title: Evidence for a genetic basis for altitude illness: 2010 update.
abstract: Altitude illness refers to a group of environmentally mediated pathophysiologies. Many people will suffer acute mountain sickness shortly after rapidly ascending to a moderately hypoxic environment, and an unfortunate few will develop potentially fatal conditions such as high altitude pulmonary edema or high altitude cerebral edema. Some individuals seem to be predisposed to developing altitude illness, suggesting an innate contribution to susceptibility. The implication that there are altitude-sensitive and altitude-tolerant individuals has stimulated much research into the contribution of a genetic background to the efficacy of altitude acclimatization. Although the effect of altitude attained and rate of ascent on the etiology of altitude illness is well known, there are only tantalizing, but rapidly accumulating, clues to the genes that may be involved. In 2006, we reviewed what was then known about the genetics of altitude illness. This article updates that review and attempts to tabulate all the available genetic data pertaining to these conditions. To date, 58 genes have been investigated for a role in altitude illness. Of these, 17 have shown some association with the susceptibility to, or the severity of, these conditions, although in many cases the effect size is small or variable. Caution is recommended when evaluating the genes for which no association was detected, because a number of the investigations reviewed in this article were insufficiently powered to detect small effects. No study has demonstrated a clear-cut altitude illness gene, but the accumulating data are consistent with a polygenic condition with a strong environmental component. The genes that have shown an association affect a variety of biological pathways, suggesting that either multiple systems are involved in altitude pathophysiology or that gene-gene interactions play a role. Although numerous studies have been performed to investigate specific genes, few have looked for evidence of heritability or familial transmission, or for epidemiological patterns that would be consistent with genetically influenced conditions. Future trends, such as genome-wide association studies and epigenetic analysis, should lead to enhanced understanding of the complex interactions within the genome and between the genome and hypoxic environments that contribute to an individual's capacity to acclimatize rapidly and effectively to altitude.
authors.affiliation: School of Human Kinetics, University of British Columbia, 6081 University Boulevard, Vancouver, BC, Canada.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: MacInnis
authors.forename: Michael S
authors.initials: MS
authors.lastname: Koehle
authors.forename: Jim L
authors.initials: JL
authors.lastname: Rupert
mesh_terms: D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2) / Q000235:genetics; D000017:ABO Blood-Group System / Q000235:genetics; D000064:Acclimatization / Q000235:genetics; D000483:Alleles; D000532:Altitude Sickness / Q000235:genetics*; D000085962:Angiotensin-Converting Enzyme 2; D000808:Angiotensinogen / Q000235:genetics; D001055:Apolipoproteins B / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D016232:Endothelins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D009051:Mountaineering; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D043782:Receptor, Bradykinin B2 / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2); D000017:ABO Blood-Group System; D000085962:Angiotensin-Converting Enzyme 2; D000808:Angiotensinogen; D001055:Apolipoproteins B; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019405:Cytochrome P-450 CYP11B2; D016232:Endothelins; D005982:Glutathione Transferase; D006360:Heat-Shock Proteins; D020962:Heterotrimeric GTP-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D052250:Nitric Oxide Synthase Type III; D007703:Peptidyl-Dipeptidase A; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D018343:Receptors, Adrenergic, beta-2; D050486:Serotonin Plasma Membrane Transport Proteins; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C534931:AGT protein, human; C544065:AGTR1 protein, human; C436291:CDKN1B protein, human; C454420:G-protein beta3 subunit; C497442:HIF1A protein, human; C493230:SLC6A4 protein, human; C496314:NOS3 protein, human; C488034:ACE protein, human; C000705307:ACE2 protein, human