountain Trust and Humanitarian Centre
Introduction
Tibetan babies born at altitude are heavier than Han-Chinese babies
(more recent mountain settlers), averaging 310 g heavier at altitudes
2,700-3,000 m and 530 g heavier at 3,000-3,800m. Additionally, HanChinese are more at risk of premature birth, elevated risk of pre/post-natal
mortality and of intra-uterine growth retardation (IUGR)
The concept of GWAS has yet to be applied in the setting of maternal
healthcare. However, the excess of IUGR observed in people newly
arrived at altitude suggests that adaptation to oxygen tension mediates
protection against IUGR. Our endpoint is the establishment of a genetic
basis for the differences in maternal outcome
An Interdisciplinary Research Project
To our knowledge, this project is the first of its kind to build links with local
healthcare professionals, community representatives and grass roots
humanitarian organisations to locate remote birthing centres in highaltitude areas. The project offers the opportunity to combine pioneering
research with the privilege of observing traditional rural birthing-traditions.
The end-point of our research is to contribute to understanding of
maternal physiology and prenatal development when under stress from
hypoxia. Furthermore, this research can be translated to the critical care
environment where it may benefit chronically hypoxic patients.
Early 2012
Objective
Figure 2: The view from Kunde Hospital in the Solukhumbu National
Park. Altitude 4000m.
Summer 2012
Previously, failure of delivery of oxygen was believed to be the cardinal
problem in adaptation at altitude. However, recent evidence points
towards adaptation in tissue consumption of available oxygen. For
example, selection of EPAS1 coding for Hypoxia Inducible Factor 2a in
Tibetans (an adapted high altitude population) actually limits haemoglobin
availability. EPAS1 selection was identified by so called genome wide
association studies (GWAS).
Research objectives approved by the
Nepalese Health Research Council. Teams
set out to make contact with hospitals
located at high altitude (>2500m)
Secondary teams reach hospitals
equipped with specialist equipment for
storing saliva for DNA analysis and with
full instructions and consent forms for
staff and participants in Nepalese
Collections continue at both lowland
hospitals (control groups) and high
altitude centres – Kunde & Lukla
Hospitals in Solukhumbu National Park
In collaboration with local clinics, hospitals and health care workers we
have collected maternal, paternal and ancestral histories from expectant
mothers in the Nepal Himalaya and taken maternal and umbilical cord
blood samples on delivery. These mothers have gestated to at least start
of third trimester above 3000m. We have repeated these collections
amongst same ethnicity groups from lowland Nepal.
Recruitment in lowland Nepal is now complete but the difficulties of
identifying and recruiting sufficient numbers of mothers at altitude means
that field work is ongoing, projected completion early 2013.
2013
Our Achievements and Timescale
Relocation of samples to a central
storage hub in Kathmandu and
transfer of those samples to the UK for
analysis
Project Output
Results will be disseminated to the scientific community through
submission of publications to peer-reviewed science journals, and through
presentation at national and international conferences.
Local teams will be fully engaged in research data analysis and
interpretation and in authorship on any scientific publications that result. In
addition once DNA is extracted an array will be lodged with the Nepali
researcher Dr Aryal.
This project has allowed young physiologists from UCL and elsewhere to
interact with the Nepali population and gain a greater understanding of
both the academic input to running a research project, and the obstacles
to obtaining results in real life. These young researchers continue to be
closely involved in the project
Acknowledgements
Figure 1: The Pasang Lhamu Nicole Niquille Hospital in Lukla,
2860m, has helped enormously in collecting samples where 45
mothers have been enrolled already in the space of 1 year
The Research Team kindly acknowledge the support of UCL Institute for Global
Health, whose generous support made the necessary boots on the ground
work feasible. Thanks also are due to The Mountain Trust, Nepal, for their
fantastic logistical support.