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.