[Exploring the causality between intestinal flora and hyperplastic scars of human based on two-sample Mendelian randomization analysis].

Chen WT ，Wang XX ，Zheng WL ，Zhang WQ ，Mao LJ ，Zhuo JN ，Zhou ST ，Yang RH ... -  《-》

HIV and risk of hypertension: a two-sample Mendelian randomization study.

Previous studies have shown that human immunodeficiency virus (HIV) infection is associated with hypertension; however, the results of these studies are affected by a variety of confounding factors. There is no definite evidence to prove a causal relationship between these two factors. This study aimed to investigate the causal relationship between HIV infection and hypertension. A two-sample Mendelian randomization (MR) study was conducted using genome-wide association study (GWAS) statistics published online. The data were collected mainly from the OpenGWAS and FinnGen databases. The HIV database contained 357 HIV patients and 218,435 control patients; the hypertension database contained 54,358 patients and 408,652 control patients; and the blood pressure database contained 436,424 samples. Random effect inverse variance weighting (IVW) was used as the main analysis method, weighted median and Mr-Egger analysis methods were used to ensure the accuracy of the results, and Cochran's Q test and Mr-Egger regression methods were used to detect heterogeneity and correct multiple horizontal effects. Finally, the leave-one-out method was used to analyse the reliability of the test results. In order to further verify the research results, different databases were used and the same statistical method was used for a replication analysis. In order to prevent false positive results caused by multiple tests, Bonferroni correction is used to correct the statistical results. After screening, a total of 9 SNPs (single-nucleotide polymorphisms) were selected as the instrumental variable (IV) used in this study. The IVW MR analysis results showed a causal relationship between HIV infection and the risk of hypertension (IVW: OR = 1.001, P = 0.03). When systolic blood pressure was the outcome, the IVW method results were positive (OR = 1.004, P = 0.01280), and when diastolic blood pressure was the outcome, the weighted median method results were positive (OR = 1.004, P = 0.04570). According to the sensitivity analysis, the results of this study were unlikely to be affected by heterogeneity and horizontal pleiotropy. The leave-one-out analysis showed that the results of this study did not change significantly with the elimination of a single SNP. In replication analysis, when diastolic blood pressure was taken as the outcome, the weighted median method was positive (OR = 1.042, P = 0.037). Sensitivity analysis shows that there is heterogeneity, but there is no horizontal pleiotropy. The leave-one-out analysis showed that the results of this study did not change significantly with the elimination of a single SNP. As the first exploratory study using MR method to study the causal relationship between HIV infection and hypertension and blood pressure, this study found that HIV infection may increase systolic and diastolic blood pressure and increase the risk of hypertension. PLWH, as a high-risk group of cardiovascular and cerebrovascular diseases, should prevent the occurrence of hypertension in order to further improve their quality of life. However, this study also has some limitations. The results of the relationship between HIV infection and hypertension and blood pressure may be affected by the lack of statistical efficacy. In order to further confirm this conclusion, more large-scale RCT or genetic studies should be carried out.

Zhu RW ，Guo HY ，Niu LN ，Deng M ，Li XF ，Jing L ... -  《BMC INFECTIOUS DISEASES》

Causal relationship between ulcerative colitis and male infertility: A two-sample Mendelian randomization study.

To explore the causal relationship between ulcerative colitis (UC) and male infertility using Mendelian randomization method with single nucleotide polymorphism (SNP) as the instrumental variables. Genetic loci closely associated with UC were extracted as instrumental variables and male infertility was the outcome variable in pooled data from the gene-wide association study (GWAS),which was derived from European ethnic groups. The UC data(ebi-a-GCST003045) contained a total sample size of 27432 individuals and 110944 SNPs, and the male infertility data(finn-b-N14_MALEINFERT) contained a total sample size of 73479 individuals and 16377329 SNPs. The SNPs highly correlated with UC were screened from ebi-a-GCST003045(P<5×10-8 as the screening condition, the linkage disequilibrium coefficient was 0.001,and the width of the linkage disequilibrium area was 10000 kb).SNPs related to male infertility from finn-b-N14_MALEINFERT (the minimum r2>0.8,replacing the missing SNPs with SNPs with high linkage, and deleting SNPs without substitution sites) were extracted. MR analysis was performed using MR-Egger regression, the weighted median and the inverse-variance weighted (IVW) respectively, and the causal relationship between UC and male infertility was evaluated by OR and 95% CI, and the Egger-intercept method was used to test for horizontal multiplicity, and the sensitivity analysis was performed using "leave-one-out method". Finally, we used Bayesian Weighted Mendelian Randomization (BWMR) approach to test the results of MR study. A total of 86 SNPs were included as IVs, with OR and 95% CI of 1.095(0.820~1.462)、1.059(0.899~1.248)、1.125(1.002~1.264) for MR-Egger, the weighted median and IVW results respectively, and P value of less than 0.05 for IVW, indicating that a causal relationship between UC and male infertility was causally related. The results of MR analysis combined with BWMR analysis also showed positive genetic causal relationship between UC and male infertility.MR-Egger regression showed an intercept of -2.21×10-3 with a standard error of 0.006 and P = 0.751, there was no horizontal pleiotropy for the IVs of exposure factors. Heterogeneity tests showed no heterogeneity and the results of the "leave-one-out" sensitivity analysis were stable. There is a causal association between UC and male infertility, which increases the risk of developing male infertility.

Wang X ，Li T ，Chen Q 《PLoS One》

Global and regional genetic association analysis of ulcerative colitis and type 2 diabetes mellitus and causal validation analysis of two-sample two-way Mendelian randomization.

Clinical co-occurrence of UC (Ulcerative Colitis) and T2DM (Type 2 Diabetes Mellitus) is observed. The aim of this study is to investigate the potential causal relationship between Ulcerative Colitis (UC) and Type 2 Diabetes Mellitus (T2DM) using LDSC and LAVA analysis, followed by genetic verification through TSMR, providing insights for clinical prevention and treatment. Genetic loci closely related to T2DM were extracted as instrumental variables from the GWAS database, with UC as the outcome variable, involving European populations. The UC data included 27,432 samples and 8,050,003 SNPs, while the T2DM data comprised 406,831 samples and 11,914,699 SNPs. LDSC and LAVA were used for quantifying genetic correlation at both global (genome-wide) and local (genomic regions) levels. MR analysis was conducted using IVW, MR-Egger regression, Weighted median, and Weighted mode, assessing the causal relationship between UC and diabetes with OR values and 95% CI. Heterogeneity and pleiotropy were tested using Egger-intercept, MR-PRESSO, and sensitivity analysis through the "leave-one-out" method and Cochran Q test. Subsequently, a reverse MR operation was conducted using UC as the exposure data and T2DM as the outcome data for validation. Univariable and bivariable LDSC calculated the genetic correlation and potential sample overlap between T2DM and UC, resulting in rg = -0.0518, se = 0.0562, P = 0.3569 with no significant genetic association found for paired traits. LAVA analysis identified 9 regions with local genetic correlation, with 6negative and 3 positive associations, indicating a negative correlation between T2DM and UC. MR analysis, with T2DM as the exposure and UC as the outcome, involved 34 SNPs as instrumental variables. The OR values and 95% CI from IVW, MR-Egger, Weighted median, and Weighted mode were 0.917 (0.848~0.992), 0.949 (0.800~1.125), 0.881 (0.779~0.996), 0.834(0.723~0.962) respectively, with IVW P-value < 0.05, suggesting a negative causal relationship between T2DM and UC. MR-Egger regression showed an intercept of -0.004 with a standard error of 0.009, P = 0.666, and MR-PRESSO Global Test P-value > 0.05, indicating no pleiotropy and no outliers detected. Heterogeneity tests showed no heterogeneity, and the "leave-one-out" sensitivity analysis results were stable. With UC as the exposure and T2DM as the outcome, 32 SNPs were detected, but no clear causal association was found. There is a causal relationship between T2DM and UC, where T2DM reduces the risk of UC, while no significant causal relationship was observed from UC to T2DM.

Hu YZ ，Chen Z ，Zhou MH ，Zhao ZY ，Wang XY ，Huang J ，Li XT ，Zeng JN ... -  《Frontiers in Immunology》

The association between immune cells and breast cancer: insights from Mendelian randomization and meta-analysis.

Breast cancer (BC) is the most common cancer among women worldwide, with 2.3 million new cases and 685 000 deaths annually. It has the highest incidence in North America, Europe, and Australia and lower rates in parts of Asia and Africa. Risk factors include age, family history, hormone replacement therapy, obesity, alcohol consumption, and lack of physical activity. BRCA1 and BRCA2 gene mutations significantly increase the risk. The 5-year survival rate is over 90% in developed countries but lower in developing ones. Early screening and diagnosis, using mammography and MRI, are crucial for reducing mortality. In recent years, significant progress has been made in studying BC immunophenotyping, particularly in multicolor flow cytometry, molecular imaging techniques, and tumor microenvironment analysis. These technologies improve diagnosis, classification, and detection of minimal residual disease. Novel immunotherapies targeting the tumor microenvironment, like CAR-T cell therapy, show high efficiency and fewer side effects. High levels of tumor-infiltrating lymphocytes correlate with better prognosis, while immune checkpoint molecules (PD-1, PD-L1) help cancer cells evade the immune system. Tumor-associated macrophages promote invasion and metastasis. Blocking molecules like CTLA-4, LAG-3, and TIM-3 enhance antitumor responses, and cytokines like IL-10 and TGF-β aid tumor growth and immune evasion. Mendelian randomization (MR) studies use genetic variants to reduce confounding bias and avoid reverse causation, providing robust causal inferences about immune cell phenotypes and BC. This approach supports the development of precision medicine and personalized treatment strategies for BC. This study aims to conduct MR analysis on 731 immune cell phenotypes with BC in the BCAC and Finngen R10 datasets, followed by a meta-analysis of the primary results using the inverse-variance weighted (IVW) method and multiple corrections for the significance P -values from the meta-analysis. Specifically, the study is divided into three parts: First, data on 731 immune cell phenotypes and BC are obtained and preprocessed from the GWAS Catalog and Open GWAS (BCAC) and the Finngen R10 databases. Second, MR analysis is performed on the 731 immune cell phenotypes with BC data from the BCAC and Finngen R10 databases, followed by a meta-analysis of the primary results using the IVW method, with multiple corrections for the significance P -values from the meta-analysis. Finally, the positively identified immune cell phenotypes are used as outcome variables, and BC as the exposure variable for reverse MR validation. The study found that two immune phenotypes exhibited strong significant associations in MR analysis combined with meta-analysis and multiple corrections. For the immune phenotype CD3 on CD28+ CD4-CD8- T cells, the results were as follows: in the BCAC dataset, the IVW result was odds ratio (OR) = 0.942 (95% CI: 0.915-0.970, P =6.76×10 -5 ), β =-0.059; MR Egger result was β =-0.095; and the weighted median result was β =-0.060. In the Finngen R10 dataset, the IVW result was OR=0.956 (95% CI: 0.907-1.01, P =0.092), β =-0.045; MR Egger result was β =-0.070; and weighted median result was β =-0.035. The β values were consistent in direction across all three MR methods in both datasets. The meta-analysis of the IVW results from both datasets showed OR=0.945 (95% CI: 0.922-0.970, P =1.70×10 -5 ). After Bonferroni correction, the significant P- value was P =0.01, confirming the immune phenotype as a protective factor against BC. For the immune phenotype HLA DR on CD33- HLA DR+, the results were as follows: in the BCAC dataset, the IVW result was OR=0.977 (95% CI: 0.964-0.990, P =7.64×10 -4 ), β =-0.023; MR Egger result was β =-0.016; and the weighted median result was β =-0.019. In the Finngen R10 dataset, the IVW result was OR=0.960 (95% CI: 0.938-0.983, P =6.51×10 -4 ), β =-0.041; MR Egger result was β =-0.064; and weighted median result was β =-0.058. The β values were consistent in direction across all three MR methods in both datasets. The meta-analysis of the IVW results from both datasets showed OR=0.973 (95% CI: 0.961-0.984, P =3.80×10 -6 ). After Bonferroni correction, the significant P -value was P =0.003, confirming this immune phenotype as a protective factor against BC. When the immune cell phenotypes CD3 on CD28+ CD4-CD8- T cells and HLA DR on CD33- HLA DR+ were used as outcomes and BC was used as exposure, the data processing and analysis procedures were the same. The MR analysis results are as follows: data from the FinnGen database regarding the effect of positive immune phenotypes on malignant neoplasm of the breast indicated a β coefficient of -0.011, OR = 0.99 (95% CI: -0.117-0.096, P =0.846); data from the BCAC database regarding favorable immune phenotypes for BC demonstrated a β coefficient of -0.052, OR=0.095 (95% CI: -0.144-0.040, P =0.266). The results suggest insufficient evidence in both databases to indicate that BC inversely affects these two immune cell phenotypes. Evidence suggests that the immune cell phenotypes CD3 on CD28+ CD4-CD8- T cells and HLA DR on CD33- HLA DR+ protect against BC. This protective effect may be achieved through various mechanisms, including enhancing immune surveillance to recognize and eliminate tumor cells; secreting cytokines to inhibit tumor cell proliferation and growth directly; triggering apoptotic pathways in tumor cells to reduce their number; modulating the tumor microenvironment to make it unfavorable for tumor growth and spread; activating other immune cells to boost the overall immune response; and inhibiting angiogenesis to reduce the tumor's nutrient supply. These mechanisms work together to help protect BC patients and slow disease progression. Both immune cell phenotypes are protective factors for BC patients and can be targeted to enhance their function and related pathways for BC treatment.

Xu W ，Zhang T ，Zhu Z ，Yang Y ... -  《-》