Long noncoding RNA ANRIL alleviates hypoxia-induced pulmonary microvascular endothelial cell damage.

BACKGROUND: High-altitude pulmonary oedema (HAPE) is a form of noncardiogenic pulmonary oedema. Studies have found that long noncoding RNA (lncRNA) plays an important role in HAPE. ANRIL is significant in pulmonary illnesses, which implies that alterations in ANRIL expression levels may be involved in the beginning and development of HAPE. However, the specific mechanism is indistinct. The present study is meant to explore the effect and mechanism of ANRIL on hypoxic-induced injury of pulmonary microvascular endothelial cells (PMEVCs). METHODS: In the hypoxic model of PMVECs, overexpression of ANRIL or knockdown of miR-181c-5p was performed to assess cell proliferation, apoptosis, and migration. Furthermore, the levels of apoptosis-related proteins, inflammatory factors, and vascular active factors were also measured. RESULTS: The results showed that, after 24 h of hypoxia, PMVECs proliferation and migration were suppressed in comparison to the control group, along with an increase in apoptosis, a decrease in the expression of ANRIL, and an increase in the expression of miR-181c-5p (all p < .05). The damage caused by hypoxia in PMVECs can be lessened by overexpressing ANRIL, which also inhibits the production of TNF-α, iNOS, and VEGF as well as BAX and cleaved caspase-3 (all p < .05). Further experimental results showed that overexpression of ANRIL and knockdown of miR-181c-5p had the same protection against hypoxic injury in PMVECs (all p < .05). CONCLUSIONS: Our study suggests that ANRIL may prevent hypoxia injury to PMVECs in HAPE through the negative regulation of miR-181c-5p.

Analysis of very important pharmacogene variants in the Tibetan population from China.

Personalized medicine, the treatment best suited for an individual, is a hot field of clinical research in the world. Many recent studies have shown that genetic variations have a great influence on the treatment. This study aimed to identify the distribution differences of very important pharmacogene (VIP) variants between the Tibetan population and the other 26 populations from the 1000 Genomes project. Based on the PharmGKB database, we successfully genotyped 50 VIP variants located in 27 genes in the Tibetan population. We also compared the genotype frequencies of VIP variants between Tibetan population and the other 26 populations. Without adjustment, the Chi-square test showed that the only significant variant between Tibetans and every other group was rs1801159 in dihydropyrimidine dehydrogenase (DPYD), followed by rs1800566 in NAD(P)H quinone dehydrogenase 1 (NQO1) and rs1051296 in solute carrier family 19 member 1 (SLC19A1). After Bonferroni's multiple adjustments, the genotype frequencies distribution of DPYD rs1801159 was found to be different in Tibetans compared to the other 26 groups, apart from ACB and ASW. Moreover, genetic structure/F-statistics (Fst) analysis and the phylogenetic tree illustrated that Tibetans had a closer affinity with CDX, CHB, CHS, JPT and KHV. Our data will complement pharmacogenomics information of the Tibetan population and provide theoretical support for the realization of individualized medical treatment for Tibetans in the future.

Genetic Variations of CYP19A1 Gene and Stroke Susceptibility: A Case-Control Study in the Chinese Han Population.

OBJECTIVE: This study aimed to explore the association between genetic variations of CYP19A1 and stroke susceptibility in the Chinese Han population. METHODS: A total of 477 stroke patients and 480 healthy controls were recruited in this study. The genotyping of CYP19A1 polymorphisms (rs4646, rs6493487, rs1062033, rs17601876, and rs3751599) was performed by the Agena MassARRAY platform. Under logistic regression models, we evaluated the associations of CYP19A1 polymorphisms and stroke susceptibility by odds ratio and 95% confidence interval. RESULTS: Our study showed that rs4646 (codominant: P = 0.020; recessive: P = 0.016) and rs17601876 (allele: P = 0.044; codominant: P = 0.011; dominant: P = 0.009; recessive: P = 0.046) significantly decreased the risk of stroke. In the stratification analysis, rs4646 is associated with decreased stroke risk among the individuals older than 64 years (codominant: P = 0.028; recessive: P = 0.010) and women (codominant: P = 0.029; recessive: P = 0.029), whereas rs1062033 increased stroke risk in the subgroup of age 64 years and younger (recessive: P = 0.042). The rs17601876 polymorphism has a strong relationship with stroke susceptibility, which is age and gender dependent. In haplotype analysis, we found a block (rs17601876 and rs3751599), and Ars17601876Grs3751599 haplotype is related to an increased stroke risk (P < 0.05). In addition, CYP19A1 variations had effects on clinical characteristics. CONCLUSION: CYP19A1 polymorphisms were significantly associated with stroke susceptibility in the Chinese Han population.

Association between DIO2 polymorphism and the risk of Kashin-Beck disease in the Tibetan population.

BACKGROUND: Kashin-Beck disease (KBD) is a local, multiple and deformable osteoarthropathy, mostly occurring in Tibet. Type 2 iodothyronine deiodinase (DIO2) is implicated in the activation of thyroid hormones to which the bones are very sensitive. Therefore, it is necessary to explore the association between KBD and DIO2 in the Tibetan population. METHODS: We carried out a case-control study among 316 cases and 320 controls from a Tibetan population. Seven single nucleotide polymorphisms in DIO2 were selected and genotyped using the Agena MassARRAY platform (Agena Bioscience, San Diego, CA, USA). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis. HaploReg (https://pubs.broadinstitute.org/mammals/haploreg/haploreg.php) and GTEx (http://www.gtexportal.org) databases were applied for functional assessment of the polymorphisms. RESULTS: The "A/C" genotype of rs1352815 (OR = 3.18, 95% CI = 1.14-8.85, p = 0.027) and the "A/G" genotype of rs1388382 (OR = 3.80, 95% CI = 1.30-11.11, p = 0.015) were associated with the susceptibility of KBD under the co-dominant model. With gender stratification analysis, rs1388382 showed obvious evidence for correlation with an elevated risk of KBD in females under the co-dominant model (OR = 3.32, 95% CI = 1.06-10.41, p = 0.039). CONCLUSIONS: The results obtained in the present study indicate that DIO2 polymorphisms rs1352815 and rs1388382 were correlated with KBD susceptibility among Tibetans, which also sheds new light on the role of DIO2 in the development of KBD.

Genetic polymorphisms analysis of CYP2D6 in the Uygur population.

BACKGROUND: This study aimed to investigate genetic polymorphisms of CYP2D6 among healthy Uygur individuals. Genetic polymorphisms of CYP2D6 could greatly affect CYP2D6 activity and lead to differences among individuals in drug efficacy or side effects. To investigate genetic polymorphisms of CYP2D6 in the Uygur population, we directly sequenced the whole gene in 96 unrelated, healthy Uygur volunteers from the Xinjiang Uygur Autonomous Region and screened for genetic variants in the promoter, intron, exons, and 3'UTR. RESULTS: We detected 62 genetic polymorphisms of CYP2D6, 16 of which were novel SNP with three novel non-synonymous mutations detected for the first time. The allelic frequencies of CYP2D6*1, *10, *39, and *48 were 0.542, 0.156, 0.068, 0.229, and 0.073, respectively. The frequency of CYP2D6*1/*10 which decreased CYP2D6 enzyme activity was 31.3 %. CONCLUSIONS: Our results provided basic information about CYP2D6 polymorphisms, suggested that the enzymatic activities of CYP2D6 might be different within the Uygur ethnic group, and provide a basis for safer drug administration and better therapeutic treatment of Uygur individuals.

Telomere length-related gene ACYP2 polymorphism is associated with the risk of HAPE in Chinese Han population.

BACKGROUND: High altitude pulmonary edema (HAPE) is a type of pneumonedema that mostly occurs under conditions such as high altitude, rapid ascent and hypoxia, amongst others. The ACYP2 polymorphism is suggested to be associated with mean telomere length, and telomere length is significantly longer at a moderate attitude than at sea-level or at simulated high attitude. The present study aimed to determine whethher there is any association between ACYP2 polymorphism and the risk of HAPE. METHODS: A total of 265 patients and 303 healthy controls were enrolled in our case-control study. Six SNPs were selected and genotyped using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by unconditional logistic regression with adjustment for gender and age. RESULTS: Using chi-squared tests, we found that the minor allele G of rs11896604 is significantly associated with a decreased risk of HAPE [odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.65-1.16, p = 0.048]. We also found that the 'A/A' genotype of rs12615793 is associated with a decreased risk of HAPE based on the recessive model (OR =0.28; 95% CI = 0.09-0.88; p = 0.017). Additionally, the 'G/G' genotype of rs11896604 was found to be associated with a decreased risk of HAPE based on the codominant model (OR =0.26; 95% CI = 0.08-0.79; p = 0.025) and recessive model (OR =0.25; 95% CI = 0.08-0.77; p = 0.007). However, only rs11896604 remained significant after Bonferroni correction (p < 0.0083). CONCLUSIONS: The present study found that the ACYP2 gene polymorphism significantly decreased the risk of HAPE. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

The relationship between polymorphisms of BDNFOS and BDNF genes and heroin addiction in the Han Chinese population.

BACKGROUND: The number of heroin addicts is increasing in the world. Both environmental and genetic factors both play critical roles in the process of heroin addiction. We aimed to investigate the associations between single nucleotide polymorphisms (SNPs) in LIN7C, BDNFOS and BDNF genes and drug addiction in the Han Chinese population. METHODS: We conducted a case-control study among 692 cases and 700 healthy controls from Xi'an, China. Eight SNPs were selected and genotyped using MassARRAY technology (Sequenom, San Diego, CA, USA). Odds ratios (OR) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for age and sex. RESULTS: Using the chi-squared test, we found that rs7481311 (OR =1.275, 95% CI = 1.087-1.497, p = 0.009) and rs11030096 (OR =1.227, 95% CI = 1.049-1.436, p = 0.011) in the BNDFOS were associated with an increased risk of heroin addiction. By contrast, rs988712 located in BDNFOS showed a decreased risk of heroin addiction (OR =0.734, 95% CI = 0.582-0.925, p = 0.003). By genetic model analysis, we found that the 'T' allele of rs988712 in BDNFOS had a protective role for heroin addiction in the additive model and dominant model (p < 0.05). By contrast, the allele 'T' of rs7481311 in BDNFOS significantly elevated the risk of heroin addiction in the additive model, recessive model and dominant model (p < 0.05). We also found that allele 'C' of rs11030096 was associated with an increased risk of addiction in the dominant model and additive model (p < 0.05). Additionally, we found that rs6265, rs11030104 and rs10767664 in BDNF were associated with a decreased risk of heroin addiction (p < 0.05). However, only rs7481311 in BDNFOS remained significant after Bonferroni correction (p < 0.00625). CONCLUSIONS: These results suggest that polymorphisms of BDNFOS play an important role in heroin addiction susceptibility in the Chinese Han population.

Identification of a shared protective genetic susceptibility locus for colorectal cancer and gastric cancer.

Risk of both colorectal cancer (CRC) and gastric cancer (GC) is considered to be heritable with mounting evidence for their genetic susceptibility. However, it remains unknown whether a shared genetic background is underlying these two cancers. A total of ten single nucleotide polymorphisms (SNPs) associated with digestive system cancers risk were selected from previous genome-wide association studies. All SNPs were genotyped in 449 CRC cases, 588 GC cases, and 703 controls using Sequenom Mass-ARRAY technology. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were estimated using unconditional logistic regression analysis with adjustment for age and gender, and evaluated their association with both cancers in a Han Chinese population using chi-squared (χ (2)) test and genetic model analysis. By χ (2) test, we found that rs2057314 (p = 0.028; OR = 1.21) was significantly associated with an increased risk of CRC, rs7758229 (p = 0.005; OR = 0.77) was significantly associated with a decreased risk of GC. Furthermore, a shared susceptibility locus rs9502893 was found to have significant protective effect against CRC (p = 0.010; OR = 0.80) and GC (p = 0.0003; OR = 0.74). Our findings could provide insight into the underlying shared a partly overlapping genetic aspect of CRC and GC in a Chinese population. Additional studies are required to verify and discover more common genetic variants associated with risk for digestive system cancers.

CLPTM1L polymorphism as a protective factor for lung cancer: a case-control study in southern Chinese population.

Variants of the cleft lip and palate trans-membrane 1 like (CLPTM1L) gene, located on chromosome 5p15.33, were previously determined to influence lung cancer susceptibility. Here, we performed a case-control study to examine the potential association of CLPTM1L single nucleotide polymorphisms (SNPs) with lung cancer in a Chinese Han population. We selected four SNPs in the CLPTM1L gene that were previously reported to be associated with lung cancer. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to estimate the strength of the relationship between each CLPTM1L SNP and lung cancer risk. Allelic model analysis revealed that the minor alleles of all four SNPs were significantly associated with decreased lung cancer risk. Similar significant results were detected using genetic model analysis. In addition, we observed a protective effect of haplotype "TT" in the CLPTM1L gene. Our results verified that certain CLPTM1L polymorphisms are protective factors against lung cancer in a southern Chinese Han population and may be potential diagnostic and molecular markers for lung cancer patients.

Genetic polymorphisms of the drug-metabolizing enzyme CYP2C19 in the Uyghur population in northwest China.

1. CYP2C19 is a clinically important enzyme and is involved in the metabolism of approximately 10% of drugs used in daily clinical practice. Previous studies mainly focused on Chinese Han populations or other ethnic groups, little is known about Uyghur populations. 2. The present study was designed to determine the genetic basis of CYP2C19 polymorphisms. 3. We used direct sequencing to investigate the promoter, exons and surrounding introns, and 3'-untranslated region of the CYP2C19 gene in 96 unrelated healthy Uyghur individuals. 4. A total of 31 different CYP2C19 polymorphisms were identified in the Uyghur population, three of which were novel, including two nonsynonymous variants (57807A > M, Gln279Pro and 19257G > R, Asp262Asn) and one synonymous variants in exon 5 (19184T > Y, Leu237Leu). In addition, CYP2C19*1, *2 and *3 alleles showed frequencies of 83.34%, 14.06% and 2.08%, respectively. 5. This is the first study that systematically screened the polymorphisms of the whole CYP2C19 gene in Uyghur population. Hence, our results provided important information on CYP2C19 polymorphisms in Uyghur population and could be helpful for future personalized medicine studies in Uyghur population generally.

Genetic polymorphisms analysis of drug-metabolizing enzyme CYP2C9 in the Uyghur population.

Genetic variations in cytochrome P450 2C9 are known to contribute to interindividual and interethnic variability in response to clinical drugs, but little is known about the genetic variation of CYP2C9 in the Uyghur population. We directly sequenced the whole CYP2C9 gene in 96 unrelated, healthy Uyghur from Xinjiang Uygur Autonomous Region of China and screened for genetic variants in the promoter, exons, introns and 3'-UTR. Thirty five previously reported alleles and six genotypes were detected in this study. The allele frequencies of CYP2C9*1, *2, *11, *12, *29 and *33 were 89.58, 7.81, 0.52, 0.52, 1.04 and 0.52%, respectively. We detected one non-synonymous novel variant at position 329 from Arg to Cys and this mutation is predicted to be intolerant by SIFT. Our results provide basic information about CYP2C9 alleles in Uyghur, which may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group.

[Tri-primer-florescence PCR-Sanger sequencing method for screening of full and pre-mutations of FMR1 gene].

OBJECTIVE: To screen for CGG repeats in the FMR1 gene among patients with fragile X syndrome and carriers of pre-mutations. METHODS: Potential full and pre-mutations of the FMR1 gene were detected with a Tri-primer-florescence PCR-Sanger sequencing method. The results were validated with positive and negative controls. RESULTS: All positive and negative controls were confirmed. A male patient was found to have > 200 CGG repeats (full mutation). For a pregnant women who was heterozygous for 35/115 CGG repeats, > 200 CGG repeats were also found with amniotic fluid sample from her fetus who was a male. The result was confirmed by following selective abortion with informed consent. CONCLUSION: Tri-primer-florescence PCR-Sanger sequencing is a simple, effective and reliable method for routine screening of patients/carriers with full/pre-mutations of the FMR1 gene in the population.

Polymorphisms of the TCF4 gene are associated with the risk of schizophrenia in the Han Chinese.

Schizophrenia (SCZ) is a complex and severe mental disorder with highly heritability (80%). Several large genome-wide association studies have identified that the transcription factor 4 (TCF4) polymorphisms were strongly associated with SCZ. Therefore, the present study was to replicate the potential relationships between the TCF4 polymorphisms and SCZ. Furthermore, the study also investigated whether other variants were associated with SCZ in the Han Chinese. We conducted a case-control study including 499 patients and 500 healthy controls. Five SNPs were successfully genotyped and evaluated the association with SCZ by using χ2 test and genetic model analysis. We found that the genotype "AG" of rs9320010 and "GA" of rs7235757 decreased SCZ risk (OR = 0.70, 95%CI = 0.50-0.99, P = 0.041; OR = 0.69, 95%CI = 0.49-0.97, P = 0.034, respectively). In the genetic model analysis, we also observed that the allele "A" of rs9320010 and "G" of rs7235757 were inversely related with the risk of SCZ in the dominant model (OR = 0.72, 95%CI = 0.52-0.98, P = 0.039; OR = 0.69, 95%CI = 0.50-0.96, P = 0.025, respectively). Further interaction and stratification analysis suggested that rs1452787 was notably correlated with increased SCZ risk in males (OR = 2.77, 95%CI = 1.43-5.35, P = 0.002). Our study indicated that rs9320010, rs7235757, and rs1452787 were prominently associated with SCZ. Further studies are required to verify our findings and focus on determining the biological functions of the SNPs. © 2016 Wiley Periodicals, Inc.

Genetic variations in the CLNK gene and ZNF518B gene are associated with gout in case-control sample sets.

A genome-wide association study of gout in European populations identified 12 genetic variants strongly associated with risk of gout, but it is unknown whether these variants are also associated with gout risk in Chinese populations. A total of 145 patients with gout and 310 healthy control patients were recruited for a case-control association study. Twelve SNPs of CLNK and ZNF518B gene were genotyped, and association analysis was performed. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the association. Overall, we found four risk alleles for gout in patients: the allele "G" of rs2041215 and rs1686947 in the CLNK gene by dominant model (OR 1.66; 95 % CI 1.04-2.63; p = 0.031) (OR 2.19; 95 % CI 1.38-3.46; p = 0.001) and additive model (OR 1.39; 95 % CI 1.00-1.93; p = 0.049) (OR 1.67; 95 % CI 1.19-2.32; p = 0.003), respectively, and the allele "A" of rs10938799 and rs10016022 in ZNF518B gene by recessive model (OR 4.66; 95 % CI 1.44-15.09; p = 0.008) (OR 4.54; 95 % CI 1.23-16.76; p = 0.020). Further haplotype analysis showed that the TCATTCTGA haplotype of CLNK was more frequent among patients with gout (adjusted OR 0.48; 95 % CI 0.24-0.95; p = 0.036). Additionally, polymorphisms of rs2041215, rs10938799, and rs17467273 were also correlated with clinical pathological parameters. This study provides evidence for gout susceptibility genes, CLNK and ZNF518B, in a Chinese population, which may have potential as diagnostic and prognostic marker for gout patients.

Novel insight into the genetic signatures of altitude adaptation related body composition in Tibetans.

Background: The Tibetan population residing in high-altitude (HA) regions has adapted to extreme hypoxic environments. However, there is limited understanding of the genetic basis of body compositions in Tibetan population adapted to HA. Methods: We performed a genome-wide association study (GWAS) to identify genetic variants associated with HA and HA-related body composition traits. A total of 755,731 single nucleotide polymorphisms (SNPs) were genotyped using the precision medicine diversity array from 996 Tibetan college students. T-tests and Pearson correlation analysis were used to estimate the association between body compositions and altitude. The mixed linear regression identified the SNPs significantly associated with HA and HA-related body compositions. LASSO regression was used to screen for important SNPs in HA and body compositions. Results: Significant differences were observed in lean body mass (LBW), muscle mass (MM), total body water (TBW), standard weight (SBW), basal metabolic rate (BMR), total protein (TP), and total inorganic salt (Is) in different altitudes stratification. We identified three SNPs in EPAS1 (rs1562453, rs7589621 and rs7583392) that were significantly associated with HA (p < 5 × 10-7). GWAS analysis of 7 HA-related body composition traits, we identified 14 SNPs for LBM, 11 SNPs for TBW, 15 SNPs for MM, 16 SNPs for SBW, 9 SNPs for BMR, 12 SNPs for TP, and 26 SNPs for Is (p < 5.0 × 10-5). Conclusion: These findings provide insight into the genetic basis of body composition in Tibetan college students adapted to HA, and lay the foundation for further investigation into the molecular mechanisms underlying HA adaptation.

Genetic polymorphisms of very important pharmacogene variants in the Chinese Lisu population.

Aim: Interindividual and interethnic differences in drug efficacy drive the development and progress of pharmacogenomics and precision medicine. This study was performed to enrich the pharmacogenomic information for the Lisu population from China. Methods: 54 very important pharmacogene variants were selected from PharmGKB and genotyped in 199 Lisu individuals. The genotype distribution data of 26 populations were downloaded from the 1000 Genomes Project and analyzed with the χ2 test. Results: Among the 26 populations in the 1000 Genomes Project, African Caribbeans in Barbados; Esan in Nigeria; Gambian in Western Divisions, The Gambia; Luhya in Webuye, Kenya; Yoruba in Ibadan; Finnish in Finland; Toscani in Italy and Sri Lankan Tamil in the UK were the top eight nationalities with the most significant differences in genotype distribution from the Lisu population. The loci of CYP3A5 rs776746, KCNH2 rs1805123, ACE rs4291, SLC19A1 rs1051298 and CYP2D6 rs1065852 were significantly different in the Lisu. Conclusion: The results showed that there were substantial differences in SNPs of very important pharmacogene variants, which can provide a theoretical basis for individualized drug use for the Lisu.

Whole-exome sequencing in searching for novel variants associated with the development of high altitude pulmonary edema.

BACKGROUND: High altitude pulmonary edema (HAPE) is a high-altitude idiopathic disease with serious consequences due to hypoxia at high altitude, and there is individual genetic susceptibility. Whole-exome sequencing (WES) is an effective tool for studying the genetic etiology of HAPE and can identify potentially novel mutations that may cause protein instability and may contribute to the development of HAPE. MATERIALS AND METHODS: A total of 50 unrelated HAPE patients were examined using WES, and the available bioinformatics tools were used to perform an analysis of exonic regions. Using the Phenolyzer program, disease candidate gene analysis was carried out. SIFT, PolyPhen-2, Mutation Taster, CADD, DANN, and I-Mutant software were used to assess the effects of genetic variations on protein function. RESULTS: The results showed that rs368502694 (p. R1022Q) located in NOS3, rs1595850639 (p. G61S) located in MYBPC3, and rs1367895529 (p. R333H) located in ITGAV were correlated with a high risk of HAPE, and thus could be regarded as potential genetic variations associated with HAPE. CONCLUSION: WES was used in this study for the first time to directly screen genetic variations related to HAPE. Notably, our study offers fresh information for the subsequent investigation into the etiology of HAPE.

The Association of Methylation Level in the CYP39A1 Gene with High Altitude Pulmonary Edema in the Chinese Population.

Background: High altitude pulmonary edema (HAPE) is still the most common fatal disease at high altitudes. DNA methylation proceeds with an important role in HAPE progression. This study was designed to investigate the association between CYP39A1 methylation and HAPE. Methods: Peripheral blood samples were enrolled from 106 participants (53 HAPE patients and 53 healthy subjects) to study the association of CYP39A1 methylation with HAPE. DNA methylation site in the promoter region of CYP39A1 was detected by Sequenom MassARRAY EpiTYPER platform. Results: Probability analysis showed that the methylation probabilities of CYP39A1_1_CpG_5 and CYP39A1_3_CpG_21 are significant differences between the cases and controls (p< 0.05). The methylation level analysis indicated that CYP39A1_1_CpG_2.3.4, CYP39A1_5_CpG_6.7, and CYP39A1_5_CpG_9.10 were higher methylation in HAPE compared to the controls (p< 0.05). CYP39A1_3_CpG_21 and CYP39A1_4_CpG_3 exhibited a lower methylation level in HAPE than that in the controls (p< 0.05). The association analysis given that CYP39A1_1_CpG_2.3.4 (OR 2.56, p= 0.035), CYP39A1_5_CpG_6.7 (OR 3.99, p= 0.003), CYP39A1_5_CpG_9.10 (OR 3.99, p= 0.003), CYP39A1_5_CpG_16.17.18 (OR 2.53, p= 0.033), and CYP39A1_5_CpG_20 (OR 3.05, p= 0.031) are associated with an increased risk of HAPE. Whereas CYP39A1_1_CpG_5 (OR 0.33, p= 0.016) and CYP39A1_3_CpG_21 (OR 0.18, p= 0.005) have a protective role in HAPE. Besides, age-stratification analysis showed that CYP39A1_1_CpG_5 (OR 0.16, p= 0.014) and CYP39A1_3_CpG_21 (OR 0.08, p= 0.023) had a protective impact on HAPE in people aged ≤32 years. CYP39A1_5_CpG_6.7 (OR 6.70, p= 0.008) and CYP39A1_5_CpG_9.10 (OR 6.70, p= 0.008) were related to an increased susceptibility to HAPE aged >32 years. Moreover, the diagnostic value of CYP39A1_3_CpG_21 (AUC = 0.712, p< 0.001) was significantly better than other CpG sites. Conclusion: The methylation level of CYP39A1 was associated with a risk of HAPE in the Chinese population, which provided new perspective for preventing and diagnosing of HAPE.

Bergamottin protects against LPS-induced endotoxic shock by regulating the NF-κB signaling pathway.

Bergamottin is a natural furanocoumarin compound that possesses antioxidative and anti-cancer properties; however, the effect of Bergamottin on lipopolysaccharide (LPS)-induced inflammation response is unknown. In this study, we investigated the protective effects and mechanisms of Bergamottin against LPS-induced inflammatory responses.Raw264.7 cells were pre-treated with Bergamottin, then stimulated with LPS. Morphologic analysis and flow cytometry were used to measure Bergamottin-related cytotoxicity. ELISA and qPCR were performed to measure secretion and transcription activities of inflammatory cytokines. Biochemical analysis was used to determine the expression of tissues damage indicators. Western blots were used to determine protein expression, and immunofluorescence staining was used to determine the co-localization of NF-κB and RelA. Hematoxylin and eosin staining was used to show the pathological damages.Bergamottin had no cytotoxic effects on Raw264.7 cells. Pre-treatment with Bergamottin inhibited inflammatory cytokines expression and secretion induced by LPS, due to the inhibition of LPS-induced NF-κB signaling pathway activation, and improved pathological damages. These findings suggest that Bergamottin protects against LPS-induced endotoxin shock by regulating the NF-κB signaling pathway.