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Streptococcus suis serotypes 2 and 14 are the most common zoonotic strains, but previous identification methods made distinguish these two serotypes from other S. suis serotypes difficult. To effectively prevent and control them, there is an urgent need for a highly sensitive and specific method to identify these two serotypes. In this study, a fluorescent probe was designed for the single nucleotide polymorphism site at cpsK 483 of Streptococcus suis type 2 and type 14 compared with other serotypes, and an enzyme-activated probe quantitative PCR (EA-probe qPCR) method was established for the detection of Streptococcus suis type 2 and type 14 by combining with the specific hydrolysis characteristics of the RNase H2 enzyme. The results showed that the optimal probe concentration for this method was 0.5 µM and the optimal RNase H2 enzyme concentration was 25 mU.This method showed no reactivity with genomic DNA from Streptococcus suis strains 1/2, 5, 7, 9, 23, 28, 29, and 31, confirming its high specificity. And its sensitivity can reach 18.4 CFU. In addition, 19 clinical strains of Streptococcus suis type 2 or type 1/2 were tested. The results showed 100% agreement with the gene sequencing method. In conclusion, this method can meet the needs of accurate laboratory testing of Streptococcus suis serotypes 2 and 14 and has value for clinical prevention. [ABSTRACT FROM AUTHOR]

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture. Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly. Genetic diagnoses are made in ∼30% of people with CDH, but the rest of the cases remain unexplained. We identified rare variants in novel genes and common variants in two loci that support a polygenic model for CDH genetic architecture. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have provided strong evidence that early- and late-onset MG have different genetic backgrounds. Recent in silico analysis based on GWAS results revealed rs231735 and rs231770 variants within CTLA-4 locus as possible MG causative genetic factors. We aimed to explore the association of rs231735 and rs231770 with MG in a representative cohort of Serbian patients. We conducted an age-, sex-, and ethnicity-matched case–control study. Using TaqMan allele discrimination assays, the frequency of rs231735 and rs231770 genetic variants was examined in 447 AChR-MG patients and 447 matched controls. There was no significant association of rs231735 and rs231770 with the entire MG cohort (P > 0.05). Nevertheless, when stratifying patients into early-onset (n = 183) and late-onset MG (n = 264), we found early-onset patients had a significantly lower frequency of the rs231735 allele T compared to controls (OR = 0.734, 95% CI = 0.575–0.938, p10e6 permutation < 0.05), and rs231735 genotype TT and rs231770 genotype TT had a protective effect on early-onset MG (OR = 0.548, 95% CI = 0.339–0.888, and OR = 0.563, 95% CI = 0.314–1.011, p10e6 permutation < 0.05). Consequently, we found that individuals with the rs231735-rs231770 haplotype GC had a higher risk for developing early-onset MG (OR = 1.360, P = 0.027, p10e6 permutation < 0.05). Our results suggest that CTLA-4 rs231735 and rs231770 may be risk factors only for patients with early-onset MG in Serbian population. [ABSTRACT FROM AUTHOR]

Background: T cell exhaustion is a state in which T cells become dysfunctional and is associated with a decreased efficacy of immune checkpoint inhibitors. Lung cancer has the highest mortality among all cancers. However, the roles of genetic variants of the T cell exhaustion-related genes in the prognosis of non-small cell lung cancer (NSCLC) patients has not been reported. Methods: We conducted a two-stage multivariable Cox proportional hazards regression analysis with two previous genome-wide association study (GWAS) datasets to explore associations between genetic variants in the T cell exhaustion-related genes and survival of NSCLC patients. We also performed expression quantitative trait loci analysis for functional validation of the identified variants. Results: Of all the 52,103 single nucleotide polymorphisms (SNPs) in 672 T cell exhaustion-related genes, 1,721 SNPs were found to be associated with overall survival (OS) of 1185 NSCLC patients of the discovery GWAS dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and 125 of these 1,721 SNPs remained significant after validation in an additional independent replication GWAS dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. In multivariable stepwise Cox model analysis, three independent SNPs (i.e., LRRC8C rs10493829 T>C, OAS2 rs2239193 A>G, and CCL25 rs3136651 T>A) remained significantly associated with OS with hazards ratios (HRs) of 0.86 (95% confidence interval (CI) = 0.77-0.96, P = 0.008), 1.48 (95% CI = 1.18-1.85, P < 0.0001) and 0.78 (95% CI = 0.66-0.91, P = 0.002), respectively. Further combined analysis for these three SNPs suggested that an unfavorable genotype score was associated with a poor OS and disease-specific survival. Expression quantitative trait loci analysis suggested that the LRRC8C rs10493829 C allele was associated with elevated LRRC8C mRNA expression levels in normal lymphoblastoid cells, lung tissue, and whole blood. Conclusion: Our findings suggested that these functional SNPs in the T cell exhaustion-related genes may be prognostic predictors for survival of NSCLC patients, possibly via a mechanism of modulating corresponding gene expression. [ABSTRACT FROM AUTHOR]

Background: Premature myocardial infarction (PMI) is one of the most pressing global issues in modern cardiology. Recently, the incidence of PMI has gradually increased. Researches found that genetics is a major contributor in its development. SIRT1, an extremely conserved class III NAD-dependent deacetylase, has been linked to numerous cardiovascular disorders and engaged in a number of cellular functions. This work investigated the association between SIRT1 SNP rs7069102 in Egyptian patients ≤ 40 years old with premature ST-elevation Myocardial infarction (STEMI). Methods: This cross sectional, single-center study included patients younger than 40 with STEMI (PMI group, n = 140) and a control group (n = 140) of healthy subjects of comparable age. In addition to clinical examination and standard tests, all participants underwent echocardiography, coronary angiography, SIRT1 (rs7069102) genotyping, and nitric oxide assay. Results: The risk for PMI was increased in CG or CC genotype carriers of SIRT1 gene rs7069102 (OR: 3.93, 95% Cl: 2.25–6.86), as did carriers of the C allele (OR: 2.26, 95% Cl: 1.65–3.86). In the PMI group, endothelial nitric oxide synthase (eNOS) was significantly decreased; whereas, neuronal nitric oxide synthase (nNOS) was significantly increased. Conclusions: SIRT1 single-nucleotide polymorphism (rs7069102) may confer an increased risk for PMI in young Egyptian patients with affecting endothelial nitric oxide synthase protein expressions. Traditional cardiovascular risk factors are prevalent in patients with PMI, with dietary behaviors, obesity, diabetes and dyslipidemia serving as independent risk factors for PMI. Clinical trial registration number: NCT05160844. [ABSTRACT FROM AUTHOR]

This study investigated the potential role of specific single-nucleotide polymorphisms (SNPs) in the genes Astrotactin 1 (ASTN1), EBF Transcription Factor 1 (EBF1), Eukaryotic Elongation Factor, Selenocysteine-tRNA Specific (EEFSEC), Microtubule-Associated Serine/Threonine Kinase 1 (MAST1), and Tumor Necrosis Factor Alpha (TNF-α) to assess whether these genetic variants contribute to the risk of spontaneous preterm birth (sPTB). A case-control study was conducted involving 573 women from Croatia and Slovenia: 248 with sporadic sPTB (positive personal and negative family history of sPTB before 37 weeks' gestation), 44 with familial sPTB (positive personal and family history of sPTB before 37 weeks' gestation), and 281 control women. The analysis of ASTN1 rs146756455, EBF1 rs2963463, EBF1 rs2946169, EEFSEC rs201450565, MAST1 rs188343966, and TNF-α rs1800629 SNPs was performed using TaqMan real-time PCR. p-values were Bonferroni-adjusted for multiple comparisons. EBF1 SNP rs2963463 was significantly associated with sPTB (p adj = 0.03). Women carrying the CC genotype had a 3–4-times lower risk of sPTB (p adj < 0.0001). In addition, a significant difference in the frequency of the minor C allele was observed when comparing familial sPTB cases with controls (p adj < 0.0001). All other associations were based on unadjusted p-values. The minor T allele of EBF1 SNP rs2946169 was more frequent in sPTB cases overall than in controls, especially in sporadic sPTB (p = 0.045). Similarly, the CC genotype of ASTN1 SNP rs146756455 was more frequent in sporadic sPTB cases compared to controls (p = 0.019). Finally, the TNF-α SNP rs1800629 minor A allele and AA genotype were more common in the familial sPTB group compared to sporadic sPTB and controls (p < 0.05). The EBF1 SNP rs2963463 polymorphism showed a protective effect in the pathogenesis of sPTB, particularly in women carrying the CC genotype. Moreover, EBF1 SNP rs2946169 and ASTN1 SNP rs146756455, as well as TNF-α SNP rs1800629, were associated with an increased risk of sPTB, representing suggestive potential risk factors for sporadic and familial sPTB, respectively. [ABSTRACT FROM AUTHOR]

Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single‐nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV‐SNPs and 133,615 CoRSIV‐mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10−5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan‐meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association. [ABSTRACT FROM AUTHOR]

Aim: Environmental features can act as selection pressures and barriers to gene flow between populations. The genetic structuring of highly mobile but philopatric seabirds creates a paradox, and the role of oceanographic and geographic variables is still poorly understood. In this study, we investigate the influence of environmental and geographic variables in the genetic and phenotypic diversity of a pantropical seabird breeding in islands and archipelagos separated by different geographic distances, up to thousand kilometres, and which differ in environmental characteristics. Location: Islands and archipelagos in the southwestern (SW) Atlantic Ocean. Taxon: Sula dactylatra, Lesson, 1831 (masked booby). Methods: The population structure of the species was accessed through mitochondrial and nuclear DNA. To test Isolation by Environment (IBE) versus by Distance (IBD), sea surface temperature, primary productivity and salinity, as well as isotopic niche based on carbon and nitrogen, and distances between colonies and from the continent, were used. We also tested the correlation between the genetic structure and the morphometry of individuals in each colony. Results: We uncover the presence of low genetic structure between populations. Nevertheless, differences were identified between inshore and offshore colonies, with the influence of landscape characteristics of these two types of environment. The morphometric and isotopic niche variations are consistent with this segregation. Main Conclusions: Environmental variables of coastal and oceanic environments seem to influence the genetic structure of masked boobies, even though it is low in the SW Atlantic Ocean, highlighting the role of environmental heterogeneity in shaping biodiversity. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) is a pathogen that is common worldwide and is often present in individuals infected with human immunodeficiency virus (HIV). Pattern recognition receptors (PRRs) are host sensors that activate the immune response against infectious agents. However, it is unclear whether PRR single-nucleotide polymorphisms (SNPs) are associated with the occurrence of CMV DNAemia in subjects coinfected with HIV and CMV. HIV/CMV-coinfected patients with and without CMV DNAemia were recruited for this study. The DDX58 rs10813831 and IFIH1 (rs3747517 and rs1990760) polymorphisms were genotyped using the TaqMan Allelic Discrimination Assay, whereas the DDX58 rs12006123 and TLR3 (rs3775291 and rs3775296) SNPs were analyzed using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. A mutation present in at least one allele of the DDX58 rs12006123 SNP occurred at least two times more frequently in HIV/CMV-coinfected patients with CMV DNAemia than in coinfected subjects without CMV DNAemia (OR, 2.50; 95% CI, 1.33–4.68; p = 0.004, in the dominant model). A higher level of CMV DNAemia was observed in subjects who had the heterozygous (GA) or homozygous recessive (AA) genotype for the DDX58 rs12006123 SNP compared with those who had the wild-type (GG) genotype (p = 0.0003). Moreover, in subjects with a mutation detected in at least one allele of the DDX58 rs12006123 SNP, a lower serum IFN-β concentration was found compared with those who had a wild-type (GG) genotype for this polymorphism (p = 0.024). The DDX58 rs12006123 SNP is associated with CMV DNAemia in HIV/CMV-coinfected patients. [ABSTRACT FROM AUTHOR]

Background and Aim: This study aimed to clarify whether several single‐nucleotide polymorphisms (SNPs)‐related chronic pancreatitis such as carboxypeptidase A1 (CPA1), carboxypeptidase B1 (CPB1), Gamma‐glutamyltransferase 1 (GGT1), G‐protein‐coupled receptor Class C Group 6 Member A (GPRC6A), and serine protease inhibitor, Kazal type 1 (SPINK‐1) genotypes were associated with clinical characteristics of patients with intraductal papillary mucinous neoplasm (IPMN) and worrisome features of IPMN. Methods: We enrolled 100 patients with IPMN and 116 patients as a control. Serum p‐amylase, lipase, trypsin, phospholipase A2 (PLA2), and elastase‐1 levels were measured. An Olympus EUS (GF‐UCT 260) was used to perform endosonography in 100 patients with IPMN. Total EUS score was evaluated using endosonography. DNA was isolated from the duodenal tissue using a commercial system and polymerase chain reaction (PCR) was performed on 7500 Fast PCR System. Results: There were no associations between glucose tolerances, lipid levels and genotypes of CPA1, GGT1, GPRC6A, and SPINK‐1 in patients with IPMN. CPA1 genotype was significantly associated with the pathophysiology of IPMN. Then, GGT1 genotype was also significantly associated with EUS total score and the size of cyst more than 20 mm and more than 30 mm as one of worrisome features of IPMN. Conclusion: Genotypes of carboxypeptidase A1 and gamma‐glutamyltransferase 1 may be useful tools for the diagnosis and the predictor of worrisome features of IPMN. [ABSTRACT FROM AUTHOR]

BACKGROUND: Osteonecrosis due to drugs is a serious adverse reaction occurring after the application of such drugs. Increasing evidence suggests that the gut microbiota composition is associated with osteonecrosis due to drugs. However, the causal relationship of the gut microbiota to osteonecrosis due to drugs is still unclear. OBJECTIVE: To evaluate the potential causal relationship between the gut microbiota and the risk of osteonecrosis due to drugs using the Mendelian randomization method. METHODS: A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genomewide association study meta-analysis (n=13 266) conducted by the MiBioGen consortium as well as the summary statistics of osteonecrosis due to drugs obtained from the FinnGen consortium R9 release data (264 cases and 377 013 controls). Inverse variance weighted, MR-Egger, weighted median, weighted model and simple model were used to examine the causal association between gut microbiota and osteonecrosis due to drugs. Sensitivity analysis was used to test whether the results of the Mendelian randomization analysis were reliable. Reverse Mendelian randomization analysis was performed on all the bacteria as an outcome for effect analysis and sensitivity analysis. RESULTS AND CONCLUSION: Inverse variance weighted estimates suggested that Lentisphaerae (phylum), Lentisphaeria (class), Melainabacteria (class), Gastranaerophilales (order), Rhodospirillales (order), Victivallales (order) and Bifidobacterium (genus) had protective causal effects on osteonecrosis due to drugs. Methanobacteria (class), Bacillales (order), Methanobacteriaceae (family), Lachnospiraceae (family), Methanobacteriales (order), Holdemania (genus), Holdemania (UCG010 group) (genus), Odoribacter (genus) and Tyzzerella3 (genus) had negative causal effects on osteonecrosis due to drugs. According to the results of reverse Mendelian randomization analysis, Clostridiaceae1 (family), Peptostreptococcaceae (family), Streptococcaceae (family), Clostridiumsensustricto1 (genus) and Streptococcus (genus) showed negative causal effects on osteonecrosis due to drugs. However, Eisenbergiella (genus) showed protective causal effects on osteonecrosis due to drugs. None of the bidirectional sensitivity analysis revealed heterogeneity or horizontal pleiotropy. When gut microbiota were used as exposure and osteonecrosis due to drugs as the outcome, Mendelian randomization analysis found that seven bacterial traits were positively correlated to osteonecrosis due to drugs, nine bacterial traits were negatively related to osteonecrosis due to drugs. When osteonecrosis due to drugs were used as exposure and gut microbiota as the outcome, reverse Mendelian randomization analysis found a negative correlated relationship with five bacterial traits and a positive causal relationship with one bacterial trait. By changing the diversity and composition of gut microbiota, it is expected to improve the incidence and prognosis of osteonecrosis due to drugs, providing new ideas for the study of orthopedic diseases. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is the most significant inherited risk factor for coronary heart disease (CHD). Current guidelines focus on monogenic FH, but the polygenic form is more common and less understood. This study aimed to assess the clinical utility of an 8-SNP LDLC polygenic score in a central Romanian cohort. The cohort included 97 healthy controls and 125 patients with premature (P)CHD. The weighted LDLC polygenic risk score (wPRS) was analyzed for associations with relevant phenotypic traits, PCHD risk, and clinical FH diagnosis. The wPRS positively correlated with LDLC and DLCN scores, and LDLC concentrations could be predicted by wPRS. A trend of increasing LDLC and DLCN scores with wPRS deciles was observed. A +1 SD increase in wPRS was associated with a 36% higher likelihood of having LDLC > 190 mg/dL and increases in LDLC (+0.20 SD), DLCN score (+0.16 SD), and BMI (+0.15 SD), as well as a decrease in HDLC (−0.14 SD). Although wPRS did not predict PCHD across the entire spectrum of values, individuals above the 90th percentile were three times more likely to have PCHD compared to those within the 10th or 20th percentiles. Additionally, wPRS > 45th percentile identified "definite" clinical FH (DLCN score > 8) with 100% sensitivity and 45% specificity. The LDLC polygenic score correlates with key phenotypic traits, and individuals with high scores are more likely to have PCHD. Implementing this genetic tool may enhance risk prediction and patient stratification. These findings, the first of their kind in Romania, are consistent with the existing literature. [ABSTRACT FROM AUTHOR]

Introduction: Autism spectrum disorders (ASD) represent a heterogeneous group of neurodevelopmental disorders with strong genetic predispositions. Although an increasing number of genetic variants have been implicated in the pathogenesis of ASD, little is known about the relationship between ASDassociated genetic variants and individual ASD traits. Therefore, we aimed to investigate these relationships. Methods: Here, we report a case-control association study of 32 Japanese children with ASD (mainly with high-functioning autism [HFA]) and 36 with typical development (TD). We explored previously established ASD-associated genes using a next-generation sequencing panel and determined the association between Social Responsiveness Scale (SRS) T-scores and intelligence quotient (IQ) scores. Results: In the genotype-phenotype analyses, 40 variants of five genes (SCN1A, SHANK3, DYRK1A, CADPS, and SCN2A) were associated with ASD/TD phenotypes. In particular, 10 SCN1A variants passed permutation filtering (false discovery rate <0.05). In the quantitative association analyses, 49 variants of 12 genes (CHD8, SCN1A, SLC6A1, KMT5B, CNTNAP2, KCNQ3, SCN2A, ARID1B, SHANK3, DYRK1A, FOXP1, and GRIN2B) and 50 variants of 10 genes (DYRK1A, SCN2A, SLC6A1, ARID1B, CNTNAP2, SHANK3, FOXP1, PTEN, SCN1A, and CHD8) were associated with SRS T- and IQ-scores, respectively. Conclusion: Our data suggest that these identified variants are essential for the genetic architecture of HFA. [ABSTRACT FROM AUTHOR]

Background: Differences of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. In more than 50% of human DSD cases, a molecular diagnosis is not available. In intensively farmed pig populations, the incidence of XX DSD pigs is relatively high, leading to economic losses for pig breeders. Interestingly, in the majority of 38, XX DSD pigs, gonads still develop into testis-like structures or ovotestes despite the absence of the testis-determining gene (SRY). However, the current understanding of the molecular background of XX DSD pigs remains limited. Methods: Anatomical and histological characteristics of XX DSD pigs were analysed using necropsy and HE staining. We employed whole-genome sequencing (WGS) with 10× Genomics technology and used de novo assembly methodology to study normal female and XX DSD pigs. Finally, the identified variants were validated in 32 XX DSD pigs, and the expression levels of the candidate variants in the gonads of XX DSD pigs were further examined. Results: XX DSD pigs are characterised by the intersex reproductive organs and the absence of germ cells in the seminiferous tubules of the gonads. We identified 4,950 single-nucleotide polymorphisms (SNPs) from non-synonymous mutations in XX DSD pigs. Cohort validation results highlighted two specific SNPs, "c.218T > C" in the "Interferon-induced transmembrane protein 1 gene (IFITM1)" and "c.1043C > G" in the "Newborn ovary homeobox gene (NOBOX)", which were found exclusively in XX DSD pigs. Moreover, we verified 14 candidate structural variants (SVs) from 1,474 SVs, identifying a 70 bp deletion fragment in intron 5 of the WW domain-containing oxidoreductase gene (WWOX) in 62.5% of XX DSD pigs. The expression levels of these three candidate genes in the gonads of XX DSD pigs were significantly different from those of normal female pigs. Conclusion: The nucleotide changes of IFITM1 (c.218T > C), NOBOX (c.1043 C > G), and a 70 bp deletion fragment of the WWOX were the most dominant variants among XX DSD pigs. This study provides a theoretical basis for better understanding the molecular background of XX DSD pigs. Plain language summary: DSD are conditions affecting development of the gonads or genitalia. These disorders can happen in many different types of animals, including pigs, goats, dogs, and people. In people, DSD happens in about 0.02–0.13% of births, and in pigs, the rate is between 0.08% and 0.75%. Pigs have a common type of DSD where the animal has female chromosomes (38, XX) but no SRY gene, which is usually found on the Y chromosome in males. XX DSD pigs may look like both males and females on the outside and have testis-like or ovotestis (a mix of ovary and testis) gonads inside. XX DSD pigs often lead to not being able to have piglets, slower growth, lower chance of survival, and poorer meat quality. Here, we used a method called whole-genome de novo sequencing to look for variants in the DNA of XX DSD pigs. We then checked these differences in a larger group of pigs. Our results reveal the nucleotide changes in IFITM1 (c.218T > C), NOBOX (c.1043 C > G), and a 70 bp deletion fragment in intron 5 of the WWOX, all linked to XX DSD pigs. The expression levels of these three genes were also different in the gonads of XX DSD pigs compared to normal female pigs. These variants are expected to serve as valuable molecular markers for XX DSD pigs. Because pigs are a lot like humans in their genes, physiology, and body structure, this research could help us learn more about what causes DSD in people. Highlights: XX DSD pigs have abnormal development of reproductive organs showing both male and female characteristics and lack of germ cells in the seminiferous tubules. Whole-genome de novo sequencing was used to reveal the characteristics of genomic variants in XX DSD pigs. The nucleotide changes of IFITM1 (c.218T > C), NOBOX (c.1043 C > G), and a 70 bp deletion fragment of WWOX were the dominant variants in XX DSD pigs, and these three genes were significantly changed in the gonadal expression levels of the XX DSD pigs compared to those of normal females. [ABSTRACT FROM AUTHOR]

Aim: Abundant data are available on the effect of the A118G (rs1799971) single‐nucleotide polymorphism (SNP) of the μ‐opioid receptor OPRM1 gene on morphine and fentanyl requirements for pain control. However, data on the effect of this SNP on intraoperative remifentanil requirements remain limited. We investigated the effect of this SNP on intraoperative remifentanil requirements. Methods: We investigated 333 Japanese women, aged 21–69 years, who underwent laparoscopic gynecological surgery for benign gynecological disease under total intravenous anesthesia at Juntendo University Hospital. Average infusion rates of propofol and remifentanil during anesthesia and the average bispectral index (BIS) during surgery were recorded. Associations among genotypes of the A118G and phenotypes were examined with the Mann–Whitney U test. Results: The average propofol infusion rate was not different between patients with different genotypes. The average remifentanil infusion rate was significantly higher in patients with the AG or GG genotype than the AA genotype (p = 0.028). The average intraoperative BIS was significantly higher in patients with the GG genotype than the AA or AG genotype (p = 0.039). Conclusions: The G allele of the A118G SNP was associated with higher intraoperative remifentanil requirements and higher intraoperative BIS values but was not associated with propofol requirements. Given that remifentanil and propofol act synergistically on the BIS, these results suggest that the G allele of the A118G SNP is associated with lower effects of remifentanil in achieving adequate intraoperative analgesia and in potentiating the sedative effect of propofol on the BIS. [ABSTRACT FROM AUTHOR]

This review deals with the functional characteristics and biological roles of enzymes participating in DNA methylation and demethylation as key factors in epigenetic regulation of gene expression. The set of enzymes that carry out such processes in human cells is limited to representatives of two families, namely DNMT (DNA methyltransferases) and TET (DNA dioxygenases). The review presents detailed information known today about each functionally important member of these families and describes the catalytic activity and roles in the mammalian body while also providing examples of dysregulation of the expression and/or activity of these enzymes in conjunction with the development of some human disorders, including cancers, neurodegenerative diseases, and developmental pathologies. By combining the up-to-date information on the dysfunction of various enzymes that control the DNA "methylome" in the human body, we hope not only to draw attention to the importance of the maintenance of a required DNA methylation level (ensuring epigenetic regulation of gene expression and normal functioning of the entire body) but also to help identify new targets for directed control over the activity of the enzymes that implement the balance between processes of DNA methylation and demethylation. [ABSTRACT FROM AUTHOR]

Background: Periodontitis is a complex disease, and bacterial factors play a crucial role in its initiation. The contributions of genetic and epigenetic factors to the pathogenesis of periodontal disease are increasingly recognized. Single-nucleotide polymorphisms (SNPs) in various molecules, including cytokines, are of particular interest due to their established involvement in numerous diseases. This study investigates the influence of SNPs in the IL-10 gene at positions −592 (rs1800872) C>A and −1082 (rs1800896) T>C (also referred to as 1082A>G) on the severity of periodontitis in a cohort of Bulgarian patients. Methods: In the recent study, both clinical and paraclinical methodologies were employed to comprehensively assess the periodontal status of the participants. The genotypic characterization of IL-10 polymorphisms was performed by PCR RFLP analysis. Statistical analyses, including principal component analysis (PCA), were executed utilizing IBM SPSS Statistics Version 21. Results: We have established a statistically significant association between the presence of at least one A-allele in the patients' genotype and the incidence of severe periodontitis (p = 0.047). Conclusions: IL-10 single-nucleotide polymorphisms (SNPs) could be effectively considered as biomarkers for the severity of periodontitis. [ABSTRACT FROM AUTHOR]

In mink breeding, balanced selection for growth and reproductive features is essential because these traits are contradictory. The variables of total number born (TNB), number born alive (NBA), and body weight (BW) are highly valuable in terms of their importance in mink production. A comprehensive understanding of the molecular mechanisms that drive these features could offer vital insights into their genetic compositions. In the present study, the single-nucleotide polymorphism (SNP) genotypes of 219 minks were obtained via double digest restriction-site associated DNA sequencing (ddRAD-seq). Following several rounds of screening, about 2,415,121 high-quality SNPs were selected for a genome-wide association study (GWAS). The GWAS was used to determine BW and reproductive traits in pink-eyed white mink. It was suggested that SLC26A36, STXBP5L, and RPS 29 serve as potential genes for the total number of kits born (TNB), while FSCB, PDPN, NKX 2-1, NFKB 1, NFKBIA, and GABBR1 are key genes for the number born alive (NBA). Moreover, RTTN, PRPF31, MACROD1, and KYAT1 are possible BW genes based on association results and available functional data from gene and mammalian phenotype databases. These results offer essential information about the variety of mink and theoretical principles for applying mink breeds. [ABSTRACT FROM AUTHOR]

The methylenetetrahydrofolate reductase (MTHFR) gene 677C➔T polymorphism is capable of altering folate metabolism and can modify certain neoplasia risk. Reports have suggested that folate can have an influence on bone development and so it is of interest to know if the MTHFR 677C➔T polymorphism is associated with the malignant transformation process of this tissue. The polymorphism was determined in 55 patients with osteosarcoma and in 180 healthy individuals. Compared with C/T+C/C genotypes, a 3.7-fold reduction in osteosarcoma probability is possible with the T/T genotype (OR 0.27, CI 95% 0.07–0.82). Undoubtedly, further studies, utilizing large samples and carried out on different populations, are necessary to confirm these results. [ABSTRACT FROM AUTHOR]

Background and Aims: Various inflammatory and immune cytokines play key roles in the progression of hepatitis B virus (HBV)‐related liver cirrhosis (LC). This study explored the relationship between single nucleotide polymorphisms (SNPs) in cytokines with the combined effect of polymorphisms and gender‐polymorphisms interaction and LC risk. Methods: In this study, a case–control design was used, samples were selected from 45 patients with hepatitis B‐related cirrhosis and 45 age‐gender‐matched chronic HBV‐infected patients without cirrhosis attending the tumor hospital of Wuwei Academy of Medical Sciences. Fifteen SNPs were examined using a real‐time polymerase chain reaction allelic discrimination system. Logistic regression was utilized to assess cytokine‐associated SNPs and the association between SNPs and LC progression in HBV‐infected patients. Results: The multivariate‐adjusted logistic model revealed that the GG/AG dominant model (OR, 16.38; 95% CI, 1.13–236.70) and G allele (OR, 5.93; 95% CI, 0.98–36.01) of rs1800896 were associated with an increased risk of cirrhosis in CHB patients. Instead, rs2227306 CT presented a reduced cirrhosis risk (OR, 0.22; 95% CI, 0.04–1.38). Rs2055979 AA/AC was negatively associated with the risk of cirrhosis, potentially reversed in males (p = 0.021). Rs1799964 CC/CT was positively related to the risk of cirrhosis but reduced the risk of cirrhosis in males (OR, 0.13; 95% CI, 0.022–0.808; p = 0.028). Both rs1799964 TT and rs1799724 CT/TT genotype showed a synergistic effect in reducing the risk of cirrhosis with rs1800896 AA (OR, 0.08; 95% CI, 0.01–1.43 and OR, 0.12; 95% CI, 0.01–2.21). Conclusion: Polymorphisms rs1800896 and rs2227306 are potentially associated with the risk of cirrhosis. For the first time, the study highlights that the rs2055979 AA/AC and rs1799964 CC/CT polymorphism interact with gender and its potential reversal of cirrhosis risk in males. Furthermore, rs1800896 AA showed a synergistic effect with rs1799964 TT and rs1799724 CT/TT to prevent the progression of HBV infection to cirrhosis. [ABSTRACT FROM AUTHOR]

Investigative genetic genealogy (IGG) has emerged as a highly effective tool for tying a forensic DNA sample to an identity. While much of the attention paid to IGG has focused on cases where the DNA is from an unknown suspect, IGG has also been used to help close hundreds of unidentified human remains (UHR) cases. Genome‐wide single‐nucleotide polymorphism (SNP) genotype data can be obtained from forensic samples using microarray genotyping or whole‐genome sequencing (WGS) with protocols optimized for degraded DNA. After bioinformatic processing, the SNP data can be uploaded to public GG databases that allow law enforcement usage, where it can be compared with other users' data to find distant relatives. A genetic genealogist can then build the family trees of the relatives to narrow down the identity of the source of the forensic DNA sample. To date, 367 UHR identifications using IGG have been publicly announced. The same IGG techniques developed and refined for UHR cases have significant potential for disaster victim identification, where DNA is often extremely compromised, and close family references may not be available. This paper reviews the laboratory, bioinformatic, and genealogical techniques used in IGG for UHR cases and presents three case studies that demonstrate how IGG is assisting with remains identification. [ABSTRACT FROM AUTHOR]

Summary: Tomato (Solanum lycopersicum) stands as one of the most valuable vegetable crops globally, and fruit firmness significantly impacts storage and transportation. To identify genes governing tomato firmness, we scrutinized the firmness of 266 accessions from core collections. Our study pinpointed an ethylene receptor gene, SlEIN4, located on chromosome 4 through a genome‐wide association study (GWAS) of fruit firmness in the 266 tomato core accessions. A single‐nucleotide polymorphism (SNP) (A → G) of SlEIN4 distinguished lower (AA) and higher (GG) fruit firmness genotypes. Through experiments, we observed that overexpression of SlEIN4AA significantly delayed tomato fruit ripening and dramatically reduced fruit firmness at the red ripe stage compared with the control. Conversely, gene editing of SlEIN4AA with CRISPR/Cas9 notably accelerated fruit ripening and significantly increased fruit firmness at the red ripe stage compared with the control. Further investigations revealed that fruit firmness is associated with alterations in the microstructure of the fruit pericarp. Additionally, SlEIN4AA positively regulates pectinase activity. The transient transformation assay verified that the SNP (A → G) on SlEIN4 caused different genetic effects, as overexpression of SlEIN4GG increased fruit firmness. Moreover, SlEIN4 exerts a negative regulatory role in tomato ripening by impacting ethylene evolution through the abundant expression of ethylene pathway regulatory genes. This study presents the first evidence of the role of ethylene receptor genes in regulating fruit firmness. These significant findings will facilitate the effective utilization of firmness and ripening traits in tomato improvement, offering promising opportunities for enhancing tomato storage and transportation capabilities. [ABSTRACT FROM AUTHOR]

Stripe rust is a serious wheat disease occurring worldwide. At present, the most effective way to control it is to grow resistant cultivars. In this study, a population of 221 recombinant inbred lines (RILs) derived via single-seed descent from a hybrid of a susceptible wheat line, SY95-71, and a resistant line, XK502, was tested in three crop seasons from 2022 to 2024 in five environments. A genetic linkage map was constructed using 12,577 single-nucleotide polymorphisms (SNPs). Based on the phenotypic data of infection severity and the linkage map, five quantitative trait loci (QTL) for adult plant resistance (APR) were detected using the inclusive composite interval mapping (ICIM) method. These five loci are QYrxk502.swust-1BL, QYrxk502.swust-2BL, QYrxk502.swust-3AS, QYrxk502.swust-3BS, and QYrxk502.swust-7BS, explaining 5.67–19.64%, 9.63–36.74%, 9.58–11.30%, 9.76–23.98%, and 8.02–12.41% of the phenotypic variation, respectively. All these QTL originated from the resistant parent XK502. By comparison with the locations of known stripe rust resistance genes, three of the detected QTL, QYrxk502.swust-3AS, QYrxk502.swust-3BS, and QYrxk502.swust-7BS, may harbor new, unidentified genes. From among the tested RILs, 16 lines were selected with good field stripe rust resistance and acceptable agronomic traits for inclusion in breeding programs. [ABSTRACT FROM AUTHOR]

Aim: MIR137 host gene (MIR137HG) variants were involved in a variety of diseases, but its role in high-altitude pulmonary edema (HAPE) has not been reported. The study aimed to study the association between MIR137HG single-nucleotide polymorphisms and HAPE risk in the Chinese population. Materials & methods: Based on the Plink software, odds ratio and 95% confidence interval were used for logistic regression analysis to evaluate the association between MIR137HG polymorphisms and the risk of HAPE. Results: We discovered that MIR137HG rs7554283 was associated with a reduced risk of HAPE. In both individuals older than 32 years and those younger than 32 years, we observed that rs7554283 was associated with a decreased risk of HAPE. Conclusion: In conclusion, MIR137HG rs7554283 may be related to a reduced susceptibility to HAPE in the Chinese population. These results provide a theoretical basis for the role of MIR137HG single-nucleotide polymorphisms in the occurrence of HAPE. Article highlights MIR137 host gene (MIR137HG) variants were involved in a variety of diseases, but its role in high-altitude pulmonary edema (HAPE) has not been reported. The overall analysis showed that MIR137HG rs7554283 was associated with a reduced risk of HAPE. In both individuals older than 32 years and those younger than 32 years, we observed that rs7554283 was associated with a decreased risk of HAPE. In conclusion, MIR137HG rs7554283 may be related to a reduced susceptibility to HAPE in the Chinese population. [ABSTRACT FROM AUTHOR]

Atherosclerosis is one of the major causes of cerebral infarction and many other ischemic cardio-cerebrovascular diseases. Although large randomized clinical trials have highlighted the impressive benefits of lipid-lowering therapies, the 50–70% of patients who have achieved their lipid-lowering goal remain at high cardiovascular disease risk. For this reason, there is a need to investigate other markers of atherosclerosis progression. LOX-1 is a scavenger receptor that accepts oxidized low-density lipoproteins as major ligand and internalizes it by endocytosis favoring its retention in subendothelial layer and triggering a wide variety of proatherogenic events. However, other factors such as cytokines, shear stress, and advanced glycation end-products can upregulate LOX-1. LOX-1 is encoded by the OLR1 gene, located in the p12.3-p13 region of chromosome 12. OLR1 gene has different isoforms induced by splicing, or single-nucleotide polymorphisms (SNPs). According to some authors, the expression of these isoforms induces a different effect on atherosclerosis and cardiovascular disease. In particular, LOXIN, an isoform lacking part of the functional domain, exerts an important role in atherosclerosis protection. In other cases, studies on SNPs showed an association with more severe forms, like in the case of 3'UTR polymorphisms. The knowledge of these variants can give rise to the development of new preventive therapies and can lead to the identification of subjects at greater risk of cardiovascular event. In this review, we reported the state of the art regarding SNPs with known effects on OLR1 splicing and how LOX-1 variants modulate the severity of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: The Jra antigen is a high-prevalence red blood cell (RBC) antigen. Reports on cases of fatal hemolytic disease of the fetus and newborn and acute hemolytic transfusion reactions suggest that antibodies against Jra (anti-Jra) have potential clinical significance. Identifying anti-Jra is challenging owing to a lack of commercially available antisera. We developed an alternative approach to rapidly predict the presence of anti-Jra using the Taq-Man single-nucleotide polymorphism (SNP)-genotyping method. Methods: Residual peripheral blood samples from 10 patients suspected of having the anti-Jra were collected. Two samples with confirmed Jr(a-) RBCs and anti-Jra were used to validate the TaqMan genotyping assay by comparing the genotyping results with direct sequencing. The accuracy of the assay in predicting the presence of anti-Jra was verified through crossmatching with in-house Jr(a-) O+ RBCs. Results: The TaqMan-genotyping method was validated with two Jr(a-) RBC- and anti-Jraconfirmed samples that showed concordant Jra genotyping and direct sequencing results. Jra genotyping for the remaining samples and crossmatching the serum samples with inhouse Jr(a-) O+ RBCs showed consistent results. Conclusions: We validated a rapid, simple, accurate, and cost-effective method for predicting the presence of anti-Jra using a TaqMan-based SNP-genotyping assay. Implementing this method in routine practice in clinical laboratories will assist in solving difficult problems regarding alloantibodies to high-prevalence RBC antigens and ultimately aid in providing safe and timely transfusions and proper patient care. [ABSTRACT FROM AUTHOR]

Abstract Streptococcus suis serotypes 2 and 14 are the most common zoonotic strains, but previous identification methods made distinguish these two serotypes from other S. suis serotypes difficult. To effectively prevent and control them, there is an urgent need for a highly sensitive and specific method to identify these two serotypes. In this study, a fluorescent probe was designed for the single nucleotide polymorphism site at cpsK 483 of Streptococcus suis type 2 and type 14 compared with other serotypes, and an enzyme-activated probe quantitative PCR (EA-probe qPCR) method was established for the detection of Streptococcus suis type 2 and type 14 by combining with the specific hydrolysis characteristics of the RNase H2 enzyme. The results showed that the optimal probe concentration for this method was 0.5 µM and the optimal RNase H2 enzyme concentration was 25 mU.This method showed no reactivity with genomic DNA from Streptococcus suis strains 1/2, 5, 7, 9, 23, 28, 29, and 31, confirming its high specificity. And its sensitivity can reach 18.4 CFU. In addition, 19 clinical strains of Streptococcus suis type 2 or type 1/2 were tested. The results showed 100% agreement with the gene sequencing method. In conclusion, this method can meet the needs of accurate laboratory testing of Streptococcus suis serotypes 2 and 14 and has value for clinical prevention.

Abstract Background Premature myocardial infarction (PMI) is one of the most pressing global issues in modern cardiology. Recently, the incidence of PMI has gradually increased. Researches found that genetics is a major contributor in its development. SIRT1, an extremely conserved class III NAD-dependent deacetylase, has been linked to numerous cardiovascular disorders and engaged in a number of cellular functions. This work investigated the association between SIRT1 SNP rs7069102 in Egyptian patients ≤ 40 years old with premature ST-elevation Myocardial infarction (STEMI). Methods This cross sectional, single-center study included patients younger than 40 with STEMI (PMI group, n = 140) and a control group (n = 140) of healthy subjects of comparable age. In addition to clinical examination and standard tests, all participants underwent echocardiography, coronary angiography, SIRT1 (rs7069102) genotyping, and nitric oxide assay. Results The risk for PMI was increased in CG or CC genotype carriers of SIRT1 gene rs7069102 (OR: 3.93, 95% Cl: 2.25–6.86), as did carriers of the C allele (OR: 2.26, 95% Cl: 1.65–3.86). In the PMI group, endothelial nitric oxide synthase (eNOS) was significantly decreased; whereas, neuronal nitric oxide synthase (nNOS) was significantly increased. Conclusions SIRT1 single-nucleotide polymorphism (rs7069102) may confer an increased risk for PMI in young Egyptian patients with affecting endothelial nitric oxide synthase protein expressions. Traditional cardiovascular risk factors are prevalent in patients with PMI, with dietary behaviors, obesity, diabetes and dyslipidemia serving as independent risk factors for PMI. Clinical trial registration number: NCT05160844.

Abstract In this work, we extend vcfdist to be the first variant call benchmarking tool to jointly evaluate phased single-nucleotide polymorphisms (SNPs), small insertions/deletions (INDELs), and structural variants (SVs) for the whole genome. First, we find that a joint evaluation of small and structural variants uniformly reduces measured errors for SNPs (− 28.9%), INDELs (− 19.3%), and SVs (− 52.4%) across three datasets. vcfdist also corrects a common flaw in phasing evaluations, reducing measured flip errors by over 50%. Lastly, we show that vcfdist is more accurate than previously published works and on par with the newest approaches while providing improved result interpretability.

Abstract Aim Abundant data are available on the effect of the A118G (rs1799971) single‐nucleotide polymorphism (SNP) of the μ‐opioid receptor OPRM1 gene on morphine and fentanyl requirements for pain control. However, data on the effect of this SNP on intraoperative remifentanil requirements remain limited. We investigated the effect of this SNP on intraoperative remifentanil requirements. Methods We investigated 333 Japanese women, aged 21–69 years, who underwent laparoscopic gynecological surgery for benign gynecological disease under total intravenous anesthesia at Juntendo University Hospital. Average infusion rates of propofol and remifentanil during anesthesia and the average bispectral index (BIS) during surgery were recorded. Associations among genotypes of the A118G and phenotypes were examined with the Mann–Whitney U test. Results The average propofol infusion rate was not different between patients with different genotypes. The average remifentanil infusion rate was significantly higher in patients with the AG or GG genotype than the AA genotype (p = 0.028). The average intraoperative BIS was significantly higher in patients with the GG genotype than the AA or AG genotype (p = 0.039). Conclusions The G allele of the A118G SNP was associated with higher intraoperative remifentanil requirements and higher intraoperative BIS values but was not associated with propofol requirements. Given that remifentanil and propofol act synergistically on the BIS, these results suggest that the G allele of the A118G SNP is associated with lower effects of remifentanil in achieving adequate intraoperative analgesia and in potentiating the sedative effect of propofol on the BIS.

Background: Chronic lymphocytic leukemia (CLL) is a malignant clonal proliferative condition of mature CD5+ B cells, with a 4.2/100,000 annual incidence rate and the median age at diagnosis is 72 years. CLL impacts mainly the elderly in Western nations. About 4%–10% of patients have 17p deleted at diagnosis, which includes tumor-suppressor protein (TP53) gene deletions and/or mutations. However, TP53 can also be acquired during the course of the disease, with a predictable incidence of 42%–45% in refractory CLL. Even when this mutation develops in a small percentage of neoplastic cells, the attending of subclonal TP53 changes has been linked to a bad prognosis. TP53 mutations are correlated with significantly lower lifespan and indicate impaired tolerance to chemoimmunotherapy, making them among the most powerful prognostic markers-guiding treatment decisions in CLL. MATERIALS AND METHODS: This cross-sectional study was performed at different centers in Iraq, including Euphrates Center for Cancerous Tumors, Najaf, and the Hematology center-medical City, Baghdad, Imam al Hussien Medical City, Karbala, from October 2023 to June 2024, with patients diagnosed by blood film and immunophenotyping CLL, included 63 patients. Results: DNA Sequencing of TP53 genes investigated by Sanger technique to detect TP53 variations. All potential genotype variations of the TP53 gene were detected across several single-nucleotide polymorphisms (SNPs). Conclusions: The vast majority, 93% of our patients, carry variant-type mutations of TP53. The genotype of SNP rs1597359353 was found P < 0.05, which is significant according to the White blood count (WBCs) count, although all patients on treatment or follow-up had TP53 mutations.

The methylenetetrahydrofolate reductase (MTHFR) gene 677C➔T polymorphism is capable of altering folate metabolism and can modify certain neoplasia risk. Reports have suggested that folate can have an influence on bone development and so it is of interest to know if the MTHFR 677C➔T polymorphism is associated with the malignant transformation process of this tissue. The polymorphism was determined in 55 patients with osteosarcoma and in 180 healthy individuals. Compared with C/T+C/C genotypes, a 3.7-fold reduction in osteosarcoma probability is possible with the T/T genotype (OR 0.27, CI 95% 0.07–0.82). Undoubtedly, further studies, utilizing large samples and carried out on different populations, are necessary to confirm these results.

Alkylating modifications induced by either exogenous chemical agents or endogenous metabolites are some of the main types of damage to DNA, RNA, and proteins in the cell. Although research in recent decades has been almost entirely devoted to the repair of alkyl and in particular methyl DNA damage, more and more data lately suggest that the methylation of RNA bases plays an equally important role in normal functioning and in the development of diseases. Among the most prominent participants in the repair of methylation-induced DNA and RNA damage are human homologs of Escherichia coli AlkB, nonheme Fe(II)/α-ketoglutarate-dependent dioxygenases ABH1–8, and FTO. Moreover, some of these enzymes have been found to act on several protein targets. In this review, we present up-to-date data on specific features of protein structure, substrate specificity, known roles in the organism, and consequences of disfunction of each of the nine human homologs of AlkB. Special attention is given to reports about the effects of natural single-nucleotide polymorphisms on the activity of these enzymes and to potential consequences for carriers of such natural variants.

Abstract Background Differences of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. In more than 50% of human DSD cases, a molecular diagnosis is not available. In intensively farmed pig populations, the incidence of XX DSD pigs is relatively high, leading to economic losses for pig breeders. Interestingly, in the majority of 38, XX DSD pigs, gonads still develop into testis-like structures or ovotestes despite the absence of the testis-determining gene (SRY). However, the current understanding of the molecular background of XX DSD pigs remains limited. Methods Anatomical and histological characteristics of XX DSD pigs were analysed using necropsy and HE staining. We employed whole-genome sequencing (WGS) with 10× Genomics technology and used de novo assembly methodology to study normal female and XX DSD pigs. Finally, the identified variants were validated in 32 XX DSD pigs, and the expression levels of the candidate variants in the gonads of XX DSD pigs were further examined. Results XX DSD pigs are characterised by the intersex reproductive organs and the absence of germ cells in the seminiferous tubules of the gonads. We identified 4,950 single-nucleotide polymorphisms (SNPs) from non-synonymous mutations in XX DSD pigs. Cohort validation results highlighted two specific SNPs, “c.218T > C” in the “Interferon-induced transmembrane protein 1 gene (IFITM1)” and “c.1043C > G” in the “Newborn ovary homeobox gene (NOBOX)”, which were found exclusively in XX DSD pigs. Moreover, we verified 14 candidate structural variants (SVs) from 1,474 SVs, identifying a 70 bp deletion fragment in intron 5 of the WW domain-containing oxidoreductase gene (WWOX) in 62.5% of XX DSD pigs. The expression levels of these three candidate genes in the gonads of XX DSD pigs were significantly different from those of normal female pigs. Conclusion The nucleotide changes of IFITM1 (c.218T > C), NOBOX (c.1043 C > G), and a 70 bp deletion fragment of the WWOX were the most dominant variants among XX DSD pigs. This study provides a theoretical basis for better understanding the molecular background of XX DSD pigs. Plain language summary DSD are conditions affecting development of the gonads or genitalia. These disorders can happen in many different types of animals, including pigs, goats, dogs, and people. In people, DSD happens in about 0.02–0.13% of births, and in pigs, the rate is between 0.08% and 0.75%. Pigs have a common type of DSD where the animal has female chromosomes (38, XX) but no SRY gene, which is usually found on the Y chromosome in males. XX DSD pigs may look like both males and females on the outside and have testis-like or ovotestis (a mix of ovary and testis) gonads inside. XX DSD pigs often lead to not being able to have piglets, slower growth, lower chance of survival, and poorer meat quality. Here, we used a method called whole-genome de novo sequencing to look for variants in the DNA of XX DSD pigs. We then checked these differences in a larger group of pigs. Our results reveal the nucleotide changes in IFITM1 (c.218T > C), NOBOX (c.1043 C > G), and a 70 bp deletion fragment in intron 5 of the WWOX, all linked to XX DSD pigs. The expression levels of these three genes were also different in the gonads of XX DSD pigs compared to normal female pigs. These variants are expected to serve as valuable molecular markers for XX DSD pigs. Because pigs are a lot like humans in their genes, physiology, and body structure, this research could help us learn more about what causes DSD in people.

Previous observational studies have suggested that there appears to be a close association between mitochondrial function and psychiatric disorders, but whether a causal role exists remains unclear. We extracted genetic instruments for 67 mitochondrial-related proteins and 10 psychiatric disorders from publicly available genome-wide association studies, and employed five distinct MR methods and false discovery rate correction to detect causal associations between them. Additionally, we conducted a series of sensitivity tests and additional model analysis to ensure the robustness of the results. For potential causal associations, we further performed reverse MR analyses to assess the impact of reverse causality. We identified a total of 2 significant causal associations and 24 suggestive causal associations. Specifically, Phenylalanine-tRNA ligase was found to increase the risk of Alzheimer's disease, while Mitochondrial glutamate carrier 2 decreased the risk of autism spectrum disorder. Furthermore, there was no evidence of significant pleiotropy, heterogeneity, or reverse causality. This study was limited to individuals of European ancestry, and the conclusions drawn are merely revelatory. This study provides novel insights into the relationship between mitochondria and psychiatric disorders, as well as the pathogenesis and treatment strategies for psychiatric disorders. • Provided evidence for the causal association between mitochondrial function and psychiatric disorders. • Performed analyses utilizing multiple large-scale genome-wide association study databases. • Offered novel insights into the pathogenesis and therapeutic strategies for psychiatric disorders. • Emphasized the potential of genomics research. [ABSTRACT FROM AUTHOR]

Background: Non‐syndromic orofacial cleft (NSOC) is a complex phenotype, involving multiple genetic and environmental factors. Association studies exploring the genetic susceptibility to this prevalent oral malformation show variability of results in different populations. Using a candidate gene approach, we aimed to verify the role of four single‐nucleotide polymorphisms (SNPs) in the susceptibility to NSOC in Portuguese patients. Methods: A total of 254 non‐consanguineous individuals of Portuguese were recruited, including 120 patients with NSOC and 134 controls. About 92% of these patients had non‐syndromic cleft lip with or without cleft palate (NSCL/P) and 8% had only non‐syndromic cleft palate (NSCP). SNPs in the MTHFR (rs1801133), IRF6 (rs642961), PAX7 (rs742071) and TP63 (rs9332461) genes were studied, using a real‐time approach with TaqMan probes. Allelic, genotypic, dominant, recessive and over‐dominant models were explored using a chi‐squared test. Adjusted p‐value was calculated for multiple comparisons using the Benjamini–Hochberg false discovery rate (FDR). Results: All SNPs were in Hardy–Weinberg equilibrium. For MTHFR, IRF6, and PAX7 SNPs, no statistically significant difference was highlighted for any of the evaluated models. For TP63 SNP, data fitted an over‐dominant model, with a protective effect for heterozygotes (OR 1.897; CI 95% [1.144–3.147]; p <.016, when comparing controls vs. cases), but significance was lost when applying adjusted p‐value for multiple comparisons (4 × 5 tests). Conclusion: In this Portuguese population, there was no evidence of an association between the evaluated SNPs and NSOC. For TP63 SNP, the possibility of a protective effect of heterozygotes should be further investigated. [ABSTRACT FROM AUTHOR]

Purpose A wide range of cytokines has been demonstrated to be involved in the etiology of type 1 diabetes mellitus (T1DM). Gene polymorphisms may potentially contribute to a hereditary predisposition toward circulating cytokine levels as (high, intermediate, or low) since they can affect cytokine production or function. The aim of this study was to investigate the roles of cytokine levels and the association of single-nucleotide polymorphisms (SNPs) within cytokine genes with T1DM in Saudi children. Methods Totals of 91 well-characterized T1DM patients and 91 T1DM-free control subjects were enrolled in this study. Results The levels of 3 circulating cytokines (transforming growth factor [TGF]-β1, interleukin [IL]-10, and IL-6) and 6 SNPs in 3 cytokine genes (TGF-β1 [rs1800470 and rs1800471], IL-10 [rs1800896, rs1800871, and rs1800872], and IL-6 [rs1800795]) that contribute to genetic susceptibility were measured by enzyme-linked immunosorbent assay and polymerase chain reaction with sequence-specific primers. Our fn dings show that TGF-β1 serum levels were signifcantly lower in the children with T1DM than in the control participants. The TGF-β1 genotypes with a high-production phenotype were signifcantly less frequent and those with a lowproduction phenotype were signifcantly more frequent in the children with T1DM compared to the control participants. respectively. Furthermore, the IL-6 genotype frequency with low level of IL-6 production were signifcantly increased in the T1DM group compared to the control group. Moreover, our data demonstrated no appreciable diferences in circulating serum level or genotype and phenotype of IL- 10 between the patients and controls. Conclusions This kind of measurement, which considers the prediction of T1DM, may be useful in assessing the severity of T1DM and susceptibility to T1DM among Saudi children.

Abstract Background Developmental dysplasia of the hip (DDH) is a common cause of childhood disability, and the incidence of DDH shows significant familial aggregation. As the genetic factors of DDH remain unknown, the correlation between five candidate single nucleotide polymorphisms (SNPs) and DDH was evaluated in the Han Chinese population of Southwest China. Methods A case‒control association study was conducted in 276 patients with DDH and 318 healthy controls. SNP genotyping in the case and control groups was performed by SNPshot and multiple PCR. SNPs were genotyped in the case and control groups by multiplex PCR. The relationship between DDH and candidate SNPs was evaluated using the χ2 test. Results The genotype distributions of rs291412 in HIBCH and rs769956 in FTCDNL1 were different between the case and control groups (P

No intervention definitively extends transplant-free survival in primary sclerosing cholangitis (PSC). Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), may enhance PSC prognosis, but their efficacy is debated.

Although sows do not directly enter the market, they play an important role in piglet breeding on farms. They consume large amounts of feed, resulting in a significant environmental burden. Pig farms can increase their income and reduce environmental pollution by increasing the litter size (LS) of swine. PCR-RFLP/SSCP and GWAS are common methods to evaluate single-nucleotide polymorphisms (SNPs) in candidate genes. We conducted a systematic meta-analysis of the effect of SNPs on pig LS. We collected and analysed data published over the past 30 years using traditional and network meta-analyses. Trial sequential analysis (TSA) was used to analyse population data. Gene set enrichment analysis and protein–protein interaction network analysis were used to analyse the GWAS dataset. The results showed that the candidate genes were positively correlated with LS, and defects in PCR-RFLP/SSCP affected the reliability of candidate gene results. However, the genotypes with high and low LSs did not have a significant advantage. Current breeding and management practices for sows should consider increasing the LS while reducing lactation length and minimizing the sows’ non-pregnancy period as much as possible.

Abstract Background The interferon‐γ (IFN‐γ) signaling pathway is activated in systemic lupus erythematosus (SLE). This study aimed to assess the causal association between IFN‐γ, IFN‐γ receptor 1 (IFN‐γR1), and IFN‐γR2 and SLE using a bidirectional Mendelian randomization (MR) design. Methods Genetic instruments for exposure to IFN‐γ, IFN‐γR1, and IFN‐γR2 were derived from a large genome‐wide association study (GWAS) that included a sample size of 3301 participants. Instrumental variables for SLE were selected from another independent GWAS analysis comprising 5201 cases and 6099 controls with European ancestry. Bidirectional two‐sample MR was performed using inverse variance weighting, MR‐Egger regression, and weighted median methods. A series of sensitivity analyses were conducted to assess the robustness of the results. Results The inverse variance weighting showed that IFN‐γ had a positive causal association with the risk of SLE (odd ratio [OR] = 1.24, 95% confidence interval [CI]: 1.03–1.47, p = 0.018). IFN‐γR2 levels were not associated with SLE risk after adjustment for multiple comparisons (OR = 0.85, 95% CI: 0.73–0.99, p = 0.034). No genetic association was also detected between IFN‐γR1 and SLE (OR = 0.97, 95% CI: 0.79–1.19, p = 0.768). Evidence from bidirectional MR did not support reverse causality. The weighted median regression also showed directionally similar estimates. Conclusion Higher levels of IFN‐γ are significantly associated with an increased risk of SLE, providing insights into the pathogenesis of SLE.

Abstract Background Toll-Like receptors (TLRs) play an important role in the immune response during hepatitis B virus (HBV) infection. In this study, we evaluated the association between two SNP variants (TLR3 rs3775290 and TLR4 rs4986790) and susceptibility to chronic HBV infection in Mauritania. Subjects and methods : A total of 188 subjects were recruited for this study: 102 chronically infected patients and 86 individuals with spontaneously resolved HBV infection who were considered controls. Targeted PCR products were sequenced using Sanger sequencing. Results We found that TLR3 rs3775290 was significantly more frequent in patients with chronic HBV than in the control population (p = 0.03). However, no association was found between the TLR4 rs3775290 polymorphism and chronic infection. Conclusion Our results suggest that the TLR3 rs3775290 polymorphism may be a risk factor for susceptibility to chronic HBV infection in the Mauritanian population.

Abstract Background Loss of function mutations in the filaggrin gene (FLG) play an important role in the pathogenesis of atopic dermatitis (AD). However, FLG is structurally challenging to sequence using conventional high‐throughput techniques. Genome‐wide association studies (GWAS) chips and imputation panels are also not designed to detect most of these mutations. Furthermore, bioinformatics tools have variable sensitivity for identification of loss of function variants. Targeted sequencing is often performed for AD but requires a comprehensive list of potential variants. Objectives This study sought to compile all published FLG single nucleotide polymorphisms (SNPs) in AD and characterize the methods for assessing the associated phenotype. Methods We searched nine electronic databases for studies that reported measures of association between FLG and AD. Data regarding FLG SNPs and participant demographics were extracted. The identified SNPs were compared to those available in the National Human Genome Research Institute‐European Bioinformatics Institute (NHGRI‐EBI) GWAS Catalogue and the 1000Genomes reference panel. Results We identified 168 SNPs in FLG that have been associated with AD, with the most studied being R501X, 2282del4, R2447X, 3321delA, S3247X and p.S2554 in European and Asian ancestries. A total of 153 of these SNPs are not available from GWAS studies, and 78 are not included in the 1000Genomes reference panel. Conclusions Because FLG is a complex gene, current GWAS chips do not capture most of the polymorphisms that have been associated with AD.

N‐terminal nonsynonymous single‐nucleotide polymorphisms (SNPs) of G protein‐coupled receptors (GPCRs) are common and often affect receptor post‐translational modifications. Their functional implications are, however, largely unknown. We have previously shown that the human β1‐adrenergic receptor (β1AR) is O‐glycosylated in the N‐terminal extracellular domain by polypeptide GalNAc transferase‐2 that co‐regulates receptor proteolytic cleavage. Here, we demonstrate that the common S49G and the rare A29T and R31Q SNPs alter these modifications, leading to distinct effects on receptor processing. This was achieved by in vitro O‐glycosylation assays, analysis of native receptor N‐terminal O‐glycopeptides, and expression of receptor variants in cell lines and neonatal rat ventricular cardiomyocytes deficient in O‐glycosylation. The SNPs eliminated (S49G) or introduced (A29T) regulatory O‐glycosites that enhanced or inhibited cleavage at the adjacent sites (P52↓L53 and R31↓L32), respectively, or abolished the major site at R31↓L32 (R31Q). The inhibition of proteolysis of the T29 and Q31 variants correlated with increased full‐length receptor levels at the cell surface. Furthermore, the S49 variant showed increased isoproterenol‐mediated signaling in an enhanced bystander bioluminescence energy transfer β‐arrestin2 recruitment assay in a coordinated manner with the common C‐terminal R389G polymorphism. As Gly at position 49 is ancestral in placental mammals, the results suggest that its exchange to Ser has created a β1AR gain‐of‐function phenotype in humans. This study provides evidence for regulatory mechanisms by which GPCR SNPs outside canonical domains that govern ligand binding and activation can alter receptor processing and function. Further studies on other GPCR SNPs with clinical importance as drug targets are thus warranted. [ABSTRACT FROM AUTHOR]

Phantom tooth pain (PTP) is one type of non-odontogenic neuropathic toothache, which rarely occurs after appropriate pulpectomy or tooth extraction. The cause of PTP is unknown. We investigated pain-related genetic factors that are associated with PTP. Four pain-associated genes, including G protein-coupled receptor 158 (GPR158) and phosphoribosyl transferase domain containing 1 (PRTFDC1), are adjacent to each other on the human genome. Some of these four genes or their genomic region may be related to PTP. We statistically analyzed associations between single-nucleotide polymorphisms (SNPs) in the genomic region and PTP in patients with PTP (PTP group), other orofacial pain (OFP group), and healthy control subjects. We then performed a database search of expression quantitative trait loci (eQTLs). For the seven SNPs that were significantly associated with PTP even after Bonferroni correction, we focused on the rs12411980 tag SNP (p = 9.42 × 10−4). Statistical analyses of the PTP group and healthy subject groups (group labels: NOC and TD) revealed that the rate of the GG genotype of the rs12411980 SNP was significantly higher in the PTP group than in the healthy subject groups (PTP group vs. NOC group: p = 2.92 × 10−4, PTP group vs. TD group: p = 5.46 × 10−4; percentage of GG: 30% in PTP group, 12% in NOC group, 11% in TD group). These results suggest that the GG genotype of the rs12411980 SNP is more susceptible to PTP. The rs2765697 SNP that is in strong linkage disequilibrium with the rs12411980 SNP is an eQTL that is associated with higher PRTFDC1 expression in the minor allele homozygotes in the healthy subject groups of the rs2765697 SNP. Thus, PRTFDC1 expression similarly increases in the minor allele homozygotes (GG genotype) in the healthy subject groups of the rs12411980 SNP, which would lead to greater susceptibility to PTP. [ABSTRACT FROM AUTHOR]

B cells are adaptive immune cells in the tumor microenvironment and play an important role in tumor development and metastasis. However, the roles of genetic variants of the immunity B cell-related genes in the survival of patients with non-small cell lung cancer (NSCLC) remain unknown. In the present study, we first evaluated associations between 10,776 single nucleotide polymorphisms (SNPs) in 220 immunity B cell-related genes and survival of NSCLC in a discovery dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that 369 SNPs were significantly associated with overall survival (OS) of NSCLC in multivariable Cox proportional hazards regression analysis (P = 0.05, Bayesian false discovery probability = 0.80), of which 18 SNPs were validated in another independent genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. We then performed linkage disequilibrium (LD) analysis, followed by stepwise analysis with a multivariable Cox regression model. Finally, two independent SNPs, inositol polyphosphate-5-phosphatase D (INPP5D) rs13385922 C>T and exosome component 3 (EXOSC3) rs3208406 A>G, remained significantly associated withNSCLC OS with a combined hazards ratio (HR) of 1.14 (95% confidence interval = 1.06-1.23, P = 2.41×10-4) and 1.20 (95% confidence interval = 1.14-1.28, P = 3.41×10-9), respectively. Furthermore, NSCLC patients with the combination of unfavorable genotypes for these two SNPs were associated with a poor OS (Ptrend = 0.0002) and disease-specific survival (DSS, Ptrend < 0.0001) in the PLCO dataset. Expression quantitative trait loci (eQTL) analysis suggested that the INPP5D rs6782875 T allele was significantly correlated with elevated INPP5D mRNA expression levels in normal lung tissues and whole blood samples, while the EXOSC3 rs3208406 G allele was significantly correlated with increased EXOSC3 mRNA expression levels in normal lung tissues. Our data indicated that genetic variants in these immunity B cell-related genes may predict NSCLC survival possibly by influencing the gene expression. [ABSTRACT FROM AUTHOR]

(1) Multiple sclerosis (MS) is identified by a complex interaction between central inflammation and neurodegeneration. Genetic individual variability could play a significative role in clinical presentation. The interleukin-5 (IL-5) rs2069812 single-nucleotide polymorphism (SNP) seems to define the clinical course of Th2 autoimmune diseases, while its role in MS has never been investigated. (2) In a group of 230 patients diagnosed with relapsing–remitting MS (RR-MS) or progressive MS (P-MS) and controls (IC), rs2069812 polymorphism, cerebrospinal fluid (CSF) levels of inflammatory mediators, and clinical and demographic characteristics were determined. In RR-MS patients, No Evidence of Disease Activity (NEDA-3) at three years of follow-up was detected. (3) We identified higher levels of proinflammatory cytokines, particularly IL-2 (median [IQR], RR-MS = 0.2 [0–0.7]; P-MS = 0.1 [0–1.6]; IC = 0.1 [0.0–0.1]; p < 0.005), IL-6 (RR-MS = 0.9 [0.3–2.3]; P-MS = 0.8 [0.1–2.7]; IC = 0.1 [0.0–0.5]; p < 0.005), IL-12 (RR-MS = 0.5 [0–1.1]; P-MS = 0.5 [0–1.1]; IC = 0.0 [0.0–0.3]; p < 0.005), and GM-CSF (RR-MS = 15.6 [4.8–26.4]; P-MS = 14 [3.3–29.7]; IC = 8.9 [4.7–11.7]; p < 0.005) in MS patients compared with IC. Conversely, anti-inflammatory cytokines, specifically IL-5 (RR-MS = 0.65 [0–2.4]; P-MS = 0.1 [0–0.8]; IC = 1.7 [0.6–2.8]; p < 0.005) and IL-1ra (RR-MS = 14.7 [4.9–26.4]; P-MS = 13.1 [4.7–22.2]; IC = 27.8 [17.7–37.6]; p < 0.005) were higher in controls. According to rs2069812, in MS patients, the T-allele was associated with higher concentrations of proinflammatory mediators (IL-2, CT/TT = 0.2 [0.0–2.0]; CC = 0.1 [0.0–0.4], p = 0.015; IL-6, CT/TT = 1.2 [0.4–3.2] vs. CC = 0.7 [0.1–1.7], p = 0.007; IL-15, CT/TT = 0.1 [0.0–9.5] vs. CC = 0.0 [0.0–0.1], p = 0.019; and GM-CSF, CT/TT = 0.1 [0.0–0.6] vs. CC = 0.05 [0.0–0.1], p < 0.001), and CC was associated with anti-inflammatory mediators (IL-5, CT/TT = 0.03 [0.0–1.9] vs. CC = 1.28 [0.0–2.7], p = 0.001; IL-1ra, CT/TT = 12.1 [4.1–25.9] vs. CC = 18.1 [12.1–26.9], p = 0.006). We found the same differences in RR-MS patients (IL-2, T-allele median [IQR] = 0.3 [0.0–2.0] vs. C-allele, median [IQR] = 0.04 [0.0–0.3]; p = 0.005; IL-6, T-allele, median [IQR] = 1.3 [0.4–3.3] vs. C-allele, median [IQR] = 0.6 [0.03–1.5]; p = 0.001; IL-15, T-allele, median [IQR] = 0.1 [0.0–9.5] vs. C-allele, median [IQR] = 0.0 [0.0–0.1]; p = 0.008; GM-CSF, T-allele, median [IQR] = 0.1 [0.0–97.9] vs. C-allele, median [IQR] = 0.0 [0.0–0.001]; p < 0.001; IL-5, T-allele, median [IQR] = 0.02 [0.0–2.2] vs. C-allele, median [IQR] = 1.5 [0.0–2.9]; p = 0.016; and IL-1ra, T-allele, median [IQR] = 12.1 [4.3–26.4] vs. C-allele, median [IQR] = 18.5 [12.7–28.3]; p = 0.006) but not in P-MS, except for IL-5 (T-allele, median [IQR] = 0.1 [0–0.23] vs. C-allele, median [IQR] = 0.6 [0.0–2.5]; p = 0.022). Finally, we identified an association between CC in RR-MS patients and NEDA-3 after three years of follow-up (p = 0.007). (4) We describe, for the first time, the role of an SNP of the IL-5 gene in regulating central neuroinflammation and influencing clinical course in MS patients. [ABSTRACT FROM AUTHOR]

Genetically modified maize (Zea mays L.) MON810 was approved for importation into China for feed use in 2004; however, the localization data concerning exogenous insertion sequences, which confer insect resistance, have been questionable. MON810 maize plants discovered in northeastern China were used to analyze the molecular characteristics of the exogenous insertion. Using PacBio-HiFi sequencing and PCR assays, we found the insertion was located in chromosome 8, and there was a CaMV35S promoter, hsp70 intron, and insecticide gene cry1Ab, except for genome sequence insertion in the MON810 event. Importantly, the 5′ and 3′ flanking sequences were located in the region of 55869747–55879326 and 68416240–68419152 on chromosome 5, respectively. The results of this study correct previous results on the genomic localization of the insertion structure for the MON810 event. We also found a single-nucleotide polymorphism (SNP) in the hsp70 intron, which is most likely the first SNP found in a transgenic insertion sequence. PCR amplification in conjunction with Sanger sequencing, allele-specific PCR (AS-PCR), and blocker displacement amplification (BDA) assays were all effective at detecting the base variance. The integrated strategy used in this study can serve as a model for other cases when facing similar challenges involving partially characterized genetic modification events or SNPs. [ABSTRACT FROM AUTHOR]

Age, ethnic background and genetic components have been identified as the established risks for prostate cancer (PCa). Pentraxin 3 (PTX3), originally identified as a pattern‐recognition molecule for defence against infectious agents, has multiple functions in tissue repair and in the regulation of cancer‐associated inflammation. In this study, we sought to investigate the impact of PTX3 gene variants on the development of PCa. Genotypes of four common single‐nucleotide polymorphisms (SNPs) of PTX3 gene, including rs1840680, rs2305619, rs3816527 and rs2120243, were profiled among 705 PCa patients and 705 ethnicity‐matched controls. In this study, we found that patients who carry at least one minor allele (C) of rs3816527 (AC and CC) tended to develop advanced forms of diseases (clinical large T stage, OR, 1.593, p = 0.032; pathologically‐confirmed nodal spread, OR, 1.987, p = 0.011; metastatic tumour, OR, 3.896, p = 0.032) as compared with those homologous for the major allele (AA). Further stratification analysis showed that such association of rs3816527 with lymphatic and distal metastasis of PCa was accentuated in the younger age group (≤65 at diagnosis) but not seen in the older age group (>65 at diagnosis), suggesting an age‐specific effect of PTX3 variants. Prediction of PTX3 protein structure implied that polymorphism may alter the quaternary organization and oligomerization of PTX3 protein. Moreover, our gene silencing experiments and survey of public datasets revealed that elevation of PTX3 levels in PCa was required for cell migration and associated with tumour metastasis. Our results highlight an association of PTX3 rs3816527 with the progression of PCa. [ABSTRACT FROM AUTHOR]

Purpose: A wide range of cytokines has been demonstrated to be involved in the etiology of type 1 diabetes mellitus (T1DM). Gene polymorphisms may potentially contribute to a hereditary predisposition toward circulating cytokine levels as (high, intermediate, or low) since they can affect cytokine production or function. The aim of this study was to investigate the roles of cytokine levels and the association of single-nucleotide polymorphisms (SNPs) within cytokine genes with T1DM in Saudi children. Methods: Totals of 91 well-characterized T1DM patients and 91 T1DM-free control subjects were enrolled in this study. Results: The levels of 3 circulating cytokines (transforming growth factor [TGF]-β1, interleukin [IL]-10, and IL-6) and 6 SNPs in 3 cytokine genes (TGF-β1 [rs1800470 and rs1800471], IL-10 [rs1800896, rs1800871, and rs1800872], and IL-6 [rs1800795]) that contribute to genetic susceptibility were measured by enzyme-linked immunosorbent assay and polymerase chain reaction with sequence-specific primers. Our fn dings show that TGF-β1 serum levels were signifcantly lower in the children with T1DM than in the control participants. The TGF-β1 genotypes with a high-production phenotype were signifcantly less frequent and those with a lowproduction phenotype were signifcantly more frequent in the children with T1DM compared to the control participants. respectively. Furthermore, the IL-6 genotype frequency with low level of IL-6 production were signifcantly increased in the T1DM group compared to the control group. Moreover, our data demonstrated no appreciable diferences in circulating serum level or genotype and phenotype of IL- 10 between the patients and controls. Conclusion: This kind of measurement, which considers the prediction of T1DM, may be useful in assessing the severity of T1DM and susceptibility to T1DM among Saudi children. [ABSTRACT FROM AUTHOR]