No association between alleles of the bradykinin receptor-B2 gene and acute mountain sickness

The pathophysiological mechanism(s) of the development of acute mountain sickness (AMS) is still unclear. Although the chance of developing AMS and the severity of the condition are influenced by ascent rate and altitude attained, previous history is a reliable predictor of subsequent affliction, and some individuals and families are clearly predisposed, suggesting a genetic component to susceptibility. As the vasodilator bradykinin may be involved in acclimatization to altitude, we hypothesized that variants in genes encoding components of this pathway might play a role in AMS susceptibility. We tested this by looking for associations between two functional polymorphisms (the in/del polymorphism +9/-9 [rs5810761] and the single-nucleotide polymorphism C - 58T [rs1799722]) of BDKRB2 (the gene encoding the bradykinin receptor B2) and susceptibility to AMS in an altitude-exposed Nepalese population. Lowland attendees (n = 233) at a religious festival at 4380 m in the Nepalese Himalaya were recruited and assessed for AMS by clinical evaluation and Lake Louise score (LLS). Those with a clinical diagnosis of AMS and an LLS >= 3 were designated AMS (n = 100) and those without a diagnosis of AMS and with an LLS <3 were categorized as AMS- (n = 117). DNA was prepared from buccal cells, genotyped for the two polymorphisms and allele frequencies compared between the two cohorts. No association was found between alleles at either polymorphism and susceptibility to AMS (P > 0.50), although C - 58T heterozygotes were significantly more common (P < 0.001, chi(2) = 49.6) in the subjects than would be predicted if the population was in Hardy-Weinberg equilibrium. The results of our association study do not support the hypothesis that variants in BDKRB2 influence altitude tolerance in a lowland Nepalese population; however, the deviation from Hardy-Weinberg equilibrium observed for the C - 58T polymorphism could be explained by self-selection for altitude tolerance in the festival attendees.