Genetic interaction of Hsp70 family genes polymorphisms with high-altitude pulmonary edema among Chinese railway constructors at altitudes exceeding 4000 meters.
BACKGROUND
High-altitude pulmonary edema (HAPE) is thought of as an independent clinical disorder with a constitutional or genetic component in its etiology. We focused on 5 common polymorphisms within HSPA1A (rs1043618 and rs1008438), HSPA1B (rs1061581 and rs539689) and HSPA1L (rs2227956) of Hsp70 family to explore their potential interaction upon susceptibility to HAPE in Chinese.


METHODS
A total of 148 HAPE patients and 483 matched controls were recruited during the construction of Qinghai-Tibet railway from 2001 to 2006. Genotyping was performed using PCR-RFLP, PCR-SSCP and PCR-direct-sequencing techniques. Promoter activity was evaluated by luciferase reporter assays. Gene-gene interaction was conducted by MDR v.2.0, and haplotype-diplotype analysis by Haplo.stats v.1.4.0.


RESULTS
Significant differences were observed in the genotype (P=0.0136) and allele (P=0.0299) distributions of rs1008438, and in rs1061581 allele distribution (P=0.0421) between HAPE patients and controls. Interaction analysis indicated that 3 polymorphisms (rs1061581, rs1043618 and rs1008438) shared strong synergism with a testing accuracy of 0.792 and cross-validation consistency 10 out of 10 (P=0.001). Haplotypes Hap4 (G-C-A, in order of rs1061581, rs1043618 and rs1008438) and Hap5 (G-G-A) had an 86% reduced risk (P=0.0009) against and Hap7 (A-C-C) had a 2.43-fold increased risk for HAPE. When considered as diplotypes, significance was noted for Dip5 (Hap1-Hap7) (OR=3.39; 95% CI: 1.28-9.17; P=0.0140). Functional assessment supported the involvement of rs1008438 in the pathogenesis of HAPE.


CONCLUSIONS
We demonstrated strong interaction of rs1061581, rs1043618 and rs1008438 polymorphisms within Hsp70 family upon susceptibility to HAPE in Chinese. Moreover, polymorphism rs1008438 might cause the development of HAPE via a change in HSPA1A promoter activity.
National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 5 Dong Dan San Tiao, 100005 Beijing, China.
Yue
Y
Qi
Wen-Quan
WQ
Niu
Tong-Chun
TC
Zhu
Jing-Liang
JL
Liu
Wei-Ya
WY
Dong
Ying
Y
Xu
Shou-Quan
SQ
Ding
Cheng-Bing
CB
Cui
Yun-Jun
YJ
Pan
Guo-Shu
GS
Yu
Wen-Yu
WY
Zhou
Chang-Chun
CC
Qiu
D000328:Adult; D000483:Alleles; D000531:Altitude; D044466:Asian People / Q000235:genetics*; D005838:Genotype; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011654:Pulmonary Edema / Q000235:genetics* / Q000378:metabolism*; D011890:Railroads; D017132:Workplace
D018840:HSP70 Heat-Shock Proteins