Endothelial nitric oxide synthase gene polymorphisms associated with susceptibility to high altitude pulmonary edema in Chinese railway construction workers at Qinghai-Tibet over 4 500 meters above sea level / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To examine whether the polymorphisms of endothelial nitric oxide synthase (eNOS) gene are associated with the susceptibility to high altitude pulmonary edema (HAPE) in Chinese railway construction workers at Qinghai-Tibet where the altitude is over 4 500 m above sea level.</p><p><b>METHODS</b>A case-control study was conducted including 149 HAPE patients in the construction workers and 160 healthy controls randomly recruited from their co-workers, matching the patients in ethnicity, age, sex, lifestyle, and working conditions. Three polymorphisms of eNOS gene, T-786C in promoter, 894G/T in exon 7, and 27bp variable number tandem repeat (VNTR) in intron 4, were genotyped using polymerase chain reaction (PCR) and confirmed with DNA sequencing.</p><p><b>RESULTS</b>The frequencies of 894T allele and heterozygous G/T of the 894G/T variant were significantly higher in HAPE patients group than in the control group (P=0.0028 and P=0.0047, respectively). However, the frequencies of the T-786C in promoter and the 27bp VNTR in intron 4 were not significantly different between the two groups. Haplotypic analysis revealed that the frequencies of two haplotypes (H3,T-T-b, b indicates 5 repeats of 27 bp VNTR; H6, C-G-a, a indicates 4 repeats of 27 bp VNTR) were significantly higher in HAPE patients (both Pü0.0001). On the contrary, the frequencies of H1 (T-G-b) and H2 (T-G-a) were lower in HAPE patients than in healthy controls (both Pü0.001).</p><p><b>CONCLUSIONS</b>Two haplotypes (T-T-b and C-G-a) may be strongly associated with susceptibility to HAPE. Compared with the individual alleles of eNOS gene, the interaction of multiple genetic markers within a haplotype may be a major determinant for the susceptibility to HAPE.</p>

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. CONCLUSION: 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.