Association Between Vaginal Gardnerella and Tubal Pregnancy in Women With Symptomatic Early Pregnancies in China: A Nested Case-Control Study

The early diagnosis and treatment of ectopic pregnancy (EP) remains a major challenge. Despite a known link between vaginal microbiota and female reproductive health, few studies have focused on the association between vaginal microbiota and pregnancy location. This nested case-control study aimed to characterize the vaginal microbiota in tubal pregnancy (TP) among symptomatic women in early pregnancy. Women with symptomatic early pregnancy of unknown location (PUL) were included in this study. 16S rDNA gene sequencing was performed to assess vaginal microbial diversity and relative abundance. Machine learning and multivariate logistic regression were also used to evaluate the association between Gardnerella and TP. The results indicate that the vaginal microbiome in TP was more diverse (Shannon, p < 0.05) and was different in composition to that of women with intrauterine pregnancy (IUP) (weighted Unifrac, R = 0.08, p = 0.01). The genus Gardnerella was significantly enriched in TP. The XGBoost analysis was able to classify Gardnerella-induced TP more reliably (AUC = 0.621). Moreover, after adjusting potential confounders, our results indicate a robust association between Gardnerella and TP (as a continuous variable, adjusted OR: 12.0, 95% CI: 2.1–67.4, p < 0.01; as a categorical variable (≥0.85%), and adjusted OR: 4.2, 95% CI: 2.0–8.8, p < 0.01). In conclusion, we found that higher virginal Gardnerella levels were associated with TP in women with symptomatic early pregnancy.

The Relationship between Epigenetic Age and Myocardial Infarction/Acute Coronary Syndrome in a Population-Based Nested Case-Control Study

We investigated the relationship between ‘epigenetic age’ (EA) derived from DNA methylation (DNAm) and myocardial infarction (MI)/acute coronary syndrome (ACS). A random population sample was examined in 2003/2005 (n = 9360, 45–69, the HAPIEE project) and followed up for 15 years. From this cohort, incident MI/ACS (cases, n = 129) and age- and sex-stratified controls (n = 177) were selected for a nested case-control study. Baseline EA (Horvath’s, Hannum’s, PhenoAge, Skin and Blood) and the differences between EA and chronological age (CA) were calculated (ΔAHr, ΔAHn, ΔAPh, ΔASB). EAs by Horvath’s, Hannum’s and Skin and Blood were close to CA (median absolute difference, MAD, of 1.08, –1.91 and –2.03 years); PhenoAge had MAD of −9.29 years vs. CA. The adjusted odds ratios (ORs) of MI/ACS per 1–year increments of ΔAHr, ΔAHn, ΔASB and ΔAPh were 1.01 (95% CI 0.95–1.07), 1.01 (95% CI 0.95–1.08), 1.02 (95% CI 0.97–1.06) and 1.01 (0.93–1.09), respectively. When classified into tertiles, only the highest tertile of ΔAPh showed a suggestion of increased risk of MI/ACS with OR 2.09 (1.11–3.94) independent of age and 1.84 (0.99–3.52) in the age- and sex-adjusted model. Metabolic modulation may be the likely mechanism of this association. In conclusion, this case-control study nested in a prospective population-based cohort did not find strong associations between accelerated epigenetic age markers and risk of MI/ACS. Larger cohort studies are needed to re-examine this important research question.

Angiotensin-Converting Enzyme Genotype–Specific Immune Response Contributes to the Susceptibility of COVID-19: A Nested Case–Control Study

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), which has resulted in a global pandemic.Methodology: We used a two-step polymerase chain reaction to detect the ACE genotype and ELISA kits to detect the cytokine factor. We also used proteomics to identify the immune pathway related to the ACE protein expression.Result: In this study, we found that the angiotensin-converting enzyme (ACE) deletion polymorphism was associated with the susceptibility to COVID-19 in a risk-dependent manner among the Chinese population. D/D genotype distributions were higher in the COVID-19 disease group than in the control group (D/D odds ratio is 3.87 for mild (p value < 0.0001), 2.59 for moderate (p value = 0.0002), and 4.05 for severe symptoms (p value < 0.0001), logic regression analysis. Moreover, genotype-specific cytokine storms and immune responses were found enriched in patients with the ACE deletion polymorphism, suggesting the contribution to the susceptibility to COVID-19. Finally, we identified the immune pathway such as the complement system related to the ACE protein expression of patients by lung and plasma proteomics.Conclusion: Our results demonstrated that it is very important to consider gene polymorphisms in the population to discover a host-based COVID-19 vaccine and drug design for preventive and precision medicine.

The AGT Epistasis Pattern Proposed a Novel Role for ZBED9 In Regulating Blood Pressure: Tehran Cardiometabolic Genetic Study (TCGS)

Backgroung: Hypertension is typically considered as the leading risk factor for cardiovascular disease. Epistasis studies may add another layer of complexity to our understanding of the genetic basis of hypertension. Methods: A nested case-control design was used on 4214 unrelated Tehran Cardiometabolic Genetic Study (TCGS) adults to evaluate 65 SNPs of previously associated genes, including ZBED9, AGT, and TNXB. The integrated effect of each gene was determined using the Sequence-based Kernel Association Test (SKAT). We used model-based multifactor dimension reduction (Mb-MDR) and entropy-based gene-gene interaction (IGENT) methods to determine interaction and epistasis patterns. Results: The integrated effect of each gene has a statistically significant association with blood pressure traits (P-value < 0.05). Single-locus analysis identified two missense variants in ZBED9 (rs450630) and AGT (rs4762) that are associated with hypertension. In the ZBED9 gene, significant local interactions were discovered. The G allele in rs450630 showed an antagonistic effect on hypertension, but interestingly, IGENT analysis revealed significant epistasis effects for different combinations of ZBED9, AGT, and TNXB loci. Conclusion: We discovered a novel interaction effect between a significant variant in an essential gene for hypertension (AGT) and a missense variant in ZBED9, which has shifted our focus to ZBED9's role in blood pressure regulation.

Identification of Thrombosis-Related Genes in Patients with Advanced Gastric Cancer: Data from AGAMENON-SEOM Registry

Advanced gastric cancer is one of the most thrombogenic neoplasms. However, genetic mechanisms underlying this complication remain obscure, and the molecular and histological heterogeneity of this neoplasm hinder the identification of thrombotic biomarkers. Therefore, our main objective was to identify genes related to thrombosis regardless of Lauren subtypes. Furthermore, in a secondary exploratory study, we seek to discover thrombosis-associated genes that were specific to each TCGA molecular subtype. We designed a nested case-control study using the cohort of the AGAMENON national advanced gastric cancer registry. Ninety-seven patients were selected—48 with and 49 without venous thromboembolism (using propensity score matching to adjust for confounding factors)—and a differential gene expression array stratified by Lauren histopathological subtypes was carried out in primary tumor samples. For the secondary objective, the aforementioned differential expression analysis was conducted for each TCGA group. Fifteen genes were determined to be associated with thrombosis with the same expression trend in both the intestinal and diffuse subtypes. In thrombotic subjects, CRELD1, KCNH8, CRYGN, MAGEB16, SAA1, ARL11, CCDC169, TRMT61A, RIPPLY3 and PLA2G6 were underexpressed (adjusted-p < 0.05), while PRKD3, MIR5683, SDCBP, EPS8 and CDC45 were overexpressed (adjusted-p < 0.05), and correlated, by logistic regression, with lower or higher thrombotic risk, respectively, in the overall cohort. In each TCGA molecular subtype, we identified a series of genes differentially expressed in thrombosis that appear to be subtype-specific. We have identified several genes associated with venous thromboembolism in advanced gastric cancer that are common to Lauren intestinal and diffuse subtypes. Should these genetic factors be validated in the future, they could be complemented with existing clinical models to bolster the ability to predict thrombotic risk in individuals with advanced gastric adenocarcinoma.