Probable role of β2-adrenergic receptor gene haplotype in high-altitude pulmonary oedema

Background and objective: The role of beta 2-adrenergic receptor (ADRB2) in pulmonary oxygenation has been ascertained during altitude acclimatization, physical performance and lung fluid clearance, but little is known about its association with high-altitude pulmonary oedema (HAPE), a non-cardiogenic pulmonary oedema. Methods: In a case-control study, 110 unrelated HAPE patients (HAPE-p) and 143 unrelated HAPE-resistant (HAPE-r) controls matched on age and ethnicity were used to examine the association between eight single nucleotide polymorphisms (SNP) and disease. The eight SNP including three tag-SNP were genotyped from promoter and exonic regions of ADRB2. Robust methods for predicting geneotype-phenotype interactions, for example, multidimensional reduction (MDR) and moving-window haplotype analysis were applied. Results: The haplotypes from 46A/G and 79C/G SNP of ADRB2 were associated with HAPE. The MDR model depicting disease association through genotype-genotype and genotype-phenotype interaction included SNP 46A/G, 79C/G and 523C/A. Its haplotype 46G_79C_523C was significantly overrepresented in HAPE-r (P = 0.0001; chi(2) = 14.95; OR = 4.52; 95% CI: 1.98-10.3). The global haplotype test showed significant association with HAPE (LR chi(2) = 86.69, P < 0.0001). A moving-window analysis revealed that haplotype -367C/T_46A/G_79C/G differed significantly between HAPE-p and HAPE-r (LR chi(2) = 22.5, P = 0.002). The MDR model depicted SNP 46A/G, 79C/G and 523C/A as the best combination predicting disease. Conclusions: The haplotypes of ADRB2 consisting of the SNP, 46A/G and 79C/G, have a greater power for predicting HAPE.