title: A Preliminary Genome-Wide Association Study of Acute Mountain Sickness Susceptibility in a Group of Nepalese Pilgrims Ascending to 4380 m.
abstract: There is significant interindividual variation in acute mountain sickness (AMS) susceptibility in humans. To identify genes related to AMS susceptibility, we used a genome-wide association study (GWAS) to simultaneously test associations between genetic variants dispersed throughout the genome and the presence and severity of AMS. DNA samples were collected from subjects who ascended rapidly to Gosainkunda, Nepal (4380 m), as part of the 2005, 2010, and 2012 Janai Purnima festivals. The Lake Louise Score was used to measure AMS severity. The primary analysis was based on 99 male subjects (43 with AMS; 56 without AMS). Genotyping for the GWAS was performed using Infinium Human Core Exome Bead Chips (542,556 single-nucleotide polymorphisms were assayed), and validation genotyping was performed with pyrosequencing in two additional cohorts (n = 101 for each). In total, 270,389 single nucleotide polymorphisms (SNPs) passed quality control, and 4 SNPs (one intronic, three nonsynonymous) in the FAM149A gene were associated with AMS severity after correcting for multiple hypothesis testing (p = 1.8E-7); however, in the validation cohorts, FAM149A was not associated with the presence or severity of AMS. No other genes were associated with AMS susceptibility at the genome-wide level. Due to the large influence of environmental factors (i.e., ascent rate and altitude attained) and the difficulties associated with the AMS phenotype (i.e., low repeatability, nonspecific symptoms, potentially independent ailments), we suggest that future studies addressing the variation in the acute human hypoxia response should focus on objective responses to acute hypoxia instead of AMS.
authors.affiliation: 1 School of Kinesiology, University of British Columbia , Vancouver, British Columbia, Canada .|2 Department of Kinesiology, McMaster University , Hamilton, Ontario, Canada .
authors.forename: Martin J
authors.initials: MJ
authors.lastname: MacInnis
authors.affiliation: 3 Faculty of Medicine, University of British Columbia , Vancouver, British Columbia, Canada .
authors.forename: Nadia
authors.initials: N
authors.lastname: Widmer
authors.affiliation: 4 Maharajgunj Medical Campus, Institute of Medicine, Tribhuvan University , Kathmandu, Nepal .
authors.forename: Utsav
authors.initials: U
authors.lastname: Timulsina
authors.affiliation: 4 Maharajgunj Medical Campus, Institute of Medicine, Tribhuvan University , Kathmandu, Nepal .
authors.forename: Ankita
authors.initials: A
authors.lastname: Subedi
authors.affiliation: 4 Maharajgunj Medical Campus, Institute of Medicine, Tribhuvan University , Kathmandu, Nepal .
authors.forename: Ashmita
authors.initials: A
authors.lastname: Siwakoti
authors.affiliation: 4 Maharajgunj Medical Campus, Institute of Medicine, Tribhuvan University , Kathmandu, Nepal .
authors.forename: Bidur Prasad
authors.initials: BP
authors.lastname: Pandit
authors.affiliation: 5 Accident and Emergency Department, Bradford Royal Infirmary , Bradford, United Kingdom .
authors.forename: Michael G
authors.initials: MG
authors.lastname: Freeman
authors.affiliation: 1 School of Kinesiology, University of British Columbia , Vancouver, British Columbia, Canada .
authors.forename: Eric A
authors.initials: EA
authors.lastname: Carter
authors.affiliation: 6 Child and Family Research Institute , Vancouver, British Columbia, Canada .|7 Department of Medical Genetics, Faculty of Medicine, University of British Columbia , Vancouver, British Columbia, Canada .
authors.forename: Irina
authors.initials: I
authors.lastname: Manokhina
authors.affiliation: 4 Maharajgunj Medical Campus, Institute of Medicine, Tribhuvan University , Kathmandu, Nepal .
authors.forename: Ghan Bahadur
authors.initials: GB
authors.lastname: Thapa
authors.affiliation: 1 School of Kinesiology, University of British Columbia , Vancouver, British Columbia, Canada .|3 Faculty of Medicine, University of British Columbia , Vancouver, British Columbia, Canada .
authors.forename: Michael S
authors.initials: MS
authors.lastname: Koehle
mesh_terms: D000208:Acute Disease; D000328:Adult; D000531:Altitude; D000532:Altitude Sickness / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009390:Nepal; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012463:Saliva / Q000737:chemistry; D012720:Severity of Illness Index
chemical_list: C000611055:FAM149A protein, human; D005819:Genetic Markers; D011506:Proteins
keywords: Nepalese; acclimatization; altitude illness; genomics; hypoxia