Exploring the Immune Landscape of Cirrhosis through Weighted Gene Co-expression Network Analysis.

Cirrhosis is a persistent hepatic ailment that emerges from a range of causes, including viral infections, alcoholic liver disease, and non-alcoholic fatty liver disease. It is distinguished by the replacement of normal liver parenchyma with fibrous scar tissue, culminating in the development of hepatic insufficiency, portal hypertension, and eventual liver collapse. Several molecular and cellular mechanisms contribute to cirrhosis' pathogenesis, including activation of immune cells and dysregulation of immune-related pathways. Weighted Gene Co-expression Network Analysis (WGCNA) is a powerful data mining application used to identify gene modules and hub genes that are closely associated with specific phenotypes or conditions of interest. In this study, we performed WGCNA on publicly available gene expression datasets and subsequently assessed the roles of immune-related genes in the etiology and progression of cirrhosis, intending to explore potential therapeutic targets for this disease. GSE36411 gene expression profiling was extracted from the Gene Expression Omnibus repository (GEO). The transcriptomic data were submitted to Weighted Gene Co-expression Network Analysis (WGCNA) to screen for the presence of key genes, and immune-related genes were filtered by comparison to the InateDB database. Cancer Genome Atlas (TCGA) was included in the study to validate the significant modules generated from WGCNA. The key gene interaction network was constructed using GeneMANIA and Metascape. Kaplan-Meier method and Spearman correlation were used to evaluate the correlation of immune-related genes with prognosis, tumor microenvironment, and immune cell infiltration. Finally, we explored a possible mechanism using gene set enrichment (GSEA) analyses. In total, 2,102 differentially expressed genes (DEGs) were identified from the gene expression profile dataset. A weighted gene co-expression network analysis was performed, resulting in the classification of genes into 3 modules. Among these modules, the turquoise module was found to be most closely associated with cirrhosis. By comparing the turquoise module genes with an InateDB immune-related gene set, we identified 157 immune-associated genes. In addition, our study found that many hub genes are strongly associated with the number of immune-related genes in liver cirrhosis, in addition to a few modules associated with immune infiltration. It turns out that these hub genes were engaged in migration, activation, and immune cell regulation, as well as in the signaling pathways that drive the immune response to infection. Our research offered a deeper understanding of the underlying processes of immune infiltration in cirrhosis and also suggested potential treatment options for this troublesome condition. Our results demonstrate the effectiveness of WGCNA in uncovering new knowledge regarding the biology of cirrhosis and the function of the immune system in this disease. More studies ought to focus on the validation of the identified hub genes and the determination of their clinical relevance. These results could serve as the basis for the creation of more potent therapies for those with liver cancer linked to cirrhosis.

Evolutionary significance of selected EDAR variants in Tibetan high-altitude adaptations.

Humans have been exposed to many environmental challenges since their evolutionary origins in Africa and subsequent migrations to the rest of the world. A severe environmental challenge to human migrants was hypoxia caused by low barometric oxygen pressure at high altitudes. Several genome-wide scans have elucidated the genetic basis of human high-altitude adaptations. However, the dearth of functional variant information has led to the successful association of only a few candidate genes. In the present study, we employed a candidate gene approach and re-sequenced the EDAR locus in 45 Tibetan individuals to identify mutations involved in hypoxia adaptation. We identified 10 and five quantitative trait-associated mutations for oxygen saturation (SaO2) and blood platelet count, respectively, at the EDAR locus. Among these, rs10865026 and rs3749110 (associated with SaO2 and platelet count, respectively) were identified as functional candidate targets. These data demonstrate that EDAR has undergone natural selection in recent human history and indicate an important role of EDAR variants in Tibetan high-altitude adaptations.

Polymorphisms of genes in neurotransmitter systems were associated with alcohol use disorders in a Tibetan population.

Studies of linkage and association in various ethnic populations have revealed many predisposing genes of multiple neurotransmitter systems for alcohol use disorders (AUD). However, evidence often is contradictory regarding the contribution of most candidate genes to the susceptibility of AUD. We, therefore, performed a case-control study to investigate the possible associations of genes selected from multiple neurotransmitter systems with AUD in a homogeneous Tibetan community population in China. AUD cases (N = 281) with an alcohol use disorder identification test (AUDIT) score ≥10, as well as healthy controls (N = 277) with an AUDIT score ≤5, were recruited. All participants were genotyped for 366 single nucleotide polymorphisms (SNPs) of 34 genes selected from those involved in neurotransmitter systems. Association analyses were performed using PLINK version 1.07 software. Allelic analyses before adjustment for multiple tests showed that 15 polymorphisms within seven genes were associated with AUD (p<0.05). After adjustment for the number of SNPs genotyped within each gene, only the association of a single marker (rs10044881) in HTR4 remained statistically significant. Haplotype analysis for two SNPs in HTR4 (rs17777298 and rs10044881) showed that the haplotype AG was significantly associated with the protective effect for AUD. In conclusion, the present study discovered that the HTR4 gene may play a marked role in the pathogenesis of AUD. In addition, this Tibetan population sample marginally replicated previous evidence regarding the associations of six genes in AUD.

Gender-specific interactions between alcohol metabolism genes and severity of quantitative alcohol-related-traits in a Tibetan population.

Association between genes influencing alcohol metabolism and alcohol use disorders (AUD) has been extensively studied, but the effect of interactions between these genes and AUD have rarely been tested. Our previous case-control study in a Tibetan population noted that the positive association between c2 allele of cytochrome P4502E1 (CYP2E1) gene and AUD might only exist in males who are homozygotes for 1 alleles of aldehyde dehydrogenase-2 (ALDH2) and alcohol dehydrogenase-1B (ADH1B) genes, but this interaction did not reach statistical significance. Using the same set of data, the present study was aimed at exploring interactions between these genes and quantitative alcohol-related-trait scores (QARTs), and whether these are influenced by gender. The sample included 383 AUD cases with the alcohol use disorders identification test (AUDIT) score ≥10 and 350 normal controls with the AUDIT score ≤5. QARTs were measured using three factors from AUDIT. Possible associations of QARTs with interactions among genotypes of ALDH2 1/ 2, ADH1B1/2 and CYP2E1 c1/c2 and sex were analyzed in AUD cases and normal controls separately. The subjects with 2 alleles of ALDH2 or/and ADH1B had significantly lower scores of alcohol intake among controls but had significantly higher scores of alcohol related problems among cases. The score of alcohol intake in male cases who are homozygous for ALDH2 1 and ADH1B 1 and with CYP2E1 c2 allele was significantly higher than that of other cases. These findings suggest that interactions between genes influencing alcohol metabolism are influenced by gender and might affect QARTs differently between the milder-/non-drinkers and AUD cases.

Interaction among genes influencing ethanol metabolism and sex is association with alcohol use disorders in a Tibet population.

Associations between alcohol use disorders and polymorphisms of genes influencing ethanol metabolism have been widely reported, but gene-gene and gene-sex interaction studies have rarely been examined. Using a set of samples collected during an epidemiological study of alcohol use disorders AUDs in a Tibetan population in China, we performed a case-control study to investigate the relationship between the functional polymorphisms of genes influencing ethanol metabolism and AUDs. The sample included 383 individuals with an AUDIT score >or=10 and 350 control subjects with the AUDIT score

Epidemiological study of Kaschin-Beck disease in Lhasa and Lhoka regions Tibet / 中国地方病学杂志

Objective To assess the endemic trend of Kaschin-Beck disease in Tibet and to provide scientific basis for prevention and etiology study of the disease. Methods A questionnaire designed by us was administered to 905 participants who were from Lhundrop county, Medro Gongkar county of Lhasa municipality and Sangri county of Lhoka region in July to November, 2007. The Kashin-Beck disease diagnostic criteria(GB 16003-1995) was used for clinical diagnosis, and children 5 to 14 years old were taken right wrist X-ray film for diagnosis.Results One hundred and forty-four genealogies were recruited in this study. The interview and clinical examination were done to 905 persons, 208 persons were detected with Kaschin-Beck disease, and the detectable rate was 22.98%(208/905). The numbers of patients with degrees Ⅰ , Ⅱ and Ⅲ of Kaschin-Beck disease were 148, 43 and 17, respectively, with proportion of 71.15%(148/208), 20.67%(43/208) and 8.17%(17/208) out of all patients, respectively. The detectable rates of Kaschin-Beck disease were 29.73% (102/343) and 18.86%(106/562), respectively in Lhasa and Lhoka district, and the difference between this two districts was statistically significant(x2= 15.257, P＜ 0.01) . A total of 368 males and 537 females were recruited in this study, the detectable rates of male and female with Kaschin-Beck disease were 19.29% (71/368) and 25.51% (137/537), respectively,and the difference between male and female was statistically significant (x2 = 5.372, P ＜ 0.01) . In this study most patient were between 31 to 70 years old, the patients with degrees Ⅱ or Ⅲ of Kaschin-Beck disease were mostly above 40 years old. There were only 5 patients who were less and equal 20 years old in chinical diagnosis. The Xray positive detectable rate of children between 5 to 14 years old was 6.85% (10/146). Conclusions The condition of Kashin-Beck disease area is relatively stable in these two regions in recent years, and shows a downward trend. However, there are still positive child cases diagnosed by X-ray, which should arouse the attention of the relevant departments to further strengthen the implementation of control measures.

An epidemiological survey of alcohol use disorders in a Tibetan population.

We performed an epidemiological survey in order to detect the prevalence of alcohol use disorders in a sub-group of the population of Tibet. The Alcohol Use Disorders Identification Test (AUDIT) questionnaire, the Severity of Alcohol Dependence Questionnaire (SADQ), and a 12-item version of the General Health Questionnaire (GHQ12) were used to obtain epidemiological data on alcohol use disorders and to assess the severity of 'problem drinking' and general mental health status. The AUDIT is a reliable and valid screening tool for both alcohol abuse and dependence in the Tibetan population to identify individuals with alcohol use problems. The cut-off points were set to be 10 and 13 of the AUDIT scores as a diagnostic discriminator of alcohol abuse and alcohol dependence, respectively, with both sensitivity and specificity>0.84. The prevalence of alcohol abuse, was 2.7% (female: 2.0%; male: 6.2%), alcohol dependence 13.5% (female: 7.6%; male: 25.4%) and alcohol use disorders 16.2% (female: 9.6%; male: 31.6%). Age and sex were the main factors affecting an individual's alcohol use and general mental health status. The epidemiological data on alcohol use disorders documented in this project may be helpful in future work seeking more valid causal inferences or interpretations related to this prevalent health problem in Tibet.