Archives of Medical Science最新文献

Introduction: The relationship between the inflammatory response (IR) and osteoporosis (OP) has been the subject of extensive research; however, their genetic link remains unclear. This study used IR-related genes as instrumental variables (IVs) to represent IR, while summary data of OP served as the outcome to explore their genetic relationship.

Material and methods: IR-related genes were retrieved from the GeneCards database. OP transcriptome datasets were collected from the Gene Expression Omnibus (GEO) database and meta-analyzed to identify differentially expressed genes (DEGs) related to IR in OP. Genetic proxy instruments for IR-related genes were derived from studies of corresponding gene expression (n = 31,684) and DNA methylation (n = 1,980) quantitative trait loci (eQTLs and mQTLs), respectively. Aggregated data for OP (1,351 OP cases and 209,313 controls) were extracted from the largest genome-wide association study (GWAS) of OP. We integrated QTL data with OP GWAS data to estimate their genetic associations using summary data-based Mendelian randomization analysis (SMR). Additionally, Bayesian colocalization analysis was employed to reveal the potential relationships between IR gene expression and inflammatory factors, as well as various hormones. Finally, to further validate whether the statistical evidence provided in GWAS comprised true-positive findings, a replication study (1,955 cases and 278,169 controls) was conducted here through genotype-phenotype associations.

Results: A meta-analysis of four datasets identified 115 IR-related DEGs in OP out of 612 IR-related genes. Through SMR analysis, we found that the expression levels of two IR-related genes were associated with OP risk. Specifically, elevated gene expression levels of FAS (odds ratio (OR) = 1.094; 95% confidence interval (CI) = 0.892-1.341; false discovery rate (FDR) = 0.034) increased the risk of OP. Conversely, increased expression levels of CHUK decreased the risk of OP (OR = 0.518; 95% CI = 0.424-0.637; FDR = 0.039). Colocalization analysis identified potential interactions between the FAS gene and estradiol (PP.H4 = 0.95) as well as interleukin-1α (IL-1α) (PP.H4 = 0.65). Potential interactions were also observed between the CHUK gene and growth hormone (PP.H4 = 0.59) as well as macrophage inflammatory protein-1α (MIP-1α) (PP.H4 = 0.62). In addition, consistent results were observed in the replication study, further demonstrating the reliability of our findings.

Conclusions: This multi-omics integration study revealed a genetic link between IR and OP, as represented by IR-related genes, and provided new insights into the potential pathogenic mechanisms of OP. Additionally, these identified candidate genes offer avenues for future targeted functional studies aimed at developing appropriate therapeutic interventions and preventing OP.

Introduction: Appropriate levels of physical activity (PA) can help prevent osteoarthritis (OA) and alleviate its symptoms. However, excessive or prolonged PA has been identified as a potential risk factor for OA. Despite these observations, the genetic causal relationship between PA and OA remains unclear. Therefore, this study aimed to clarify the causal link between PA and OA by investigating their shared genetic factors.

Material and methods: The study utilized genome-wide association study (GWAS) summary data to investigate the relationship between three types of PA - moderate to vigorous physical activity (MVPA), vigorous physical activity (VPA) and strenuous sports or other exercises (SSOE) - and knee osteoarthritis (KOA). A two-sample Mendelian randomization (MR) analysis was conducted using the TwoSampleMR and MRPRESSO packages in R. Sensitivity analyses were performed. Cochran's Q statistic and Rucker's Q statistic were employed to assess heterogeneity. The MR-Egger intercept test was used to evaluate horizontal pleiotropy. Additionally, the MR pleiotropy residual sum and outlier (MR-PRESSO) method was applied to detect horizontal pleiotropy and identify outlier SNPs. A leave-one-out analysis was conducted to determine whether the genetic associations were influenced by any single nucleotide polymorphism (SNP). The MR robust adjusted profile score (MR-RAPS) method was further used to validate the normal distribution of the MR analysis.

Results: The results of the MR analysis indicate that MVPA (p = 0.436, odds ratio [OR] = 1.814, 95% confidence interval [CI] [0.405-8.119]), VPA (p = 0.995, OR = 1.011, 95% CI [0.040-25.224]) and SSOE (p = 0.266, OR = 0.258, 95% CI [0.024-2.812]) have no significant genetic causal relationship with KOA. We did not detect any heterogeneity or horizontal pleiotropy (p > 0.05), nor were there any outliers in our MR analysis. Our MR results were not driven by a single SNP and were normally distributed (p > 0.05).

Conclusions: The results of this study provide evidence against a genetic causal relationship between PA and KOA, thereby contributing to the understanding of their correlation. However, the study does not rule out the possibility of a relationship through non-genetic mechanisms.

Introduction: Biallelic pathogenic variants in the LPL gene are associated with familial lipoprotein lipase (LPL) deficiency. Homozygotes exhibit very severe hypertriglyceridemia (HTG) already in childhood, with phenotypic features such as pancreatitis, abdominal pain and xanthomata. Recent studies showed that HTG levels varied greatly between monoallelic LPL pathogenic/likely pathogenic variant carriers. The aim of our study was to investigate whether heterozygotes for pathogenic variants in the LPL gene in the Polish population may have clinical symptoms and, if so, to what extent.

Material and methods: Genetic data were derived from a Polish cohort of 5623 whole exome sequenced patients. In 52 cases the indication for WES genetic testing was "hypertriglyceridemia '' and for 5571 there was another clinical indication, mainly autism spectrum disorder, dysmorphia and neurodegenerative diseases.

Results: We present 22 heterozygous and 2 homozygous/compound heterozygous individuals for the pathogenic/likely pathogenic LPL variant and describe HTG levels, phenotypic manifestations and age of onset in the context of molecular findings where available. We report for the first time heterozygous LPL individuals with very severe HTG (TG ≥ 22.6 mmol/l; > 2000 mg/dl) and additional symptoms such as pancreatitis and recurrent abdominal pain.

Conclusions: We argue that although the individuals carrying the single LPL pathogenic/likely pathogenic variant display the whole disease spectrum, the severe phenotype of heterozygotes with dominantly inherited LPL-related HTG may also exist.

Introduction: Obesity and aging are established independent risk factors for osteoarthritis (OA). This study aimed to evaluate the correlation between the age-adjusted visceral adiposity index (AVAI) and OA.

Material and methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) collected between 1999 and 2018. The correlation between AVAI and prevalence of OA was explored through receiver operating characteristic (ROC) regression, multivariate logistic regression, restricted cubic spline regression, and subgroup analysis.

Results: The study cohort comprised 20,628 participants, of whom 2,297 (11.1%) were diagnosed with OA. An increase in the quartile range of AVAI was correlated with a significant rise in the prevalence of OA (1.5% vs. 5.1% vs. 14.4% vs. 23.6%, p < 0.001). Logistic regression analysis demonstrated a significant positive correlation between AVAI and the risk of OA (OR = 1.14, 95% CI: 1.06, 1.23). Subgroup analyses indicated that this correlation was more pronounced in individuals aged over 60 years and those with diabetes. RCS regression analysis further identified a non-linear positive correlation, with an inflection point at -6.03. Finally, the area under the ROC curve (AUC) for AVAI was notably greater (AUC = 0.757, 95% CI: 0.747, 0.766) compared to traditional obesity indices.

Conclusions: This study is the first to demonstrate a significant positive correlation between the prevalence of OA and AVAI, with AVAI exhibiting superior diagnostic performance over traditional obesity indices in identifying OA.

Introduction: Meningioma, a prevalent intracranial tumor, presents diagnostic and therapeutic challenges due to its heterogeneous nature. Metabolic profiling has emerged as a promising approach to elucidate its underlying molecular mechanisms and discover potential biomarkers.

Material and methods: This study employed bidirectional Mendelian randomization (MR) analysis to investigate the causal relationship between plasma metabolites and meningioma risk. Genetic instruments were used as surrogates for both plasma metabolites and meningioma, allowing MR analysis in both directions to assess the impact of metabolites on meningioma risk and vice versa. This study encompassed data on 1400 plasma metabolites and 314,708 participants (1316 individuals diagnosed with meningioma and 313,392 individuals without meningioma).

Results: Initially, 46 plasma metabolites/metabolite ratios were found to be associated with meningioma risk (p < 0.05), with 23 associated with a decreased risk and 23 associated with an increased risk of meningioma. Furthermore, the identified relationships between the 46 plasma metabolites/metabolite ratios and meningioma showed no significant horizontal pleiotropy (p > 0.05), suggesting that the results are not influenced by other confounding factors. Reverse MR analysis revealed that meningioma has no significant impact on the levels of 24 plasma metabolites/metabolite ratios, and is unaffected by confounding factors. In addition, the identified plasma metabolites influence the occurrence of meningioma through nine metabolic pathways.

Conclusions: The findings of this bidirectional MR study indicate that 24 plasma metabolites/metabolite ratios lead to a significantly increased/decreased risk of meningioma, suggesting that the plasma metabolite profile characteristics serve as important serological tools for the early diagnosis of meningioma.

Introduction: Personalized medicine in inflammatory bowel disease (IBD) aims to achieve maximum effectiveness through rapid induction and maintenance of remission. To achieve this goal, reliable predictors of disease course are needed. The aim of this study was to identify early markers of IBD's poor course understood as the need for anti-tumor necrosis factor (anti-TNF-α) treatment.

Material and methods: We analyzed the clinical, laboratory, radiological, and endoscopic data of children with IBD. These parameters were assessed at the time of diagnosis (T0) and 8-12 weeks (T1) after the start of induction therapy. The results of patients who did not require anti-TNF-α treatment were compared to children who needed such treatment during the 2-year observation time.

Results: 58.14% of patients with Crohn's disease (CD) and 31.71% of patients with ulcerative colitis (UC) required biological therapy. Patients with CD and UC receiving biological therapy, compared with those without, differed in selected clinical and laboratory parameters both at T0 and T1. In multivariate analysis, the risk of anti-TNF-α therapy in patients with CD was associated with the lack of normalization of mean corpuscular volume (MCV) and Pediatric Crohn's Disease Activity Index (PCDAI). In patients with UC, higher albumin levels reduced this risk.

Conclusions: In children with IBD, disease activity and concentrations of selected biochemical parameters assessed within 3 months after diagnosis may be helpful in predicting a poor outcome of CD and UC.