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Sequencing the exons of human glucocorticoid receptor (NR3C1) gene in Han Chinese with high-altitude pulmonary edema.

ABSTRACT: High-altitude pulmonary edema (HAPE) is a serious acute mountain sickness that mainly occurs in non-acclimatized individuals after rapid ascent to high altitude. The precise etiology of HAPE remains unclear. This study aimed to investigate whether NR3C1 gene polymorphism is associated with the susceptibility to HAPE.The exons of NR3C1 gene were sequenced by a ABI 3730 DNA analyzer in 133 HAPE patients and matched 135 healthy Han Chinese controls from the Yushu area in Qinghai (the altitude greater than 3500 m).DNA sequencing showed the heterozygous substitutions at codon 588 (rs6194) in exon 6 and 766 (rs6196) in exon 9 of NR3C1 gene. The genotypic distributions and allelic frequencies of NR3C1 SNP rs6194 showed significant differences in two groups (P?

SUBMITTER: Du H

PROVIDER: S-EPMC5869773 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Sequencing the exons of human glucocorticoid receptor (NR3C1) gene in Han Chinese with high-altitude pulmonary edema.

Du Hui H Zhao Jing J Su Zhanhai Z Liu Yongnian Y Yang Yingzhong Y

Journal of physiological anthropology 20180327 1

<h4>Background</h4>High-altitude pulmonary edema (HAPE) is a serious acute mountain sickness that mainly occurs in non-acclimatized individuals after rapid ascent to high altitude. The precise etiology of HAPE remains unclear. This study aimed to investigate whether NR3C1 gene polymorphism is associated with the susceptibility to HAPE.<h4>Methods</h4>The exons of NR3C1 gene were sequenced by a ABI 3730 DNA analyzer in 133 HAPE patients and matched 135 healthy Han Chinese controls from the Yushu ...[more]

PMID: 29587872

Similar Datasets

NR3C1 gene polymorphisms are associated with high-altitude pulmonary edema in Han Chinese.

Project description:BACKGROUND:High-altitude pulmonary edema (HAPE) is a life-threatening form of non-cardiogenic edema which occurs in unacclimatized individuals after rapid ascent to high altitude. NR3C1 gene encodes for glucocorticoid receptor (GR) which plays an important role in stress and inflammation. This study aimed to investigate the association of NR3C1 polymorphisms with the susceptibility to HAPE in Han Chinese. METHODS:The 30 SNPs in the NR3C1 gene were genotyped by the Sequenom MassARRAY SNP assay in 133 HAPE patients (HAPE-p) and 135 matched Han Chinese resistant to HAPE (HAPE-r). The genotypic and allele frequencies, odds ratios (ORs), and 95% confidence intervals (95% CIs) were calculated, respectively. RESULTS:The 12 SNPs showed a significant difference between the HAPE-p and HAPE-r groups. In allelic model analysis, we found that the allele "A" of rs17287745, rs17209237, rs17209251, rs6877893, and rs1866388; the allele "C" of rs6191, rs6188, and rs2918417; the allele "T" of rs33388 and rs4634384; and the allele "G" of rs41423247 and rs10052957 were associated with increased the risk of HAPE. In the genetic model analysis, we found that rs17287745, rs6191, rs6188, rs33388, rs2918417, rs6877893, rs1866388, rs41423247, rs4634384, and rs10052957 were relevant to the increased HAPE risk under the dominant model. In addition, the haplotype AACACTCAAGTG of the 12 SNPs was detected to be significantly associated with HAPE risk (OR?=?2.044, 95%CI?=?1.339~3.120, P?=?0.0008), while the haplotype GGAGCACGACCG was associated with the decreased risk of HAPE (OR?=?0.573, 95% CI?=?0.333~0.985, P?=?0.0422). CONCLUSIONS:Our findings provide new evidence for the association between SNPs in NR3C1 and an increased risk of HAPE in the Chinese population. NR3C1 polymorphisms are associated with the susceptibility to HAPE in Han Chinese.

| S-EPMC6472084 | biostudies-literature

Genome-wide association study of high-altitude pulmonary edema in a Han Chinese population.

Project description:A two-stage genome-wide association study (GWAS) was performed to identify and analyze genes and single nucleotide polymorphisms (SNPs) associated with high-altitude pulmonary edema (HAPE) in a Han Chinese patient population. In the first stage, DNA samples from 68 patients with recurrent HAPE were scanned using Affymetrix SNP Array 6.0 Chips, and allele frequencies were compared to those of 84 HapMap CHB samples to identify candidate SNPs. In the second stage, the 77 identified candidate SNPs were examined in an independent cohort of samples from 199 HAPE patients and 304 controls. Associations between SNPs and HAPE risk were tested using various genetic models. Of the 77 original SNPs, 7 were found to be associated with HAPE susceptibility in the second stage of the study. GO and pathway enrichment analysis of the 7 SNPs revealed 5 adjacent genes involved in various processes, including regulation of nucleoside diphosphate metabolism, thyroid hormone catabolism, and low-density lipoprotein receptor activity. These results suggest the identified SNPs and genes may contribute to the physiopathology of HAPE.

| S-EPMC5458230 | biostudies-literature

Genetic adaptation to extreme hypoxia: study of high-altitude pulmonary edema in a three-generation Han Chinese family.

Project description:Organismal response to hypoxia is essential for critical regulation of erythropoiesis, other physiological functions, and survival. There is evidence of individual variation in response to hypoxia as some but not all of the affected individuals develop polycythemia, and or pulmonary and cerebral edema. A significant population difference in response to hypoxia exist as many highland Tibetan, Ethiopian, and Andean natives developed adaptive mechanisms to extreme hypoxia. A proportion of non-adapted individuals exposed to high altitude develop pulmonary edema (HAPE), pulmonary hypertension, cerebral edema, and extreme polycythemia. The isolation of causative gene(s) responsible for HAPE and other extreme hypoxia complications would provide a rational basis for specific targeted therapy of HAPE, allow its targeted prevention for at-risk populations, and clarify the pathophysiology of other hypoxic maladaptations. The only suggested genetic linkage among unrelated individuals with HAPE has been with endothelial nitric oxide synthase (eNOS) gene. Here we describe a family with multiple members affected with HAPE in three generations. Families with multiple affected members with HAPE have not been described. We first ruled out linkage of HAPE with the eNOS gene. We then performed an analysis of the whole genome using high-density SNP arrays (Affymetrix v5.0) and, assuming a single gene causation of HAPE, ruled out linkage with 34 other candidate genes. Only the HIF2A haplotype was shared by individuals who exhibit the HAPE phenotype, and work on its possible causative role in HAPE is in progress. The small size of our family does not provide sufficient power for a conclusive analysis of linkage. We hope that collaboration with other investigators with access to more HAPE patients will lead to the identification of gene(s) responsible for HAPE and possibly other maladaptive hypoxic complications.

| S-EPMC3506116 | biostudies-literature

Association Between the Polymorphism of Steroid Hormone Metabolism Genes and High-Altitude Pulmonary Edema in the Chinese Han Population.

Project description:PurposeSteroid hormone metabolism plays an essential role in high-altitude pulmonary edema (HAPE) progression. This study aimed to investigate the association between polymorphism in seven steroid hormone metabolism genes (STAR, HSD3B1, HSD3B2, CYP17A1, CYP21A2, CYP11B1, and CYP11B2) and HAPE susceptibility among Han Chinese.Patients and methodsA total of 41 tagSNPs in the seven genes were genotyped using Sequenom MassARRAY SNP assays from 169 HAPE patients (HAPE-p) and 309 matched Han Chinese individuals resistant to HAPE (HAPE-r). The genotypic and allele frequencies, odds ratios (ORs), and 95% confidence intervals (95% CIs) were calculated.ResultsFour SNPs, including the allele C of rs6203 (p = 0.034, OR [95% CI] = 1.344 [1.022-1.767]) in HSD3B1, allele G of rs3740397 (p = 0.044, OR [95% CI] = 1.314 [1.007-1.714]) and allele C of rs10786712 (p = 0.039, OR [95% CI] = 0.751 [0.572-0.986]) in CYP17A1, and allele T of rs6402 (p = 0.006, OR [95% CI] = 0.504 [0.306-0.830]) in CYP11B1, were significantly associated with HAPE. The distribution of the genotypes of these SNPs also significantly differed between the HAPE-p and HAPE-r groups. Moreover, six haplotypes (the linkage disequilibrium block including rs10883783, rs4919686, rs3740397, rs3824755, and rs10786712) of CYP17A1 were also significantly associated with HAPE.ConclusionThe four SNPs located in HSD3B1 (rs6203), CYP17A1 (rs3740397 and rs10786712), and CYP11B1 (rs6402) and the six haplotypes of CYP17A1 are likely to have an effect on HAPE.

| S-EPMC8787081 | biostudies-literature

Association between single nucleotide polymorphisms in ADRB2, GNB3 and GSTP1 genes and high-altitude pulmonary edema (HAPE) in the Chinese Han population.

Project description:High altitude pulmonary edema (HAPE) occurs mainly under conditions such as high altitude, rapid ascent, or hypoxia. Previous studies suggest that ADRB2, GNB3, TH, and GSTP1 polymorphisms are associated with various lung diseases. We evaluated whether those polymorphisms are associated with the risk of HAPE in a Chinese Han population. ADRB2, GNB3, TH and GSTP1 polymorphisms were genotyped using a Sequenom MassARRAY. Logistic regression, adjusted for age and gender, was used to evaluate the association between the genotypes and the risk of HAPE by computing odds ratios (ORs) and 95% confidence intervals (95% CIs). The results revealed that GNB3 rs4963516 allele ''G'' (G vs T: OR = 0.70, 95% CI = 0.55-0.90, p = 0.006) was associated with HAPE risk. The ADRB2 rs1042718 alleles had a 1.29-fold (95%CI = 1.00-1.66; p = 0.045) increased risk of HAPE, and the GSTP1 rs749174 alleles had a 0.71-fold (95%CI = 0.52-0.99; p = 0.042) decreased risk of HAPE. Co-dominant and dominant models of GNB3 rs4963516 decreased the risk of HAPE (p = 0.023 and p = 0.008, respectively). Our results indicate GNB3 and GSTP1 polymorphisms may protect against HAPE progression, while ADRB2 polymorphisms are associated with an increased risk of HAPE.

| S-EPMC5392320 | biostudies-literature

Angiotensin II receptor 1 gene variants are associated with high-altitude pulmonary edema risk.

Project description:Previous studies demonstrated that Angiotensin II Receptor 1 (AGTR1) may play an important role in the development of high-altitude pulmonary edema. We envisaged a role for AGTR1 gene variants in the pathogenesis of HAPE and investigated their potential associations with HAPE in a Han Chinese population. We genotyped seven AGTR1 polymorphisms in 267 patients with diagnosed HAPE and 304 controls and evaluated their association with risk of HAPE. Statistically significant associations were found for the single nucleotide polymorphisms (SNPs) rs275651 (p = 0.017; odds ratio [OR] = 0.65) and rs275652 (p = 0.016; OR = 0.64). Another SNP rs10941679 showed a marginally significant association after adjusting for age and sex in the additive genetic model (adjusted OR = 1.44, 95% CI = 1.01-2.04, p = 0.040). Haplotype analysis confirmed that the haplotype "AG" was associated with a 35% reduction in the risk of developing HAPE, while the haplotype "AA" increased the risk of developing HAPE by 44%. These results provide the first evidence linking genetic variations in AGTR1 with HAPE risk in Han Chinese individuals.

| S-EPMC5363573 | biostudies-literature

Three plasma metabolite signatures for diagnosing high altitude pulmonary edema.

Project description:High-altitude pulmonary edema (HAPE) is a potentially fatal condition, occurring at altitudes greater than 3,000 m and affecting rapidly ascending, non-acclimatized healthy individuals. However, the lack of biomarkers for this disease still constitutes a bottleneck in the clinical diagnosis. Here, ultra-high performance liquid chromatography coupled with Q-TOF mass spectrometry was applied to study plasma metabolite profiling from 57 HAPE and 57 control subjects. 14 differential plasma metabolites responsible for the discrimination between the two groups from discovery set (35 HAPE subjects and 35 healthy controls) were identified. Furthermore, 3 of the 14 metabolites (C8-ceramide, sphingosine and glutamine) were selected as candidate diagnostic biomarkers for HAPE using metabolic pathway impact analysis. The feasibility of using the combination of these three biomarkers for HAPE was evaluated, where the area under the receiver operating characteristic curve (AUC) was 0.981 and 0.942 in the discovery set and the validation set (22 HAPE subjects and 22 healthy controls), respectively. Taken together, these results suggested that this composite plasma metabolite signature may be used in HAPE diagnosis, especially after further investigation and verification with larger samples.

| S-EPMC4602305 | biostudies-literature

Raised HIF1α during normoxia in high altitude pulmonary edema susceptible non-mountaineers.

Project description:High altitude pulmonary edema (HAPE) susceptibility is associated with EGLN1 polymorphisms, we hypothesized that HAPE-susceptible (HAPE-S, had HAPE episode in past) subjects may exhibit abnormal HIF1α levels in normoxic conditions. We measured HIF1α levels in HAPE-S and HAPE resistant (HAPE-R, no HAPE episode) individuals with similar pulmonary functions. Hemodynamic responses were also measured before and after normobaric hypoxia (Fi02 = 0.12 for 30 min duration at sea level) in both groups. . HIF1α was higher in HAPE-S (320.3 ± 267.5 vs 58.75 ± 33.88 pg/ml, P < 0.05) than HAPE-R, at baseline, despite no significant difference in baseline oxygen saturations (97.7 ± 1.7% and 98.8 ± 0.7). As expected, HAPE-S showed an exaggerated increase in pulmonary artery pressure (27.9 ± 6 vs 19.3 ± 3.7 mm Hg, P < 0.05) and a fall in peripheral oxygen saturation (66.9 ± 11.7 vs 78.7 ± 3.8%, P < 0.05), when exposed to hypoxia. HIF1α levels at baseline could accurately classify members of the two groups (AUC = 0.87). In a subset of the groups where hemoglobin fractions were additionally measured to understand the cause of elevated hypoxic response at baseline, two of four HAPE-S subjects showed reduced HbA. In conclusion, HIF 1 α levels during normoxia may represent an important marker for determination of HAPE susceptibility.

| S-EPMC4876441 | biostudies-other

Glucocorticoid receptor (NR3C1) gene polymorphisms and onset of alcohol abuse in adolescents.

Project description:Onset of alcohol use at an early age increases the risk for later alcohol dependence. We investigated the role of the glucocorticoid receptor (GR) gene (NR3C1) in onset of alcohol use and abuse in 14-year-old adolescents (n=4534). Several NR3C1 polymorphisms were associated with onset of alcohol drinking or drunkenness at this age. Strongest associations were observed in females, with one marker (rs244465) remaining significant after correction for multiple testing (P(adj) =0.0067; odds ratio=1.7, for drunkenness). Our data provide the first evidence that GR modulates initiation of alcohol abuse and reveal a polymorphism that might contribute to susceptibility to addiction.

| S-EPMC3428936 | biostudies-literature

Human glucocorticoid receptor alpha gene (NR3C1) pharmacogenomics: gene resequencing and functional genomics.

Project description:The human glucocorticoid receptor alpha (GRalpha) is a nuclear hormone receptor that regulates multiple physiological and pathophysiological processes. There are large variations in both physiological and therapeutic response to glucocorticoids. Multiple previous studies suggested that genetic polymorphisms in GRalpha (NR3C1) might play an important role.The aim of the study was to identify and determine the functional implications of common genetic variation in NR3C1.We resequenced the NR3C1 gene using 240 DNA samples from four ethnic groups, followed by functional characterization of the effects of selected polymorphisms.A total of 108 polymorphisms were identified in GRalpha, including nine nonsynonymous coding single nucleotide polymorphisms (cSNPs) and four synonymous cSNPs with a minor allele frequency greater than 5%. Functional studies showed that SNPs encoding Phe(65)Val and Asp(687)Glu displayed slightly increased levels of protein compared with WT, and Asp(687)Glu also caused increased GRalpha receptor number. In addition, Ala(229)Thr and Ile(292)Val showed slightly decreased ligand binding affinity in COS-1 cells. A genotype-phenotype association study of NR3C1 gene expression in 240 lymphoblastoid cell lines identified one SNP, Cm746T>C, located 5'-upstream of noncoding exon 1C, and one haplotype, Cm237delC/Cm238C>T/Cm240G>C in exon 1C of the gene that were associated with GRalpha mRNA expression and a trend with GRalpha number.These results represent a step toward understanding the functional role of common sequence variation in the GRalpha gene (NR3C1) and the potential application of those SNPs in translational studies.

| S-EPMC2730876 | biostudies-literature

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