Multiple Genetic Polymorphisms In Susceptibility To High-altitude Pulmonary Edema(HAPE) Among The Chinese Han

Background:High-altitude pulmonary edema (HAPE) is the major cause of death from altitude illness, and it is an uncommon form of pulmonary edema that occurs in healthy individuals within a few days of arrival at altitudes above 2,500-3,000 m, representing a serious public health threat. Previous genomic surveys have identified the association between multiple single nucleotide polymorphisms (SNPs) and HAPE in recent years. However, no study to date has assessed the relationship between these common SNPs and HAPE risk in Chinese population. Therefore, our aim was to replicate the association between these polymorphisms in Han Chinese and to determine whether other variants could explain the association. In addition, we also selected some additional variants from previously reported telomere length-related genes to assess their association with HAPE.Methods:We genotyped one hundred and nine polymorphisms in 267 patients with diagnosed HAPE and 304 controls and evaluated their association with risk of HAPE.Results:Through the association analysis, we identified seven SNPs (rs275651, rs275652, rs4524238 and rs385338 in AGTR1, rs1042718 in ADRB2, rs749174 in GSTP1 and rs4963516 in GNB3) and two haplotypes (AG and AA both in AGTR1) with statistically significant associations with HAPE risk (rs275651, A vs. T,p= 0.017; rs275652, G vs. T, p= 0.016; rs385338, CG/CC vs. GG,p= 0.045; rs4524238, AA vs. AG/AG vs. GG, adjusted p= 0.040; rs 1042718, A vs. C, p= 0.045; rs749174, A vs. G,p= 0.042; rs4963516, G vs. T,p= 0.006; Haplotype AG vs. TT, p= 0.018; Haplotype AA vs. GG, p= 0.040). For the analysis of telomere length-related genes, statistically significant associations with HAPE were found for the SNPs in ACYP2 (rs6713088, GG vs. CC, p= 0.049; rs17045754, CC vs. GG, p= 0.044), TSPYL6 (rsl2615793, AA vs. GG,p= 0.035; rs11896604, GG vs. CC,p= 0.026) and RTEL1 (rs6089953, G vs. A,p= 0.009; rs6010621, G vs. T,p< 0.001; rs2297441, A vs. G,p= 0.021; rs4809324, CT vs. TT, p= 0.022). Following haplotype analysis, GT and AT (rs6089953-rs6010621) have emerged as the major risk haplotypes (GT, p= 0.013; AT, p= 0.008) whereas GG (rs6089953-rs6010621) as the chief protective haplotype (p< 0.001) for the development of HAPE among Han Chinese.Conclusion:These results above provide independent evidence that certain genetic variations were significantly associated with HAPE in Han Chinese individuals, which could potentially be used as diagnostic and prognostic molecular markers of HAPE in clinical study.