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Obesity is a complex health risk influenced by genetic, environmental, and lifestyle factors. This review systematically assessed the association between interleukin gene polymorphisms (rs16944, rs17561, rs1143623, rs1143633, rs1143634, rs1800587, rs2234677, and rs4848306), IL-4 (rs180275, rs1805010, IL-6 rs13306435, rs1800795, rs1800796, rs1800797, rs2228145, rs2228145, rs2229238, and rs4845623), IL-10 (rs1518110, rs1518111, rs1800871, rs1800872, rs1800896, rs1878672, rs2834167, rs3024491, rs3024496, rs3024498, and rs3024505), IL-15 (rs3136617, rs3136618, and rs2296135), and IL-18 (rs187238, rs1946518, rs2272127, rs2293225, and rs7559479) and the risk of overweight and obesity in adults, focusing on IL-6 rs1800795 through a meta-analysis. The focus on IL-6 in this review arises from its pleiotropic nature and unclear effect on obesity risk. The review included studies published from 1998 to 2023, sourced from Science Direct, EBSCOhost, Web of Science, and Google Scholar. Bias was assessed with the Cochrane Collaboration tool, and funnel plots were used for publication bias. Results were synthesized into pooled odds ratios (ORs) and confidence intervals (CIs). Thirty studies comprising approximately 29,998 participants were included. The selection criteria required that the articles include participants who were overweight or obese, and this condition needed to be linked to IL polymorphisms. In a meta-analysis, in the dominant model, the pooled OR was 1.26 (95% CI 1.08 to 1.47), indicating those with the GC/CC genotype for IL-6 rs1800795 are 1.26 times more likely to be overweight/obese than GG genotype carriers. For the recessive model, the OR was 1.25 (95% CI 1.04 to 1.51). The overdominant model showed no significant association (OR 1.08, 95% CI 0.94 to 1.25). Interleukin gene variation, particularly the IL-6 rs1800795 variant, is modestly associated with obesity risk. This suggests that other factors, such as the environment, also play a role in obesity. Thus, individuals with this particular IL-6 variant may have a slightly higher likelihood of being overweight or obese compared to those without it, but this is just one of many factors influencing obesity risk. [ABSTRACT FROM AUTHOR]

Physical activity increases the risk of non-contact injuries, mainly affecting muscles, tendons, and ligaments. Genetic factors are recognized as contributing to susceptibility to different types of soft tissue injuries, making this broad condition a complicated multifactorial entity. Understanding genetic predisposition seems to offer the potential for personalized injury prevention and improved recovery strategies. The candidate gene analysis approach used so far, has often yielded inconclusive results. This manuscript reviews the most commonly studied genetic variants in genes involved in the musculoskeletal system's structure and recovery processes (ACTN3, ACE, CKM, MLCK, AMPD1, IGF2, IL6, TNFα, CCL2, COL1A1, COL5A1, MMP3, and TNC). Referring to the literature, it was highlighted that single-gene analyses provide limited insight. On the other hand, novel genetic testing methods identify numerous variants of uncertain physiological relevance. Distinguishing between functionally important variants, modifying variants, and the thousands of irrelevant variants requires advanced bioinformatics methods and basic multiomics research to identify the key biological pathways contributing to injury susceptibility. Tools like the Total Genotype Score (TGS) and Polygenic Risk Score (PRS) offer a more holistic view by assessing the combined effect of multiple variants. However, these methods, while useful in research, lack clinical applicability. In conclusion, it is too early to determine the clinical implications of genetic variability as a tool for improving well-established training and injury prevention methods, as the predictive power of genetic testing for injury predisposition is currently low. [ABSTRACT FROM AUTHOR]

Presenilin 1 (PS1) forms, via its large cytosolic loop, a trimeric complex with N-cadherin and β-catenin, which is a key component of Wnt signaling. PS1 undergoes phosphorylation at 353 and 357 serines upon enhanced activity and elevated levels of the GSK3β isoform. PS1 mutations surrounding these serines may alter the stability of the β-catenin complex. Such mutations are found in some cases of familial early-onset Alzheimer's disease (fEOAD), but their functional impact remains obscure. One of such variants of PS1, the A360T substitution, is located close to GSK3β-targeted serine residues. This variant was recently demonstrated in the French population, but more detail is needed to understand its biological effects. To assess the significance of this variant, we employed functional studies using a fibroblast cell line from an Alzheimer's disease case (a female proband) carrying the A360T mutation. Based on functional transcriptomic, cellular, and biochemical assays, we demonstrated atypically impaired β-catenin/GSK3β signaling in the A360T patient's fibroblasts. In detail, this was characterized by a decreased level of active cytosolic β-catenin and bound by PS1, an increased level of nuclear β-catenin, an increased level of inhibited GSK3β phosphorylated on Ser9, and enhanced interaction of GSK3β(Ser9) with PS1. Based on the transcriptomic profile of the A360T fibroblasts, we proposed a dysregulated transcriptional activity of β-catenin, exemplified by increased expression of various cyclin-dependent kinases and cyclins, such as cyclin D1, potentially inducing neurons' cell cycle re-entry followed by apoptosis. The A360T cells did not exhibit significant amyloid pathology. Therefore, cell death in this PS1 cytosolic loop mutation may be attributed to impaired β-catenin/GSK3β signaling rather than amyloid deposition per se. We further estimated the biological and clinical relevance of the A360T variant by whole exome sequencing (WES). WES was performed on DNA from the blood of an A360T female proband, as well as an unrelated male patient carrying the A360T mutation and his mutation-free daughter (both unavailable for the derivation of the fibroblast cell lines). WES confirmed the highest-priority AD causality of the A360T variant in PS1 and also profiled the pathways and processes involved in the A360T case, highlighting the greatest importance of altered Wnt signaling. [ABSTRACT FROM AUTHOR]

Abstract Background Peptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1) plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD) and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Also PIN1 genetic variation was inconsistently associated with AD risk. Methods We performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD) patients in comparison with healthy controls. Results Analysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk. In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed. Conclusion Our data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.

Mutations in SOD1 cause approximately 12–25% of familial ALS and ≈2% of apparently sporadic ALS cases. Clinical phenotypes linked to SOD1 mutations are heterogeneous and intra-familial variability of the clinical phenotype is frequently observed. SOD1 L144S mutation, identified also in Brazil, Iran and United States, is the second most frequent mutation among ALS patients in Poland. So far, 10 FALS pedigrees with SOD1 L144S mutation have been reported worldwide. The aim of the study was to establish the origin of SOD1 L144S mutation in geographically distinct populations. The clinical presentation of the Polish patients was compared with those from the previously reported populations (26 ever-reported patients). Clinically, L144S mutation is associated with both sporadic and familial ALS of relatively slow uniform course, a prevalent onset in the lower limbs, either classic or PMA presentation and a long survival time. Like in the case of other previously described SOD1 mutations, there was an intra-familial heterogeneity and reduced penetrance for ALS was observed. We propose that the L144S SOD1 mutation in the three studied populations has a common founder most likely of Polish origin. [ABSTRACT FROM AUTHOR]