Search Results (17)

Background: Colorectal cancer (CRC), the most common malignancy of the gastrointestinal tract, is the second leading cause of cancer-related deaths worldwide. In this context, investigating low-penetrance gene variants associated with the increased risk of CRC represents a novel and crucial approach to enhancing prevention strategies and clinical surveillance. By focusing on these genetic variants, there is potential for more accurate prediction of individual CRC risk, which could contribute to the refinement of current screening and prophylactic programs. The aim of this case–control study was to explore the association between SIRT1 polymorphisms and CRC risk. Methods: We analyzed three SNPs—rs12778366 (T/C), rs3758391 (C/T), and rs7895833 (A/G)—in the promoter region of the SIRT1 gene, which may influence SIRT1 expression and thus play a role in cancer development. Our study included 200 patients with colorectal adenocarcinoma and 115 controls. Genomic DNA was extracted from blood samples, and SIRT1 SNP analysis was performed using the qPCR method and endpoint genotyping. Results: Univariate regression analysis revealed a slightly increased risk of developing CRC in individuals with minor alleles of the analyzed polymorphisms; however, the observed differences were not statistically significant. Conclusions: Although our findings did not reveal statistically significant differences in SIRT1 gene polymorphism frequencies between the CRC group and the control group, we observed a tendency that suggests further investigation in larger cohorts is warranted. This research underscores the importance of understanding low-penetrance genetic factors in CRC, highlighting their potential to inform more personalized and effective prevention strategies. Full article

Semen quality and persistence are critical for evaluating the usability of individual boars in AI, a standard practice in pig breeding. We conducted GWASs on various semen traits of Duroc boars, including MOT, DEN, ABN, MMP, AIR, and ROS levels. These traits were assessed using FCM and CASA. A total of 1183 Duroc boars were genotyped using the GeneSeek GGP Porcine 50 K SNP BeadChip. The GWAS was performed using three different models: GLM, MLM, and FarmCPU. Additionally, trait heritability was estimated using single- and multiple-trait PBLUP models, yielding 0.19, 0.29, 0.13, 0.18, 0.11, and 0.14 heritability for MOT, DEN, ABN, MMP, AIR, and ROS, respectively. All semen traits exhibited low heritability except ABN, which demonstrated medium heritability. Nine candidate genes (GPX5, AWN, PSP-II, CCDC62, TMEM65, SLC8B1, TRPV4, UBE3B, and SIRT5) were potentially associated with semen traits. These genes are associated with antioxidant and mitochondrial functions in porcine sperm. Our findings provide insight into the genetic architecture of semen traits in Duroc boars, and the identified SNPs and candidate genes may enhance economic outcomes in the pig breeding industry while improving sperm quality through targeted breeding strategies. Full article

Ovarian aging results in reproductive disorders and infertility in mammals. Previous studies have reported that the ferroptosis and autophagy caused by oxidative stress may lead to ovarian aging, but the mechanisms remain unclear. In this study, we compared the morphological characteristics between the aged and young ovaries of pigs and found that the aged ovaries were larger in size and showed more corpora lutea. TUNEL assay further showed that the apoptosis level of granulosa cells (GCs) was relatively higher in the aged ovaries than those in young ovaries, as well as the expressions of autophagy-associated genes, e.g., p62, ATG7, ATG5, and BECN1, but that the expressions of oxidative stress and aging-associated genes, e.g., SOD1, SIRT1, and SIRT6, were significantly lower. Furthermore, the RNA-seq, Western blotting, and immunofluorescence suggested that phospholipid phosphatase 3 (PLPP3) protein was significantly upregulated in the aged ovaries. PLPP3 was likely to decrease the expressions of SIRT1 and SIRT6 to accelerate cellular senescence of porcine GCs, inhibit the expressions of SOD1, CAT, FSP1, FTH1, and SLC7A11 to exacerbate oxidative stress and ferroptosis, and arouse autophagy to retard the follicular development. In addition, two SNPs of PLPP3 promoter were significantly associated with the age at puberty. g.155798586 (T/T) and g.155798718 (C/C) notably facilitated the mRNA and protein level of PLPP3. In conclusion, PLPP3 might aggravate the oxidative stress of GCs to accelerate ovarian aging, and two molecular markers of PLPP3 were identified for ovarian aging in pigs. This work not only contributes to investigations on mechanisms for ovarian aging but also provides valuable molecular markers to postpone ovarian aging in populations. Full article

The 9p21.3 genomic locus is a hot spot for disease-associated single-nucleotide polymorphisms (SNPs), and its strongest associations are with coronary artery disease (CAD). The disease-associated SNPs are located within the sequence of a long noncoding RNA ANRIL, which potentially contributes to atherogenesis by regulating vascular cell stress and proliferation, but also affects pancreatic β-cell proliferation. Altered expression of a neighboring gene, CDKN2B, has been also recognized to correlate with obesity and hepatic steatosis in people carrying the risk SNPs. In the present study, we investigated the impact of 9p21.3 on obesity accompanied by hyperlipidemia in mice carrying a deletion of the murine ortholog for the 9p21.3 (Chr4^Δ70/Δ70) risk locus in hyperlipidemic Ldlr^−/−ApoB^100/100 background. The Chr4^Δ70/Δ70 mice showed decreased mRNA expression of insulin receptors in white adipose tissue already at a young age, which developed into insulin resistance and obesity by aging. In addition, the Sirt1-Ppargc1a-Ucp2 pathway was downregulated together with the expression of Cdkn2b, specifically in the white adipose tissue in Chr4^Δ70/Δ70 mice. These results suggest that the 9p21.3 locus, ANRIL lncRNA, and their murine orthologues may regulate the key energy metabolism pathways in a white adipose tissue-specific manner in the presence of hypercholesterolemia, thus contributing to the pathogenesis of metabolic syndrome. Full article

Certain genetic factors, including single-nucleotide polymorphisms (SNPs) in the SIRT1 gene, have been linked to medication-related osteonecrosis of the jaw (MRONJ). This study examined four SNPs in the SIRT1 gene and implemented multivariate statistical analysis to analyze genetic and clinical factors in MRONJ patients. Genomic DNA was isolated from peripheral blood samples of 63 patients of European origin treated for MRONJ, and four SNP genotypes in the gene encoding the SIRT-1 protein were determined by Sanger sequencing. The allele frequencies measured in the MRONJ population were compared with allele frequencies measured in the European population in the National Center for Biotechnology Information Allele Frequency Aggregator (NCBI ALFA) database. Genetic and clinical factors were examined with multivariate statistical analysis. A C:A allele distribution ratio of 77.8:22.2 was measured in the rs932658 SNP. In the ALFA project, a C:A allele distribution ratio of 59.9:40.1 was detected in the European population, which was found to be a significant difference (p = 4.5 × 10⁻⁵). Multivariate statistical analysis revealed a positive correlation (0.275) between the genotype of SNP rs932658 and the number of stages improved during appropriate MRONJ therapy. It is concluded that allele A in SNP rs932658 in the SIRT1 gene acts as a protective factor in MRONJ. Full article

Aim: The purpose of this work was to investigate the prevalence of SIRT1 rs3818292, rs3758391, and rs7895833 single nucleotide polymorphisms and SIRT1 serum levels associated with multiple sclerosis (MS) in the Lithuanian population. Methods: A total of 250 MS patients and 250 healthy controls were included in the study. Genotyping was performed using the RT-PCR method. Statistical analysis was performed using “IBM SPSS version 29.0”. The serum SIRT1 level was determined by the ELISA method. Results: We found that rs3818292 was associated with increased odds of developing MS under the dominant (p = 0.007) and allelic genetic (p = 0.004) models. rs3758391 was associated with increased odds of developing under the co-dominant (p < 0.001), overdominant (p < 0.001), dominant (p < 0.001), and allelic (p = 0.002) genetic models. rs7895833 was associated with increased odds of developing MS under co-dominant (p < 0.001), overdominant (p < 0.001), dominant (p < 0.001), and allelic (p < 0.001) genetic models. Additional sex-differentiated analysis within females revealed that the rs3758391 was associated with an increased odds ratio for the occurrence of MS among the co-dominant (p = 0.006), dominant (p = 0.002), and allelic (p = 0.001). rs7895833 was associated with an increased odds ratio for the development of MS under the co-dominant (p < 0.001), overdominant (p < 0.001), dominant (p < 0.001), and allelic (p < 0.001) genetic models. Age-differentiated analysis showed that rs3758391 was associated with an increased odds ratio for the development of MS in younger patients under the codominant (p = 0.002), overdominant (p = 0.003), and dominant (p = 0.004) genetic models. rs7895833 was associated with an increased odds ratio for the occurrence of MS under the overdominant genetic model (p = 0.013). In elderly patients, rs3818292 was associated with an increased odds ratio for the occurrence of MS under the dominant (p = 0.008) and allelic (p = 0.009) genetic models. rs7895833 was associated with an increased odds ratio for the occurrence of MS under the codominant (p = 0.011 and p = 0.012), dominant (p = 0.001), and allelic (p < 0.001) genetic models. We also found that serum SIRT1 levels were statistically significantly different between MS patients and control group subjects (p < 0.001). In addition, comparison of SIRT1 levels between study groups and genotypes showed that rs3818292 AA (p = 0.001), rs3758391 CT (p < 0.001), and rs7895833 AA (p = 0.002) and AG (p = 0.004) had higher SIRT1 levels in the control group than in the MS group. All results were provided after strict Bonferroni correction. Conclusions: Genetic variations in SIRT1 rs3818292, rs3758391, and rs7895833 are associated with multiple sclerosis, with possible differences in gender and age, as well as lower serum SIRT1 levels. Full article

The aim of the study was to identify genetic variants associated with personal best scores in Turkish track and field athletes and to compare allelic frequencies between sprint/power and endurance athletes and controls using a whole-exome sequencing (WES) approach, followed by replication studies in independent cohorts. The discovery phase involved 60 elite Turkish athletes (31 sprint/power and 29 endurance) and 20 ethnically matched controls. The replication phase involved 1132 individuals (115 elite Russian sprinters, 373 elite Russian endurance athletes (of which 75 athletes were with VO_2max measurements), 209 controls, 148 Russian and 287 Finnish individuals with muscle fiber composition and cross-sectional area (CSA) data). None of the single nucleotide polymorphisms (SNPs) reached an exome-wide significance level (p < 2.3 × 10⁻⁷) in genotype–phenotype and case–control studies of Turkish athletes. However, of the 53 nominally (p < 0.05) associated SNPs, four functional variants were replicated. The SIRT1 rs41299232 G allele was significantly over-represented in Turkish (p = 0.047) and Russian (p = 0.018) endurance athletes compared to sprint/power athletes and was associated with increased VO_2max (p = 0.037) and a greater proportion of slow-twitch muscle fibers (p = 0.035). The NUP210 rs2280084 A allele was significantly over-represented in Turkish (p = 0.044) and Russian (p = 0.012) endurance athletes compared to sprint/power athletes. The TRPM2 rs1785440 G allele was significantly over-represented in Turkish endurance athletes compared to sprint/power athletes (p = 0.034) and was associated with increased VO_2max (p = 0.008). The AGRN rs4074992 C allele was significantly over-represented in Turkish sprint/power athletes compared to endurance athletes (p = 0.037) and was associated with a greater CSA of fast-twitch muscle fibers (p = 0.024). In conclusion, we present the first WES study of athletes showing that this approach can be used to identify novel genetic markers associated with exercise- and sport-related phenotypes. Full article

Copy number variation (CNV) is an important class of genetic variations widely associated with the porcine genome, but little is known about the characteristics of CNVs in foreign and indigenous pig breeds. We performed a genome-wide comparison of CNVs between Anhui indigenous pig (AHIP) and Western commercial pig (WECP) breeds based on data from the Porcine 80K SNP BeadChip. After analysis using the PennCNV software, we detected 3863 and 7546 CNVs in the AHIP and WECP populations, respectively. We obtained 225 (loss: 178, gain: 47) and 379 (loss: 293, gain: 86) copy number variation regions (CNVRs) randomly distributed across the autosomes of the AHIP and WECP populations, accounting for 10.90% and 22.57% of the porcine autosomal genome, respectively. Functional enrichment analysis of genes in the CNVRs identified genes related to immunity (FOXJ1, FOXK2, MBL2, TNFRSF4, SIRT1, NCF1) and meat quality (DGAT1, NT5E) in the WECP population; these genes were a loss event in the WECP population. This study provides important information on CNV differences between foreign and indigenous pig breeds, making it possible to provide a reference for future improvement of these breeds and their production performance. Full article

We investigated whether long-term consumption of two healthy diets (low-fat (LF) or Mediterranean (Med)) interacts with SIRT1 genotypes to modulate aging-related processes such as leucocyte telomere length (LTL), oxidative stress (OxS) and inflammation in patients with coronary heart disease (CHD). LTL, inflammation, OxS markers (at baseline and after 4 years of follow-up) and SIRT1-Single Nucleotide Polymorphisms (SNPs) (rs7069102 and rs1885472) were determined in patients from the CORDIOPREV study. We analyzed the genotype-marker interactions and the effect of diet on these interactions. Regardless of the diet, we observed LTL maintenance in GG-carriers for the rs7069102, in contrast to carriers of the minor C allele, where it decreased after follow-up (p = 0.001). The GG-carriers showed an increase in reduced/oxidized glutathione (GSH/GSSG) ratio (p = 0.003), lower lipid peroxidation products (LPO) levels (p < 0.001) and a greater decrease in tumor necrosis factor-alpha (TNF-α) levels (p < 0.001) after follow-up. After the LF diet intervention, the GG-carriers showed stabilization in LTL which was significant compared to the C allele subjects (p = 0.037), although the protective effects found for inflammation and OxS markers remained significant after follow-up with the two diets. Patients who are homozygous for the SIRT1-SNP rs7069102 (the most common genotype) may benefit from healthy diets, as suggested by improvements in OxS and inflammation in patients with CHD, which may indicate the slowing-down of the aging process and its related diseases. Full article

Background and Objectives: Nicotinamide adenine dinucleotide (NAD) is an important coenzyme in various physiological processes, including sirtuins (SIRTs) and kynurenine pathway (KP). Previous studies have shown that lower NAD levels can be indicative of increased risks of cancer and psychiatric disorders. However, there has been no prior study exploring the link between NAD homeostasis and psychiatric disorders from a genetic perspective. Therefore, we aimed to investigate the association of genetic polymorphism in the pathways of NAD biosynthesis with major depressive disorder (MDD). Methods: A total of 317 patients were included in the case group and were compared with sex-matched control group of 1268 participants (1:4 ratio) from Taiwan Biobank (TWB). All subjects in the control group were over 65 years old, which is well past the average age of onset of MDD. Genomic DNA extracted from patients’ blood buffy coat was analyzed using the Affymetrix TWB array. Full-model tests were conducted for the analysis of single nucleotide polymorphism (SNPs) in all candidate genes. We focused on genes within the NAD-related candidate pathways, including 15 in KP, 12 in nicotinate metabolism, 7 in SIRTs, and 19 in aldehyde dehydrogenases (ALDHs). A total of 508 SNPs were analyzed in this study. After significant SNPs were determined, 5000 genome-wide max(T) permutations were performed in Plink. Finally, we built a predictive model with logistic regression and assessed the interactions of SNPs with the haplotype association tests. Results: We found three SNPs that were significantly associated with MDD in our NAD-related candidate pathways, one within the KP (rs12622574 in ACMSD) and two within the nicotinate metabolism (rs28532698 in BST1 and rs3733593 in CD38). The observed association with MDD was significant in the dominant model of inheritance with marital status, education level, and body mass index (BMI) adjusted as covariates. Lastly, in haplotype analysis, the three associated SNPs consisted of one haploblock in ACMSD, four haploblocks in BST1, and two haploblocks in CD38. Conclusions: This study provides the first evidence that genetic variations involved in NAD homeostasis in the KP and nicotinate metabolism may be associated with the occurrence of MDD. Full article

Background: The aim of this paper was to determine the frequency of SIRT1 rs3818292, rs3758391, rs7895833 single nucleotide polymorphism genotypes and SIRT1 serum levels associated with age-related macular degeneration (AMD) in the Lithuanian population. Methods: Genotyping of SIRT1 rs3818292, rs3758391 and rs7895833 was performed using RT-PCR. SIRT1 serum level was determined using the ELISA method. Results: We found that rs3818292 and rs7895833 were associated with an increased risk of developing exudative AMD. Additional sex-differentiated analysis revealed only rs7895833 was associated with an increased risk of developing exudative AMD in women after strict Bonferroni correction. The analysis also revealed that individuals carrying rs3818292, rs3758391 and rs7895833 haplotype G-T-G are associated with increased odds of exudative AMD. Still, the rare haplotypes were associated with the decreased odds of exudative AMD. After performing an analysis of serum SIRT1 levels and SIRT1 genetic variant, we found that carriers of the SIRT1 rs3818292 minor allele G had higher serum SIRT1 levels than the AA genotype. In addition, individuals carrying at least one SIRT1 rs3758391 T allele also had elevated serum SIRT1 levels compared with individuals with the wild-type CC genotype. Conclusions: Our study showed that the SIRT1 polymorphisms rs3818292 and rs7895833 and rs3818292-rs3758391-rs7895833 haplotype G-T-G could be associated with the development of exudative AMD. Also, two SNPs (rs3818292 and rs3758391) are associated with elevated SIRT1 levels. Full article

The aim of the study was to find the association between SIRT1 concentration, SIRT1 rs3758391, rs3818292, rs7895833 polymorphisms and clinical manifestations of pituitary adenoma (PA). The study included 108 patients with PA and 216 healthy individuals. Using commercial kits, DNA was extracted from peripheral blood leukocytes. To determine the PA and control group subjects genotypes was used real-time PCR method, for SIRT concentration measurement we used ELISA method. The statistical data analysis was completed using the “BM SPSS Statistics 20.0” software. Results: We performed statistical analysis of SNPs in the patient and healthy controls and patients’ subgroups and found statistically significant differences in rs7895833 genotype (A/A, A/G, G/G) distributions between the active PA and control groups (67.9%, 24.6%, 5.7% vs. 72.2%, 27.3%, 0.5%; p = 0.02) Also, the results showed that the rs7895833 G/G genotype is associated with about 13-fold increased odds of active PA development compared to the A/A (OR = 13.95% CI: 1.314–128.632; p = 0.028) and both A/A and A/G genotypes (OR = 12.9; 95% CI: 1.314–126.624; p = 0.028). There is ample evidence that SIRT1 in the pituitary and other target organs modifies the synthesis, secretion, and activity of hormones to trigger adaptive responses, thus we decided to include this in our study. When determining the serum concentration of SIRT1, we did not find a statistically significant difference between the PA group and the control group. SIRT1 serum level was statistically significantly higher in women with PA than in healthy control women (1.115 (3.748) vs. 136 (0.211); p = 0.008). To conclude—SIRT1 rs7895833 G/G genotype is associated with about 13-fold increased odds of active PA development compared to the A/A and both A/A and A/G genotypes. SIRT1 serum levels are higher in women with PA than in healthy women. Full article

The detrimental effects of organophosphates (OPs) on human health are thought to be of systemic, i.e., irreversible inhibition of acetylcholinesterase (AChE) at nerve synapses. However, several studies have shown that AChE inhibition alone cannot explain all the toxicological manifestations in prolonged exposure to OPs. The present study aimed to assess the status of antioxidants malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) (reduced), catalase, and ferric reducing antioxidant power (FRAP) in chronic OP-exposed groups from Cameroon and Pakistan. Molecular analysis of genetic polymorphisms (SNPs) of glutathione transferases (GSTM1, GSTP1, GSTT1), catalase gene (CAT, rs7943316), sirtuin 1 gene (SIRT1, rs10823108), acetylcholinesterase gene (ACHE, rs2571598), and butyrylcholinesterase gene (BCHE, rs3495) were screened in the OP-exposed individuals to find the possible causative association with oxidative stress and toxicity. Cholinesterase and antioxidant activities were measured by colorimetric methods using a spectrophotometer. Salting-out method was employed for DNA extraction from blood followed by restriction fragment length polymorphism (RFLP) for molecular analysis. Cholinergic enzymes were significantly decreased in OP-exposed groups. Catalase and SOD were decreased and MDA and FRAP were increased in OP-exposed groups compared to unexposed groups in both groups. GSH was decreased only in Pakistani OPs-exposed group. Molecular analysis of ACHE, BCHE, Catalase, GSTP1, and GSTM1 SNPs revealed a tentative association with their phenotypic expression that is level of antioxidant and cholinergic enzymes. The study concludes that chronic OPs exposure induces oxidative stress which is associated with the related SNP polymorphism. The toxicogenetics of understudied SNPs were examined for the first time to our understanding. The findings may lead to a newer area of investigation on OPs induced health issues and toxicogenetics. Full article

Silent information regulator 1 and 2 (SIRT1, 2) were NAD+-dependent histone or non-histone deacetylase, which emerged as key metabolic sensors in several tissues of mammals. In the present study, the search for polymorphisms within the ovine SIRT1 and SIRT2 loci as well as association analyses between SNPs and growth-related traits were performed in Tibetan sheep. To determine the expression pattern of SIRT1 and SIRT2 genes in Tibetan sheep, the quantitative real-time polymerase chain reaction (qPCR) analysis revealed that those two genes were widely expressed in diverse tissues. Expression of SIRT1 was less in abomasum of lamb, whereas it was greater in duodenum within adult stage. In the case of SIRT2, the greatest expression was observed in reticulum (lamb) and in muscle (adult), whereas the least expression was in liver for lamb and in kidney for adult animals. The association analysis demonstrated that g.3148 C > T polymorphism of SIRT1 affected heart girth (p = 0.002). The g.8074 T > A SNP of SIRT2 had a significant correlation with body weight (p = 0.011) and body length (p = 0.008). These findings suggested that the SIRT1 and SIRT2 polymorphism was involved in growth-related traits in Tibetan sheep, which may be considered to be genetic markers for improving the growth traits of Tibetan sheep. Full article

Nicotinamide phosphoribosyltransferase (NAMPT) has crucial roles for myocardial development, cardiomyocyte energy metabolism and cell death/survival by regulating NAD⁺-dependent sirtuin-1 (SIRT1) deacetylase. This study aimed to determine if the single nucleotide polymorphisms (SNPs) of the NAMPT gene may affect the susceptibility and prognosis for patients with dilated cardiomyopathy (DCM) and to describe the association of serum NAMPT levels with clinical features of DCM. Three SNPs (rs61330082, rs2505568, and rs9034) were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method in a case-control study of 394 DCM patients and 395 controls from China. Serum NAMPT levels were measured by enzyme-linked immunosorbent assay kits. The homozygote for the minor allele at rs2505568 and rs9034 could not be detected in this study. Rs9034 T allele and CT genotype were associated with increased DCM risk (OR: 1.63, 95% CI = 1.16–2.27, p = 0.005 and OR: 1.72, 95% CI = 1.20–2.50, p = 0.0027, respectively). Nominally significant decreased DCM risk was found to be associated with the A allele and AT genotype of rs2505568 (OR: 0.48, 95% CI = 0.35–0.67, p < 0.0001 and OR: 0.44, 95% CI = 0.31–0.62, p < 0.0001, respectively), but it should be interpreted with caution because of Hardy-Weinberg disequilibrium in the control group. Of five haplotypes constructed, TAC (rs61330082-rs2505568-rs9034) was a protective haplotype to DCM (OR: 0.22, 95% CI = 0.13–0.39, p = 1.84 × 10⁻⁸). The Cox multivariate survival analysis indicated that the rs9034 CT genotype (hazard ratio (HR): 0.59, 95% CI = 0.37–0.96, p = 0.03) was an independently multivariate predictor for longer overall survival in DCM patients. Serum NAMPT levels were significantly higher in the DCM group than controls (p < 0.0001) and gradually increased with the increase of New York Heart Association grade in DCM patients. However, there was a lack of association of the three SNPs with serum NAMPT levels. Spearman correlation test revealed that the NAMPT level was positively associated with brain natriuretic peptide (r = 0.56, p = 0.001), left ventricular end-diastolic diameter (r = 0.293, p = 0.011) and left ventricular end-diastolic volume (r = 0.294, p = 0.011). Our study suggested that NAMPT may play an important role in the development of DCM. Full article