title: Synergistic effect of the genetic polymorphisms of the renin-angiotensin-aldosterone system on high-altitude pulmonary edema: a study from Qinghai-Tibet altitude.
abstract: The pathogenesis of high-altitude pulmonary edema (HAPE) has been at least partially attributed to the local dysregulation of the renin-angiotensin-aldosterone system (RAAS) cascade. To address this issue, we conducted the largest nested case-control study to-date to explore the association between variations in RAAS genes and HAPE in Chinese population. We recruited 140 HAPE patients and 144 controls during the construction of Qinghai-Tibet railway and genotyped 10 gene polymorphisms evenly interspersed in 5 RAAS candidate genes. The data were analyzed by haplotype and multifactor dimensionality reduction (MDR). The single-locus analysis showed that CYP11B2 C-344T and K173R and ACE A-240T polymorphisms were significantly associated with HAPE after Bonferroni correction (P<0.005). The linkage analysis constructed a linkage block including C-344T and K173R polymorphisms in complete linkage disequilibrium with each other, while occurred with significantly different frequencies between HAPE and control groups. The gene-gene interaction analysis found the overall best model including ACE A-240T and A2350G and CYP11B2 C-344T polymorphisms with strong synergistic effect. This model had a maximum testing accuracy of 68.61% and a maximum cross validation consistency of 9 out of 10 (P=0.004). The homozygous genotype combination of -240AA, 2350GG and -344TT conferred high genetic susceptibility to HAPE, which was further strengthened by haplotype analysis. Our results add evidence for synergistic effect of RAAS gene polymorphisms on HAPE susceptibility. Moreover, we proposed a promising data-mining analytical approach (MDR) for detecting and characterizing gene-gene interactions.
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/Peking Union Medical College, No.5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Qi
authors.forename: Wenquan
authors.initials: W
authors.lastname: Niu
authors.forename: Tongchun
authors.initials: T
authors.lastname: Zhu
authors.forename: Wenyu
authors.initials: W
authors.lastname: Zhou
authors.forename: Changchun
authors.initials: C
authors.lastname: Qiu
mesh_terms: D000328:Adult; D000532:Altitude Sickness / Q000235:genetics*; D016022:Case-Control Studies; D002681:China / Q000208:ethnology; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011654:Pulmonary Edema / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000235:genetics*; D018609:Tibet
chemical_list: D019405:Cytochrome P-450 CYP11B2; D007703:Peptidyl-Dipeptidase A