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》

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》

The Association between Rheumatic Diseases and the Risk of Polycystic Ovary Syndrome: A Two-Sample Mendelian Randomization Analysis.

Wang J ，Zhou Q 《BRITISH JOURNAL OF HOSPITAL MEDICINE》

The harmful effect of ankylosing spondylitis on diabetes mellitus: new evidence from the Mendelian randomization analysis.

While observational research has highlighted a possible link between ankylosing spondylitis (AS) and type 2 diabetes (T2DM), the quality of evidence remains limited, and the causal relationship is yet to be established. This study aims to explore the causal link between AS and T2DM, as well as its impact on traits related to glucose metabolism. To infer a causal relationship between AS and various diabetes-related traits, including type 1 diabetes (T1DM), T2DM, blood glucose levels, fasting glucose, glycated hemoglobin, and fasting insulin, we employed Mendelian randomization (MR) analysis. We sourced GWAS summary data for both exposure and outcome variables from the IEU OpenGWAS database, GWAS Catalog, and FinnGen database. To synthesize the results of the MR analyses, we applied meta-analysis techniques using either a fixed or random effects model. For identifying and excluding instrumental variants (IVs) that exhibit horizontal pleiotropy with the outcomes, we utilized the MR-PRESSO method. Sensitivity analyses were conducted using the MR-Egger method, along with Q and I^2 tests, to ensure the robustness of our findings. Our analysis revealed a significant association between AS and an increased risk of T1DM with an odds ratio (OR) of 1.5754 (95% CI: 1.2935 to 1.9187) and T2DM with an OR of 1.0519 (95% CI: 1.0059 to 1.1001). Additionally, AS was associated with elevated levels of fasting glucose (beta coefficient = 0.0165, 95% CI: 0.0029 to 0.0301) and blood glucose (beta coefficient = 0.0280, 95% CI: 0.0086 to 0.0474), alongside a decrease in fasting insulin levels (beta coefficient = -0.0190, 95% CI: -0.0330 to -0.0050). Our findings collectively underscore the detrimental impact of AS on the development of diabetes, highlighting the critical influence of autoimmune disorders in diabetes onset. This provides profound insights into the pathogenesis of diabetes from an immunological standpoint.

Ren Z ，He L ，Wang J ，Shu L ，Li C ，Ma Y ... -  《Frontiers in Endocrinology》

Causal association between depression and constipation: A bidirectional two-sample Mendelian randomization study.

There is currently insufficient research on the causal relationship between depression and constipation. This study aims to provide clear evidence for the positive and negative causal relationship between depression and constipation through bidirectional two-sample Mendelian randomization (MR) analysis. MR is a statistical method used to evaluate the credible causal relationship between exposure and outcomes. In this study, we extracted corresponding genetic data from independent cohorts of patients with depression and constipation. Depression data was obtained from the Finngen database, while constipation data was obtained from the IEU OPEN genome-wide association study database. MR analysis was conducted using 5 methods: inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode. In addition, we also used Cochran Q test, MR-Egger intercept test, and leave-one-out analysis to test for the existence of horizontal pleiotropy and evaluate the robustness of MR analysis results. In the analysis of the impact of depression on constipation, we identified 15 significant and statistically strong single nucleotide polymorphisms, and the IVW random effects analysis showed a causal relationship (OR = 1.005 [1.003, 1.007], P = 1.26 × 10-5). When analyzing the impact of constipation on depression, 10 significant and statistically strong single nucleotide polymorphisms were identified, but IVW analysis did not find a causal relationship (OR = 73.768 [0.004, 1.306 × 10-6], P = .389). There is no heterogeneity in the impact of depression on constipation in the bidirectional analysis results, and there is heterogeneity in the impact of constipation on depression, but there is no horizontal pleiotropy. Our bidirectional two-sample MR analysis identified a causal relationship between depression and constipation. This discovery may help clinical doctors to intervene in depression patients in a timely and effective manner when treating constipation patients, avoiding further deterioration of the condition.

Guan X ，Ni Q ，Zhai Z ，Sun Y ，Zhang Y ... -  《-》