| Summary: | Purpose: Acute mountain sickness (AMS) is the most common and most benign altitude illness. The main symptoms (i.e. headache, nausea, fatigue, dizziness, and disturbed sleep) appear in 6 – 12 h after rapid ascent (usually to above 2500 m) and often subside after 4 – 5 days without further ascent. The etiology is unclear and may be partially due to an innate susceptibility, which could be genetic. The studies described in this thesis focused on genetic predisposition to AMS susceptibility in Nepalese. Given that ancestral background of Nepalese is strongly influenced by its neighbouring populations (e.g. Tibetan and Indian) who may have different levels of AMS susceptibility, due to differing in evolutionary history, population stratification was assessed. Methods: Two hundred and thirty five Nepalese who permanently live below 1800 m were recruited in 2005 (n = 103) and 2008 (n = 132) while attending a religious festival at Gosainkunda (4380 m). Subjects were assigned to the AMS+ and AMS- groups based on clinical diagnosis performed by physicians and using Lake Louise Scoring (LLS) system. Twenty polymorphisms in five candidate genes (ACE, AGTR1, BDKRB2, ADRB2, and NOS3) that encode important components of vascular and pulmonary physiological pathways were investigated. Allele and genotype frequencies at the polymorphic loci were compared between the AMS+ and AMS- groups. Population stratification was assessed by comparing allele and genotype frequencies of fifteen ancestry informative markers and estimating Tibetan and South Asian genetic contributions to Nepalese subjects. Results: No significant difference in allele and genotype frequencies of 19 polymorphisms was found between the AMS+ and AMS- groups. An association was found between the alleles of the NOS3G⁸⁹⁴T polymorphism (rs1799983) in NOS3 and AMS in the 2005 cohort as well as in native Andean highlanders (Quechua) collected in the late 1990s; however, the association was not replicated in the 2008 Nepalese cohort. No population stratification was found in the Nepalese cohorts. Conclusion: Genetic predisposition to AMS in Nepalese was not shown strongly influenced by either alleles in the genes investigated in the studies described in this thesis or by ancestry (South Asian or Tibetan). === Education, Faculty of === Kinesiology, School of === Graduate
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