BACKGROUND: Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder. Recent studies indicate that GERD may exert systemic effects, potentially elevating the risk of severe infections, including sepsis. Nevertheless, the causal relationship between GERD and sepsis, as well as sepsis-related 28-day mortality, remains uncertain.
OBJECTIVE: The aim of this study is to investigate the causal relationship between GERD and the risk of sepsis, including 28-day mortality of sepsis.
METHODS: This study utilized a two-sample Mendelian Randomization (MR) approach to analyze data from publicly available genome-wide association studies (GWAS) databases ( https://gwas.mrcieu.ac.uk/ ). The analysis comprised 129,080 cases and 473,524 controls for GERD; 11,643 patients and 474,841 controls for sepsis; and 1,896 patients and 484,588 controls for 28-day mortality from sepsis. The objective was to evaluate the causal impact of GERD on the risk of sepsis and 28-day sepsis mortality. Genetic variation data pertinent to GERD were obtained from the most recent genome-wide association studies (GWAS). The primary analysis employed the Inverse Variance Weighted (IVW) method. Sensitivity and pleiotropy analyses were performed to validate the robustness of the findings.
RESULTS: MR analysis revealed a notable link between genetically predicted GERD and increased sepsis risk (odds ratio [OR] 1.37, 95% confidence interval [CI] 1.24-1.52; p = 2.79 × 10-9). Moreover, GERD correlated with elevated 28-day mortality of sepsis (OR 1.44, 95% CI 1.11-1.85; p = 5.34 × 10-3). These results remained consistent throughout various sensitivity analyses, indicating their resilience against potential pleiotropy and other biases.
CONCLUSIONS: This study indicates that genetic predisposition to GERD may be linked to an elevated risk of sepsis and its associated 28-day mortality. However, the study does not establish a direct causal relationship for GERD itself, nor does it assess the impact of GERD treatment. Further research is needed to explore the underlying mechanisms and potential therapeutic interventions involved.

BACKGROUND: Urolithiasis is a highly prevalent global disease closely associated with metabolic factors; however, the causal relationship between blood metabolites and urolithiasis remains poorly understood.
METHODS: In our study, we employed a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between urolithiasis and metabolites. The random-effects inverse-variance weighted (IVW) estimation method was utilized as the primary approach, complemented by several other estimators including MR-Egger, weighted median, colocalization and MR-PRESSO. Furthermore, the study included replication and meta-analysis. Finally, we conducted metabolic pathway analysis to elucidate potential metabolic pathways.
RESULTS: After conducting multiple tests for correction, glycerol might contribute to the urolithiasis and dehydroisoandrosterone sulfate (DHEA-S) might inhibit this process. Furthermore, several blood metabolites had shown potential associations with a causal relationship. Among the protective metabolites were lipids (dehydroisoandrosterone sulfate and 1-stearoylglycerol (1-monostearin)), amino acids (isobutyrylcarnitine and 2-aminobutyrate), a keto acid (acetoacetate) and a carbohydrate (mannose). The risk metabolites included lipids (1-palmitoylglycerophosphoethanolamine, glycerol and cortisone), a carbohydrate (erythronate), a peptide (pro-hydroxy-pro) and a fatty acid (eicosenoate). In reverse MR analysis, urolithiasis demonstrated a statistically significant causal relationship with butyrylcarnitine, 3-methyl-2-oxobutyrate, scyllo-inositol, leucylleucine and leucylalanine. However, it was worth noting that none of the blood metabolites exhibited statistical significance after multiple corrections. Additionally, we identified one metabolic pathway associated with urolithiasis.
CONCLUSIONS: The results we obtained demonstrate the causal relevance between two metabolites and urolithiasis, as well as identify one metabolic pathway potentially associated with its development. Given the high prevalence of urolithiasis, further investigations are encouraged to elucidate the mechanisms of these metabolites and explore novel therapeutic strategies.

UNASSIGNED: Benign prostatic hyperplasia (BPH) is a common disease occurring in elderly and middle-aged men, and cardiovascular diseases (CVDs) are one of the major causes of death worldwide. Many observational studies examined have found a strong association between BPH and CVDs, but the causal relationship between them is unclear. The aim of this study was to determine the causal relationship between BPH and CVDs, specifically five diseases: stroke, coronary heart disease (CHD), heart failure, myocardial infarction (MI), and atrial fibrillation (AF).
UNASSIGNED: In this study, we obtained single nucleotide polymorphisms (SNPs) of patients with BPH from the UK Biobank database and patients with CVDs from the UK Biobank, the HERMES Consortium, and the FinnGen Genome Database, each used as a genetic tool for a Mendelian randomization (MR) study. We used conventional MR analysis to assess potential causal direction between BPH and CVDs, as well as MR-Egger, MR-PRESSO, model-based estimation (MBE) and weighted median methods for sensitivity analysis.
UNASSIGNED: Using a bidirectional two-sample MR study, we found that BPH patients had an increased risk of developing CHD (ConMix OR = 1.152, 95% CI: 1.011-1.235, p = 0.035) and MI (ConMix OR = 1.107.95% CI: 1.022-1.164, p = 0.013), but a decreased risk of stroke (ConMix OR = 0.872, 95% CI: 0.797-0.926, p = 0.002). The reverse study was not statistically significant and further research may be needed.
UNASSIGNED: Our study suggests a potential causal relationship between BPH and CVDs. BPH appears to be a risk factor for CHD and MI, but it may be protective against stroke. There was no evidence of a causal association in the reverse study, and a larger sample size was needed in follow-up to further explore the potential association.

暂无摘要。

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide while still lacks drugs for treatment or prevention. We aimed to investigate the causal role of glucose-dependent insulinotropic polypeptide receptor agonists (GIPRAs) on NAFLD and identify the mediated risk factors by which GIPRAs exert their therapeutic effects.
METHODS: Genetic proxies of GIPRAs were identified as cis-SNPs of GIPR associated with both the gene expression level and HbA1c and analyses including colocalization and linkage disequilibrium (LD) were performed for validation. We then performed two-sample two-step mendelian randomization to determine the causal effect of GIPRAs on NAFLD.
RESULTS: The MR analysis suggested genetic proxies of GIPRAs were causally associated with reduced risk of NAFLD (Odds ratio (OR): 0.46, 95 % confidence interval (95 % CI): 0.24-0.88, P = 0.02) and T2DM (OR: 0.10, 95 % CI: 0.07-0.13, P < 0.01). In addition, Mediation analysis showed evidence of indirect effect of GIPRAs on NAFLD via TRIG (0.88, [0.85-0.92], P < 0.01) and HDL-C (0.85, [0.80-0.90], P < 0.01).
CONCLUSIONS: Our study provided strong evidence to support the causal role of GIPRAs on reducing the risk of NAFLD probably through improving lipid metabolism, especially TG and HDL-C, providing guidance for future clinical trials.

UNASSIGNED: Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies worldwide. While several environmental risk factors for cSCC are well established, there is conflicting evidence on cigarette smoking (and its potential causal effect) and cSCC risk. Furthermore, it is unclear if these potential associations represent causal, modifiable risk factors for cSCC development. This study aims to assess the nature of the associations between cigarette smoking traits (smoking initiation, amount smoked, and lifetime smoking exposure) and cSCC risk using two-sample Mendelian randomization analyses.
UNASSIGNED: Genetic instruments, based on common genetic variants associated with cigarette smoking traits (P < 5 × 10-8), were derived from published genome-wide association studies (GWASs). For cSCC, we used GWAS summary statistics from the Kaiser Permanente GERA cohort (7701 cSCC cases and 60,167 controls; all non-Hispanic Whites).
UNASSIGNED: We found modest evidence that genetically determined lifetime smoking was associated with cSCC (inverse-variance weighted method: OR[95% CI] = 1.47[1.09-1.98]; P = .012), suggesting it may be a causal risk factor for cSCC. We did not detect any evidence of association between genetically determined smoking initiation or amount smoked and cSCC risk.
UNASSIGNED: Study findings highlight the importance of smoking prevention and may support risk-stratified cSCC screening strategies based on carcinogen exposure and other genetic and clinical information.

Increasing observational studies have indicated that hormonal reproductive factors were associated with ovarian cyst, a common gynecological disease. A two-sample Mendelian randomization (MR) was carried out by investigating the causality of reproductive factors including age at first birth (AFB), age at natural menopause (ANM), and age at menarche (AAM), and the risk of ovarian cyst (OC).
Summary statistics were collected from a large genome-wide association study (GWAS), and we used a two-sample MR study to clarify the causal association between the exposure of AFB (N = 542,901), ANM (N = 69,360), and AAM (N = 29,346) and the outcome of the OC (N case = 20,750, N control = 107,564). We separately selected 51, 35, and 6 single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for assaying the influence of AFB, ANM, and AAM on OC, respectively. Then, the causal relationship was tested through multiple approaches including an inverse-variance weighted method, an MR-Egger regression, and a weighted median method. In addition, the MR-PRESSO method was also used to verify the horizontal pleiotropy. Subsequently, we adjust the confounders for MR design.
The MR analysis results showed that AFB was negatively associated with the OC (IVW Beta: -0.09, OR: 0.91, 95% CI: 0.86-0.96, p = 0.00185), and the greater AAM decreased the risk of OC (IVW Beta: -0.10, OR: 0.91, 95% CI: 0.82-0.99, p = 0.0376). However, ANM has a positive correlation with the OC (IVW Beta: 0.05, OR: 1.05, 95% CI: 1.03-1.08, p = 8.38 × 10-6). After adjusting BMI, alcohol intake frequency, and ever smoked, we also obtained a negative relationship between AFB and OC (p < 0.005). Meanwhile, we adjusted weight, alcohol intake frequency, and height, and then found a causal relationship between older AMN and an increased risk of OC (p < 0.005).
A causal effect of reproductive factors on the development of OC, affected by AFB, ANM, and AAM, was found convincingly. After adjusting the confounders, we also successfully found the substantial causal effect of younger AFB, younger AAM, and older ANM on an increased risk of OC.

Observational studies have discovered a contradictory phenomenon between interleukin-17 (IL-17) and inflammatory bowel disease (IBD). The study aimed to confirm the causal association between each subtype of IL-17 and IBD.
We performed a 2-sample univariable and multivariable mendelian randomization (MR) to determine which subtype of IL-17 is causally related to IBD and its subtypes, and used a series of sensitivity analysis to examine the reliability of the main MR assumptions.
We found that IL-17B, IL-17E and IL-17RB were significantly associated with an increased risk of UC (IL-17B: OR: 1.26, 95% CI, 1.09-1.46, P < 0.01; IL-17E: OR: 1.17, 95% CI, 1.05-1.30, P < 0.01; IL-17RB: OR: 1.30, 95% CI, 1.20-1.40, P < 0.0001) while IL-17C and IL-17RC showed causal effects on the increased risk of CD (IL-17C: OR: 1.23, 95% CI, 1.21-1.26, P < 0.0001; IL-17RC: OR: 2.01, 95% CI, 1.07-3.75, P=0.03). The results of multivariable MR (MVMR) showed that the causal effects of IL-17B and IL-17E on UC were unilaterally dependent on IL-17RB, while the effects of IL-17C and IL-17RC on CD were interdependent.
Our study provided new genetic evidence for the causal relationships between each subtype of IL-17 and IBD, promoting future mechanistic research in IBD.

BACKGROUND: Numerous observational epidemiological studies have reported a bidirectional relationship between periodontitis and urological cancers. However, the causal link between these two phenotypes remains uncertain. This study aimed to examine the bidirectional causal association between periodontitis and four types of urological tumors, specifically kidney cancer (KC), prostate cancer (PC), bladder cancer (BC), and testis cancer (TC).
METHODS: Based on large-scale genome-wide association study (GWAS) data, we utilized the two-sample Mendelian randomization (MR) approach to evaluate causal relationships between periodontitis and urological cancers. Several MR methods covering various consistency assumptions were applied in this study, including contamination mixture and Robust Adjusted Profile Score to obtain robust results. Summary-level data of individuals with European ancestry were extracted from the UK Biobank, the Kaiser GERA cohorts, and the FinnGen consortium.
RESULTS: Our findings revealed significant positive genetic correlations between periodontitis and kidney cancer (OR 1.287; 95% CI 1.04, 1.594; P = 0.020). We did not find a significant association of periodontitis on prostate cancer, bladder cancer, and testis cancer. In reverse MR, no significant results were observed supporting the effect of urologic cancers on periodontitis (all P > 0.05).
CONCLUSIONS: Our study provides the evidence of a potential causal relationship between periodontitis and kidney cancer. However, large-scale studies are warranted to confirm and elucidate the underlying mechanisms of this association.

This study investigates the distribution of PAX6-associated congenital aniridia (AN) and WAGR syndrome across Russian Federation (RF) districts while characterizing PAX6 gene variants. We contribute novel PAX6 pathogenic variants and 11p13 chromosome region rearrangements to international databases based on a cohort of 379 AN patients (295 families, 295 probands) in Russia. We detail 100 newly characterized families (129 patients) recruited from clinical practice and specialized screening studies. Our methodology involves multiplex ligase-dependent probe amplification (MLPA) analysis of the 11p13 chromosome, PAX6 gene Sanger sequencing, and karyotype analysis. We report novel findings on PAX6 gene variations, including 67 intragenic PAX6 variants and 33 chromosome deletions in the 100 newly characterized families. Our expanded sample of 295 AN families with 379 patients reveals a consistent global PAX6 variant spectrum, including CNVs (copy number variants) of the 11p13 chromosome (31%), complex rearrangements (1.4%), nonsense (25%), frameshift (18%), and splicing variants (15%). No genetic cause of AN is defined in 10 patients. The distribution of patients across the Russian Federation varies, likely due to sample completeness. This study offers the first AN epidemiological data for the RF, providing a comprehensive PAX6 variants spectrum. Based on earlier assessment of AN prevalence in the RF (1:98,943) we have revealed unexamined patients ranging from 55% to 87%, that emphases the need for increased awareness and comprehensive diagnostics in AN patient care in Russia.