An Investigation into the Genetic Determinants of

Maternal Physiology and Birth Weight at High Altitude

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

*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

Objective

An Interdisciplinary Research Project

Project Output

Acknowledgements

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, Han-

Chinese are more at risk of premature birth, elevated risk of pre/post-natal

mortality and of intra-uterine growth retardation (IUGR)

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).

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 high-

altitude 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.

Figure 2: The view from Kunde Hospital in the Solukhumbu National

Park. Altitude 4000m.

Our Achievements and Timescale

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.

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

Research objectives approved by the Nepalese Health Research Council. Teams set out to make contact with hospitals located at high altitude (>2500m)

Collections continue at both lowland

hospitals (control groups) and high

altitude centres – Kunde & Lukla

Hospitals in Solukhumbu National Park

Relocation of samples to a central

storage hub in Kathmandu and

transfer of those samples to the UK for

analysis

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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.

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

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

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