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OBJECTIVE: To investigate the effect of higher cumulative defined daily dose per year (cDDD/y) compared with lower cDDD/y of statin use in the incidence of any joint osteoarthritis (OA). DESIGN: In this population-based retrospective cohort study, patients who were aged ≥40 years were newly initiated on statin therapy between 2002 and 2011, and had a statin prescription for ≥90 days in the first year of treatment were identified from the 2000 Longitudinal Generation Tracking Database. All patients were separated into groups with higher cDDD/y (>120 cDDD/y) and lower cDDD/y (≤120 cDDD/y; as an active comparator) values. Propensity score matching was performed to balance potential confounders. All recruited patients were followed up for 8 years. Marginal Cox proportional hazard models were used to estimate time-to-event outcomes of OA. RESULTS: Compared with lower cDDD/y use, higher cDDD/y use did not reduce the risk of any joint OA (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99-1.14). Dose-related analysis did not reveal any dose-dependent association. A series of sensitivity analyses showed similar results. Joint-specific analyses revealed that statin did not reduce the incidence of knee, hand, hip, and weight-bearing (knee or hip) OA. CONCLUSIONS: Higher cDDD/y statin use did not reduce the risk of OA in this Taiwanese nationwide cohort study. The complexity of OA pathogenesis might contribute to the ineffectiveness of statin. Repurposing statin with its anti-inflammation properties might be ineffective for OA development, and balancing the catabolism and anabolism of cartilage might be a major strategy for OA prevention.

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Traumatic brain injury (TBI), often referred to as the "silent epidemic", is the most common cause of mortality and morbidity worldwide among all trauma-related injuries. It is associated with considerable personal, medical, and economic consequences. Although remarkable advances in therapeutic approaches have been made, current treatments and clinical management for TBI recovery still remain to be improved. One of the factors that may contribute to this gap is that existing therapies target only a single event or pathology. However, brain injury after TBI involves various pathological mechanisms, including inflammation, oxidative stress, blood-brain barrier (BBB) disruption, ionic disturbance, excitotoxicity, mitochondrial dysfunction, neuronal necrosis, and apoptosis. Statins have several beneficial pleiotropic effects (anti-excitotoxicity, anti-inflammatory, anti-oxidant, anti-thrombotic, immunomodulatory activity, endothelial and vasoactive properties) in addition to promoting angiogenesis, neurogenesis, and synaptogenesis in TBI. Supposedly, using agents such as statins that target numerous and diverse pathological mechanisms, may be more effective than a single-target approach in TBI management. The current review was undertaken to investigate and summarize the protective mechanisms of statins against TBI. The limitations of conducted studies and directions for future research on this potential therapeutic application of statins are also discussed.

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BACKGROUND: Although phenotypic associations between female reproductive characteristics and uterine leiomyomata have long been observed in epidemiologic investigations, the shared genetic architecture underlying these complex phenotypes remains unclear. OBJECTIVE: We aimed to investigate the shared genetic basis, pleiotropic effects, and potential causal relationships underlying reproductive traits (age at menarche, age at natural menopause, and age at first birth) and uterine leiomyomata. STUDY DESIGN: With the use of large-scale, genome-wide association studies conducted among women of European ancestry for age at menarche (n=329,345), age at natural menopause (n=201,323), age at first birth (n=418,758), and uterine leiomyomata (ncases/ncontrols=35,474/267,505), we performed a comprehensive, genome-wide, cross-trait analysis to examine systematically the common genetic influences between reproductive traits and uterine leiomyomata. RESULTS: Significant global genetic correlations were identified between uterine leiomyomata and age at menarche (rg, -0.17; P=3.65×10-10), age at natural menopause (rg, 0.23; P=3.26×10-07), and age at first birth (rg, -0.16; P=1.96×10-06). Thirteen genomic regions were further revealed as contributing significant local correlations (P<.05/2353) to age at natural menopause and uterine leiomyomata. A cross-trait meta-analysis identified 23 shared loci, 3 of which were novel. A transcriptome-wide association study found 15 shared genes that target tissues of the digestive, exo- or endocrine, nervous, and cardiovascular systems. Mendelian randomization suggested causal relationships between a genetically predicted older age at menarche (odds ratio, 0.88; 95% confidence interval, 0.85-0.92; P=1.50×10-10) or older age at first birth (odds ratio, 0.95; 95% confidence interval, 0.90-0.99; P=.02) and a reduced risk for uterine leiomyomata and between a genetically predicted older age at natural menopause and an increased risk for uterine leiomyomata (odds ratio, 1.08; 95% confidence interval, 1.06-1.09; P=2.30×10-27). No causal association in the reverse direction was found. CONCLUSION: Our work highlights that there are substantial shared genetic influences and putative causal links that underlie reproductive traits and uterine leiomyomata. The findings suggest that early identification of female reproductive risk factors may facilitate the initiation of strategies to modify potential uterine leiomyomata risk.

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Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) reduce plasma cholesterol and improve endothelium-dependent vasodilation, inflammation, and oxidative stress. The effect of statins on the central nervous system (CNS), particularly on cognition and neurological disorders such as cerebral ischemic stroke, multiple sclerosis (MS), and Alzheimer's disease (AD), has received increasing attention in recent years, both within the scientific community and in the media. This review aims to provide an updated discussion on the effects of statins on the differentiation and function of various nervous system cells, including neurons and glial cells. Additionally, the mechanisms of action and how different types of statins enter the CNS will be discussed.

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Acidovorax citrulli (Ac) is a causal agent of watermelon bacterial fruit blotch (BFB) disease. Because resistance cultivars/lines have not yet been developed, it is imperative to elucidate Ac's virulence factors and their mechanisms to develop resistant cultivars/lines in different crops, including watermelon. The glucose-6-phosphate isomerase (GPI) is a reversible enzyme in both glycolysis and gluconeogenesis pathways in living organisms. However, the functions of GPI are not characterized in Ac. In this study, we determined the roles of GpiAc (GPI in Ac) by proteomic and phenotypic analyses of the mutant lacking GPI. The mutant displayed significantly reduced virulence to watermelon in two different virulence assays. The mutant's growth patterns were comparable to the wild-type strain in rich medium and M9 with glucose but not with fructose. The comparative proteome analysis markedly identified proteins related to virulence, motility, and cell wall/membrane/envelope. In the mutant, biofilm formation and twitching halo production were reduced. We further demonstrated that the mutant was less tolerant to osmotic stress and lysozyme treatment than the wild-type strain. Interestingly, the tolerance to alkali conditions was remarkably enhanced in the mutant. These results reveal that GpiAc is involved not only in virulence and glycolysis/gluconeogenesis but also in biofilm formation, twitching motility, and tolerance to diverse external stresses suggesting the pleiotropic roles of GpiAc in Ac. Our study provides fundamental and valuable information on the functions of previously uncharacterized glucose 6-phosphate isomerase and its virulence mechanism in Ac.

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Objectives: This study aims to investigate the electrophysiological, scintigraphic, and histopathological effects of pitavastatin and its impact on functional status in rats with sciatic nerve injury. Materials and methods: A total of 30 Wistar albino rats were divided into three equal groups including 10 rats in each group: sham group (no injury), control group (nerve injury induced), and pitavastatin group (nerve injury induced and 2 mg/kg of pitavastatin administered orally once a day for 21 days). Before and at the end of intervention, quantitative gait analysis with the CatWalk system and sciatic nerve conduction studies were performed. After the intervention, the gastrocnemius muscle was scintigraphically evaluated, and the sciatic nerve was histopathologically examined. Results: There was no significant difference in the sciatic nerve conduction before the intervention and Day 21 among the groups (p>0.05). According to the quantitative gait analysis, there were significant differences in the control group in terms of the individual, static, dynamic, and coordination parameters (p<0.05). The histopathological examination revealed a significant difference in the total myelinated axon count and mean axon diameter among the groups (p<0.001). Conclusion: Pitavastatin is effective in nerve regeneration and motor function recovery in rats with sciatic nerve injury.

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BACKGROUND: Tibetans are genetically adapted to high-altitude environments. Though many studies have been conducted, the genetic basis of the adaptation remains elusive due to the poor reproducibility for detecting selective signatures in the Tibetan genomes. RESULTS: Here, we present whole-genome sequencing (WGS) data of 1001 indigenous Tibetans, covering the major populated areas of the Qinghai-Tibetan Plateau in China. We identify 35 million variants, and more than one-third of them are novel variants. Utilizing the large-scale WGS data, we construct a comprehensive map of allele frequency and linkage disequilibrium and provide a population-specific genome reference panel, referred to as 1KTGP. Moreover, with the use of a combined approach, we redefine the signatures of Darwinian-positive selection in the Tibetan genomes, and we characterize a high-confidence list of 4320 variants and 192 genes that have undergone selection in Tibetans. In particular, we discover four new genes, TMEM132C, ATP13A3, SANBR, and KHDRBS2, with strong signals of selection, and they may account for the adaptation of cardio-pulmonary functions in Tibetans. Functional annotation and enrichment analysis indicate that the 192 genes with selective signatures are likely involved in multiple organs and physiological systems, suggesting polygenic and pleiotropic effects. CONCLUSIONS: Overall, the large-scale Tibetan WGS data and the identified adaptive variants/genes can serve as a valuable resource for future genetic and medical studies of high-altitude populations.

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Pho91 is a vacuolar phosphate transporter that exports phosphate from the vacuolar lumen to the cytosol in yeast cells. In this study, we have demonstrated the pleiotropic effects of the PHO91 gene knockout in the methylotrophic yeast Ogataea parapolymorpha (Hansenula polymorpha, Ogataea angusta). The content of both acid-soluble and acid-insoluble inorganic polyphosphate (polyP) in the ∆pho91 cells was slightly higher compared to the strain with wild-type PHO91, when the cells were cultivated on glucose. The pho91-Δ mutations both in O. parapolymorpha and in Saccharomyces cerevisiae diminished resistance to cadmium and increased resistance to manganese and peroxide stresses. The cells of the mutant strain of O. parapolymorpha were unable to consume methanol due to the lack of methanol oxidase activity. We speculate that these effects are associated with the inability of mutant cells to mobilize phosphate from the vacuolar pool and/or defects in the signaling pathways involving phosphate, polyP, and inositol polyphosphates.

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Stigma exsertion rate (SER) is an index of outcrossing ability in rice and is a key trait of male sterile lines (MSLs) in hybrid rice. In this study, it was found that the maintainer lines carrying gs3 and gs3/gw8 showed higher SER. Single-segment substitution lines (SSSLs) carrying gs3, gw5, GW7 or gw8 genes for grain shape and gene pyramiding lines were used to reveal the relationship between grain shape and SER. The results showed that the grain shape regulatory genes had pleiotropic effects on SER. The SERs were affected by grain shapes including grain length, grain width and the ratio of length to width (RLW) not only in low SER background, but also in high SER background. The coefficients of determination (R2) between grain length and SER, grain width and SER, and grain RLW and SER were 0.78, 0.72, and 0.91 respectively. The grain RLW was the most important parameter affecting SER, and a larger grain RLW was beneficial to stigma exsertion. The pyramiding line PL-gs3/GW7/gw8 showed the largest grain RLW and the highest SER, which will be a fine breeding resource. Further research showed that the grain shape regulatory genes had pleiotropic effects on stigma shape, although the R2 values between grain shape and stigma shape, and stigma shape and SER were lower. Our results demonstrate that grain shape is a factor affecting SER in rice, in part by affecting stigma shape. This finding will be helpful for breeding MSLs with high SER in hybrid rice.

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Brain-derived neurotrophic factor (BDNF) is the most abundant brain neurotrophin and plays a critical role in neuronal growth, survival and plasticity, implicated in the pathophysiology of Bipolar Disorders (BD). The single-nucleotide polymorphism in the BDNF gene (BDNF rs6265) has been associated with decreased hippocampal BDNF secretion and volume in met carriers in different populations, although the val allele has been reported to be more frequent in BD patients. The anterior cingulate cortex (ACC) is a key center integrating cognitive and affective neuronal connections, where consistent alterations in brain metabolites such as Glx (Glutamate + Glutamine) and N-acetylaspartate (NAA) have been consistently reported in BD. However, little is known about the influence of BDNF rs6265 on neurochemical profile in the ACC of Healthy Controls (HC) and BD subjects. The aim of this study was to assess the influence of BDNF rs6265 on ACC neurometabolites (Glx, NAA and total creatine- Cr) in 124 euthymic BD type I patients and 76 HC, who were genotyped for BDNF rs6265 and underwent a 3-Tesla proton magnetic resonance imaging and spectroscopy scan (1 H-MRS) using a PRESS ACC single-voxel (8cm3) sequence. BDNF rs6265 polymorphism showed a significant two-way interaction (diagnosis × genotype) in relation to NAA/Cr and total Cr. While met carriers presented increased NAA/Cr in HC, BD-I subjects with the val allele revealed higher total Cr, denoting an enhanced ACC metabolism likely associated with increased glutamatergic metabolites observed in BD-I val carriers. However, these results were replicated only in men. Therefore, our results support evidences that the BDNF rs6265 polymorphism exerts a complex pleiotropic effect on ACC metabolites influenced by the diagnosis and sex.

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In clinical settings, the benefit of statin for stroke is debatable as regular statin users may suffer from myalgia, statin-associated myopathy (SAM), and rarely rhabdomyolysis. Studies suggest that patients on statin therapy show lesser vulnerability toward ischemic stroke and post-stroke frailty. Both pre- and post-treatment benefits of statin have been reported as evident by its neuroprotective effects in both cases. As mitochondrial dysfunction following stroke is the fulcrum for neuronal death, we hereby explore the role of statin in alleviating mitochondrial dysfunction by regulating the mitochondrial dynamics. In the present study, we intend to evaluate the role of statin in modulating cardiolipin-mediated mitochondrial functionality and further providing a therapeutic rationale for repurposing statins either as preventive or an adjunctive therapy for stroke.

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Barley (Hordeum vulgare L.) thrives in the arid and semi-arid regions of the world; nevertheless, it suffers large grain yield losses due to drought stress. A panel of 426 lines of barley was evaluated in Egypt under deficit (DI) and full irrigation (FI) during the 2019 and 2020 growing seasons. Observations were recorded on the number of days to flowering (NDF), total chlorophyll content (CH), canopy temperature (CAN), grain filling duration (GFD), plant height (PH), and grain yield (Yield) under DI and FI. The lines were genotyped using the 9K Infinium iSelect single nucleotide polymorphisms (SNP) genotyping platform, which resulted in 6913 high-quality SNPs. In conjunction with the SNP markers, the phenotypic data were subjected to a genome-wide association scan (GWAS) using Bayesian-information and Linkage-disequilibrium Iteratively Nested Keyway (BLINK). The GWAS results indicated that 36 SNPs were significantly associated with the studied traits under DI and FI. Furthermore, eight markers were significant and common across DI and FI water regimes, while 14 markers were uniquely associated with the studied traits under DI. Under DI and FI, three (11_10326, 11_20042, and 11_20170) and five (11_20099, 11_10326, 11_20840, 12_30298, and 11_20605) markers, respectively, had pleiotropic effect on at least two traits. Among the significant markers, 24 were annotated to known barley genes. Most of these genes were involved in plant responses to environmental stimuli such as drought. Overall, nine of the significant markers were previously reported, and 27 markers might be considered novel. Several markers identified in this study could enable the prediction of barley accessions with optimal agronomic performance under DI and FI.

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Milk production and body conformation traits are critical economic traits for dairy cows. To understand the basic genetic structure for those traits, a genome wide association study was performed on milk yield, milk fat yield, milk fat percentage, milk protein yield, milk protein percentage, somatic cell score, body form composite index, daily capacity composite index, feed, and leg conformation traits, based on the Illumina Bovine HD100k BeadChip. A total of 57, 12 and 26 SNPs were found to be related to the milk production, somatic cell score and body conformation traits in the Holstein cattle. Genes with pleiotropic effect were also found in this study. Seven significant SNPs were associated with multi-traits and were located on the PLEC, PLEKHA5, TONSL, PTGER4, and LCORL genes. In addition, some important candidate genes, like GPAT3, CEBPB, AGO2, SLC37A1, and FNDC3B, were found to participate in fat metabolism or mammary gland development. These results can be used as candidate genes for milk production, somatic cell score, and body conformation traits of Holstein cows, and are helpful for further gene function analysis to improve milk production and quality.

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Background: The cardiovascular complications of Coronavirus Disease 2019 (COVID-19) may be attributed to the hyperinflammatory state leading to increased mortality in patients with COVID-19. HMG-CoA Reductase Inhibitors (statins) are known to have pleiotropic and anti-inflammatory effects and may have antiviral activity along with their cholesterol-lowering activity. Thus, statin therapy is potentially a potent adjuvant therapy in COVID-19 infection. This study investigated the impact of statin use on the clinical outcome of critically ill patients with COVID-19. Methods: A multicenter, retrospective cohort study of all adult critically ill patients with confirmed COVID-19 who were admitted to Intensive Care Units (ICUs) between March 1, 2020, and March 31, 2021. Eligible patients were classified into two groups based on the statin use during ICU stay and were matched with a propensity score based on patient's age and admission APACHE II and SOFA scores. The primary endpoint was in-hospital mortality, while 30 day mortality, ventilator-free days (VFDs) at 30 days, and ICU complications were secondary endpoints. Results: A total of 1,049 patients were eligible; 502 patients were included after propensity score matching (1:1 ratio). The in-hospital mortality [hazard ratio 0.69 (95% CI 0.54, 0.89), P = 0.004] and 30-day mortality [hazard ratio 0.75 (95% CI 0.58, 0.98), P = 0.03] were significantly lower in patients who received statin therapy on multivariable cox proportional hazards regression analysis. Moreover, patients who received statin therapy had lower odds of hospital-acquired pneumonia [OR 0.48 (95% CI 0.32, 0.69), P < 0.001], lower levels of inflammatory markers on follow-up, and no increased risk of liver injury. Conclusion: The use of statin therapy during ICU stay in critically ill patients with COVID-19 may have a beneficial role and survival benefit with a good safety profile.

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Since domestication, a wide variety of phenotypes including coat color variation has developed in livestock. This variation is mostly based on selective breeding. During the beginning of selective breeding, potential negative consequences did not become immediately evident due to low frequencies of homozygous animals and have been occasionally neglected. However, numerous studies of coat color genetics have been carried out over more than a century and, meanwhile, pleiotropic effects for several coat color genes, including disorders of even lethal impact, were described. Similar coat color phenotypes can often be found across species, caused either by conserved genes or by different genes. Even in the same species, more than one gene could cause the same or similar coat color phenotype. The roan coat color in livestock species is characterized by a mixture of white and colored hair in cattle, pig, sheep, goat, alpaca, and horse. So far, the genetic background of this phenotype is not fully understood, but KIT and its ligand KITLG (MGF) are major candidate genes in livestock species. For some of these species, pleiotropic effects such as subfertility in homozygous roan cattle or homozygous embryonic lethality in certain horse breeds have been described. This review aims to point out the similarities and differences of the roan phenotype across the following livestock species: cattle, pig, sheep, goat, alpaca, and horse; and provides the current state of knowledge on genetic background and pleiotropic effects.

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Ratooning ability is a key factor that influences ratoon rice yield, in the area where light and temperature are not enough for second season rice. In the present study, an introgression line population derived from Minghui 63 as the recipient parent and 02428 as the donor parent was developed, and a high-density bin map containing 4568 bins was constructed. Nine ratooning-ability-related traits were measured, including maximum tiller number, panicle number, and grain yield per plant in the first season and ratoon season, as well as three secondary traits, maximum tiller number ratio, panicle number ratio, and grain yield ratio. A total of 22 main-effect QTLs were identified and explained for 3.26-18.63% of the phenotypic variations in the introgression line population. Three genomic regions, including 14.12-14.65 Mb on chromosome 5, 4.64-5.76 Mb on chromosome 8, and 10.64-15.52 Mb on chromosome 11, were identified to simultaneously control different ratooning-ability-related traits. Among them, qRA5 in the region of 14.12-14.65 Mb on chromosome 5 was validated for its pleiotropic effects on maximum tiller number and panicle number in the first season, as well as its maximum tiller number ratio, panicle number ratio, and grain yield ratio. Moreover, qRA5 was independent of genetic background and delimited into a 311.16 kb region by a substitution mapping approach. These results will help us better understand the genetic basis of rice ratooning ability and provide a valuable gene resource for breeding high-yield ratoon rice varieties.

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The biguanide metformin has been used as first-line therapy in type 2 diabetes mellitus (T2DM) treatment for several decades. In addition to its glucose-lowering properties and its prevention of weight gain, the landmark UK Prospective Diabetes Study (UKPDS) demonstrated cardioprotective properties in obese T2DM patients. Coupled with a favorable side effect profile and low cost, metformin has become the cornerstone in the treatment of T2DM worldwide. In addition, metformin is increasingly being investigated for its potential anticancer and neuroprotective properties both in T2DM patients and non-diabetic individuals. In the meantime, new drugs with powerful cardioprotective properties have been introduced and compete with metformin for its place in the treatment of T2DM. In this review we will discuss actual insights in the various working mechanisms of metformin and the evidence for its beneficial effects on (the prevention of) cardiovascular disease, cancer and dementia. In addition to observational evidence, emphasis is placed on randomized trials and recent meta-analyses to obtain an up-to-date overview of the use of metformin in clinical practice.

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BACKGROUND: The common non-synonymous mutation of the glucokinase regulator (GCKR) gene, namely rs1260326, is widely reported to have pleiotropic effects on cardio-metabolic traits and hematological parameters. OBJECTIVE: This study aimed to identify whether other GCKR variants may have pleiotropic effects independent of the rs1260326 genotypes. METHODS: In total, 81,097 Taiwan Biobank participants were enrolled for the regional plot association studies and candidate variant analysis of the region around the GCKR gene. RESULTS: The initial candidate variant approach showed the significant association of the rs1260326 genotypes with multiple phenotypes. Regional plot association analysis of the GCKR gene region further revealed genome-wide significant associations between GCKR variants and serum total and low-density lipoprotein cholesterol; triglyceride, uric acid, creatinine, aspartate aminotransferase, γ-Glutamyl transferase, albumin, and fasting plasma glucose levels; estimated glomerular filtration rate; leukocyte and platelet counts; microalbuminuria, and metabolic syndrome, with rs1260326 being the most common lead polymorphism. Serial conditional analysis identified genome-wide significant associations of two low-frequency exonic mutations, rs143881585 and rs8179206, with high serum triglyceride and albumin levels. In five rare GCKR exonic non-synonymous or nonsense mutations available for analysis, GCKR rs146175795 showed an independent association with serum triglyceride and albumin levels and rs150673460 showed an independent association with serum triglyceride levels. Weighted genetic risk scores from the combination of GCKR rs143881585 and rs146175795 revealed a significant association with metabolic syndrome. CONCLUSION: In addition to the rs1260326 variant, low-frequency and rare GCKR exonic mutations exhibit pleiotropic effects on serum triglyceride and albumin levels and the risk of metabolic syndrome. These results provide evidence that both common and rare GCKR variants may play a critical role in predicting the risk of cardiometabolic disorders.

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The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are administered as first-line therapy for hypercholesterolemia, both as primary and secondary prevention. Besides the lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. The preventive effect of statins on atherothrombotic stroke has been well established, but statins can influence other cerebrovascular diseases. This suggests that statins have many neuroprotective effects in addition to lowering cholesterol. Furthermore, research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies. Preclinical and clinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established; however, the effects of statins on cancer patients have not been fully elucidated and are still controversial. This review discusses the recent evidence on the effects of statins on cardiovascular and cerebrovascular diseases and cancer. Additionally, this study describes the pharmacological action of statins, focusing on the aspect of 'beyond lipid-lowering'.