Association Of Single Nucleotide Polymorphisms Research Articles

Anti-citrullinated α-enolase peptide as a highly sensitive autoantigen in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is the most common autoimmune rheumatic disease in Taiwan. Anti-cyclic citrullinated peptide (anti-CCP) assay is widely used for RA diagnosis; however, not all anti-CCPs are detectable in RA-joint lesions. Citrullinated α-enolase peptide (CEP), which has a unique immunodominant epitope, can be detected in synovial fluid. Here, we aimed to evaluate the potential of anti-CEP as a serologic marker for the early diagnosis of RA and a prognostic predictor of joint destruction. We also determined the association of single-nucleotide polymorphisms (SNPs) in genes with the serological status and clinical characteristics of RA. Clinical records of 30 patients with RA were collected, and their serum and DNA samples were evaluated using enzyme-linked immunosorbent assay (ELISA) and SNP cross-reaction analysis. A considerable amount of anti-CEP was detected in patients with RA, a trend similar to that of anti-CCP. Moreover, anti-CEP was considerably associated with the protein-arginine deiminase type-2 SNP rs1005753.

Association of MMP3, MMP14, and MMP25 gene polymorphisms with cerebral stroke risk: a case-control study

BackgroundCerebral stroke (CS) is the leading cause of death in China, and a complex disease caused by both alterable risk factors and genetic factors. This study intended to investigate the association of MMP3, MMP14, and MMP25 single nucleotide polymorphisms (SNPs) with CS risk in a Chinese Han population.MethodsA total of 1,348 Han Chinese were recruited in this case-control study. Four candidate loci including rs520540 A/G and rs679620 T/C of MMP3, rs2236302 G/C of MMP14, and rs10431961 T/C of MMP25 were successfully screened. The correlation between the four SNPs and CS risk was assessed by logistic regression analysis. The results were analyzed by false-positive report probability (FPRP) for chance or significance. The interactions between four SNPs associated with CS risk were assessed by multifactor dimensionality reduction (MDR).Resultsrs520540 A/G and rs679620 C/T SNP in MMP3 were associated with risk of CS in allele, codominant, dominant and log-additive models. Ischemic stroke risk were significantly lower in carriers with rs520540-A allele and rs679620-T allele than those with G/G or C/C genotypes. However, rs520540-A allele and rs679620-T allele were associated with higher risk of hemorrhagic stroke. Stratified analysis showed that these two SNPs were associated with reduced risk of CS in aged < 55 years, non-smoking and non-drinking participants, and rs679620 SNP also reduced CS risk in male participants. The levels of uric acid, high-density lipoprotein cholesterol, and eosinophil were different among patients with different genotypes of rs520540 and rs679620. No statistically significant association was found between MMP14 rs2236302 G/C or MMP25 rs10431961 T/C with CS even after stratification by stroke subtypes, age, gender as well as smoking and drinking conditions in all the genetic models.ConclusionMMP3 rs520540 A/G and rs679620 C/T polymorphisms were associated with CS risk in the Chinese Han population, which provides useful information for the prevention and diagnosis of CS.

Association Of PTPN22 Gene Polymorphisms in Patients with Graves’ Disease in Iranian Papulation

Background: Graves’ disease (GD) is an autoimmune disease that is associated with increased thyroid gland irritation and, consequently, hyperthyroidism. Autoimmune diseases are common in the general population and are influenced by genetic and environmental factors. PTPN22, which was reported as a susceptible locus for GD in several populations, acts as a negative regulator for activation of primary T-cells, and LYP polymorphism could potentially increase susceptibility to Graves' disease, which may play a role in other autoimmune conditions as well. In this study, we investigated the association of several PTPN22 single nucleotide polymorphisms (SNPs) with Graves patients.&#x0D; Methods: After DNA extraction from peripheral blood cells, SNP Genotyping was performed through real-time PCR with allelic discrimination TaqMan genotyping assays (ABI Applied Biosystems, 7300 Real-Time PCR System, USA) based on manufacturer protocols. The frequencies of alleles and genotypes of PTPN22 SNPs (rs12760457, rs2476601, rs1310182, and rs1217414) were recorded.&#x0D; Results: In our study, the rs1310182 was significantly more frequent in patients with GD than in healthy individuals. While the C allele of rs1310182 was 1.78 times more frequent in GD patients (95%CI: 1.18- 2.69, P=0.005), the T allele was more frequent in healthy subjects (OR=0.56, 95% CI: 0.37-0.84, P=0.005). In addition, the CC genotype of this SNP was 1.86 times more common in patients (P=0.05). No significant differences were observed between the other SNPs of this gene in case and control.&#x0D; Conclusion: The results demonstrate that one SNP (rs1310182) of the PTPN22 gene is associated with susceptibility to GD in an Iranian population. Further studies, including functional analyses, are required.

A better understanding of coronary artery disease molecular biology through an intermediate phenotype

Abstract Coronary Artery Disease (CAD) remains a common cause of death worldwide; over half of these deaths are asymptomatic until the first fatal presentation. Previous studies have often compared coronary artery calcification (CAC) with coronary stenosis or its sequelae. However, the genetic contribution to CAC in sub-clinical atherosclerosis is controversial. Purpose This study intended to assess the relationship between a set of single nucleotide polymorphisms associated with CAD (GWAS) and CAC score in an asymptomatic population. Methods Prospective study performed in an asymptomatic cohort from GENEMACOR population-based sample of 1207 subjects aged 51.7±8.3, 73.8 male, without apparent prior CAD. CAC score was performed by cardiac computed tomography and reported as Agatston units according to the Hoff nomogram (Low, Moderate and High-risk categories). For the present work, we considered two groups: Group 1 (0≤CAC&amp;lt;100 and Percentile&amp;lt;50) and Group 2 (CAC≥100 or Percentile≥50). We genotyped thirty-three single nucleotide polymorphisms (SNP) associated with CAD by TaqMan real-time PCR. Anthropometric, conventional, and biochemical risk factors were assessed. The association of these SNPs with CAC score groups were evaluated by bivariate and multivariate logistic regression analysis, and the dominant genetic model was considered for comparison. Results After bivariate analysis, only PHACTR1 rs1332844 C&amp;gt;T (CT+TT genetic model) showed a significative association with CAC score (OR=1.45; 95%CI 1.09-1.94; p=0.011). Multivariate logistic regression analysis, adjusted to traditional risk factors, genetic model and CAC score showed that PHACTR1 rs1332844 remained in the equation as significantly associated to CAC score (P=0.009) together with age (0.0001), hypertension (0.006), Diabetes (0.0001), smoking (0.001) and obesity (0.028). Conclusion PHACTR1 genetic variant is known to contribute to atherosclerosis and plaque formation. In the present study it showed a significant association with plaque calcium. More research in this field is critical to understanding the genetic basis of CAD through an intermediate phenotype, plaque calcification. We highlight this point since it can be crucial for the prognosis and therapy of the asymptomatic population.

Association between GLO1 variants and gestational diabetes mellitus susceptibility in a Chinese population: a preliminary study.

Glyoxalase 1 (GLO1) plays a crucial role in defending against glycation. Single nucleotide polymorphism (SNP) variants in the GLO1 gene may affect gene expression and alter enzyme activity. However, there have been limited studies evaluating the association between GLO1 and diabetes, especially gestational diabetes mellitus (GDM). Therefore, this study is the first to explore the association of GLO1 SNPs and GDM risk. The study included a total of 500 GDM patients and 502 control subjects. The SNPscan™ genotyping assay was used to genotype rs1781735, rs4746 and rs1130534. To assess the disparities in genotype, allele, and haplotype distributions and their correlation with GDM risk, the independent sample t-test, logistic regression, and chi-square test were employed during the data processing phase. Furthermore, one-way ANOVA was conducted to determine the differences in genotype and blood glucose and methylglyoxal(MG) levels. Significant differences were observed in prepregnancy body mass index (pre-BMI), age, systolic blood pressure (SBP), diastolic blood pressure (DBP), and parity between GDM and healthy subjects (P < 0.05). After adjusting for these factors, GLO1 rs1130534 TA remained associated with an increased risk of GDM (TA vs. TT + AA: OR = 1.320; 95% CI: 1.008-1.728; P = 0.044), especially in the pre-BMI ≥ 24 subgroup (TA vs. TT + AA: OR = 2.424; 95% CI: 1.048-5.607; P = 0.039), with fasting glucose levels being significantly elevated in the TA genotype compared to the TT genotype (P < 0.05). Conversely, the GLO1 rs4746 TG was associated with a decreased risk of GDM (TG vs. TT: OR = 0.740; 95% CI: 0.548-0.999; P = 0.049; TG vs. TT + GG: OR = 0.740; 95% CI: 0.548-0.998; P = 0.048). Additionally, the haplotype T-G-T of rs1781735, rs4746 and rs1130534 was associated with a decreased risk of GDM among individuals with a pre-BMI ≥ 24 (OR = 0.423; 95% CI: 0.188-0.955; P = 0.038). Furthermore, the rs1781735 GG genotype was found to be more closely related to maternal MG accumulation and neonatal weight gain (P < 0.05). Our findings suggested that GLO1 rs1130534 was associated with an increased susceptibility to GDM and higher blood glucose levels, but GLO1 rs4746 was associated with a decreased risk of GDM. The rs1781735 has been associated with the accumulation of maternal MG and subsequent weight gain in neonates.

Human-genome single nucleotide polymorphisms affecting transcription factor binding and their role in pathogenesis.

Single nucleotide polymorphisms (SNPs) are the most common type of variation in the human genome. The vast majority of SNPs identified in the human genome do not have any effect on the phenotype; however, some can lead to changes in the function of a gene or the level of its expression. Most SNPs associated with certain traits or pathologies are mapped to regulatory regions of the genome and affect gene expression by changing transcription factor binding sites. In recent decades, substantial effort has been invested in searching for such regulatory SNPs (rSNPs) and understanding the mechanisms by which they lead to phenotypic differences, primarily to individual differences in susceptibility to diseases and in sensitivity to drugs. The development of the NGS (next-generation sequencing) technology has contributed not only to the identification of a huge number of SNPs and to the search for their association (genome-wide association studies, GWASs) with certain diseases or phenotypic manifestations, but also to the development of more productive approaches to their functional annotation. It should be noted that the presence of an association does not allow one to identify a functional, truly disease-associated DNA sequence variant among multiple marker SNPs that are detected due to linkage disequilibrium. Moreover, determination of associations of genetic variants with a disease does not provide information about the functionality of these variants, which is necessary to elucidate the molecular mechanisms of the development of pathology and to design effective methods for its treatment and prevention. In this regard, the functional analysis of SNPs annotated in the GWAS catalog, both at the genome-wide level and at the level of individual SNPs, became especially relevant in recent years. A genome-wide search for potential rSNPs is possible without any prior knowledge of their association with a trait. Thus, mapping expression quantitative trait loci (eQTLs) makes it possible to identify an SNP for which - among transcriptomes of homozygotes and heterozygotes for its various alleles - there are differences in the expression level of certain genes, which can be located at various distances from the SNP. To predict rSNPs, approaches based on searches for allele-specific events in RNA-seq, ChIP-seq, DNase-seq, ATAC-seq, MPRA, and other data are also used. Nonetheless, for a more complete functional annotation of such rSNPs, it is necessary to establish their association with a trait, in particular, with a predisposition to a certain pathology or sensitivity to drugs. Thus, approaches to finding SNPs important for the development of a trait can be categorized into two groups: (1) starting from data on an association of SNPs with a certain trait, (2) starting from the determination of allele-specific changes at the molecular level (in a transcriptome or regulome). Only comprehensive use of strategically different approaches can considerably enrich our knowledge about the role of genetic determinants in the molecular mechanisms of trait formation, including predisposition to multifactorial diseases.

Pharmacogenomics to Predict Asparaginase Premedication-Related Hypersensitivity in Pediatric and Adolescent Young Adults (AYAs) with Acute Lymphoblastic Leukemia or Lymphoma

Pediatric acute lymphoblastic leukemia (ALL) patients have had significantly improved outcomes over the last few decades with overall survival (OS) rates exceeding 90%. Several factors, including the incorporation of asparaginase therapy in chemotherapy regimens of pediatric and AYA patients with ALL have played a critical role in improving outcomes. Asparaginase is a bacteria-derived enzyme which depletes the non-essential amino acid asparagine and leads to subsequent apoptosis in lymphoblastic leukemia cells. One of the main limitations of the frontline pegaspargase (PEG) chemotherapy is the development of hypersensitivity reactions and subsequent development of anti-asparaginase neutralizing antibodies that lead to PEG inactivation. When hypersensitivity reactions to PEG occur, patients are often switched to alternative forms of asparaginase, such as that isolated from Erwinia chrysanthemi. A prospective multi-institutional study initiated by Children's Hospital of Orange County (CHOC) and conducted at 6 pediatric cancer centers: 1) evaluated the efficacy of premedicating pediatric and AYA patients with B or T-ALL or lymphoblastic lymphoma (LBL) receiving PEG with antihistamines (H1 and H2 blockers), and 2) performed therapeutic drug monitoring to better identify patients with true hypersensitivity reactions versus those with non-antibody mediated infusion reactions with the goal of reducing incidences of substitution to Erwinia asparaginase. This study also aimed to characterize the pharmacogenomics which may be driving differences in asparaginase hypersensitivity to better understand which single nucleotide polymorphisms (SNPs) are involved in the immunogenicity of PEG and whether certain populations are more at risk for hypersensitivity. Here, we report preliminary evidence showing an association between a combination of 3 SNPs in 3 genes and incidence of hypersensitivity to PEG. The analysis cohort consisted of 126 non-Down syndrome patients premedicated prior to PEG treatment. In this cohort, the median age was 7.7 years, 48 were female (38%) and 78 male (62%), 65 patients identified as Hispanic (52%), 56 as non-Hispanic (44%) and 5 declined to state (4%). Overall, 28 patients had a hypersensitive reaction to PEG within 15 minutes of infusion. Patient characteristics by hypersensitivity incidence are summarized in Fig 1A, with age and National Cancer Institute (NCI) risk groups being the factors that significantly differ by hypersensitivity. DNA from all 126 patients was used to genotype for 6 SNPs in 5 genes involved in pathways implicated in hypersensitivity to PEG. We tested each SNP genotype in 3 modes of inheritance (additive, dominant, and recessive) in all possible combinations of up to two SNPs per model using Cox-proportional hazard models for association with incidences of hypersensitivity post-infusion in 126 patients for whom clinical data was available. We then performed 1000 permutation tests for each model to determine the likelihood of obtaining them falsely. Models were ordered according to their Bayesian Information Criterion (BIC) and weight in favor of each model and those with least BIC and a 1000 permutation p&amp;lt;0.05 were selected for development of Asp_PGx3 score. This was defined by adding the genotype scores of 3 SNPs in 3 genes ( ARHGAP28, CNOT3, and NFATC2), accounting for the mode of inheritance and the direction of their association with outcome. This score ranged from -5 to 0, with patients with score &amp;lt;0 stratified as low score and those with scores of 0 as high score groups. A significantly higher proportion of patients in the low Asp_PGx3 score group (29%) had an incidence of PEG hypersensitivity compared to those in the high Asp_PGx3 score group (16%) (Fig 1B). In conclusion, we show a combination of 3 SNPs (in ARHGAP28, CNOT3, and NFATC2) associated with PEG hypersensitivity in a cohort of 126 pediatric and AYA ALL/LBL patients. Instead of a single SNP association approach, identifying combinations of variations in pathway specific genes provides a more robust means to predict drug response. Our preliminary results provide a rationale for identification of genome level variations in this cohort and association analysis to establish clinically relevant pharmacogenomics score to optimize PEG treatment. Funding for this study was provided by CHOC PSF Tithe Grant, CHOC Hyundai Cancer Institute Research Grant, and Servier Pharmaceuticals.

An intronic genetic variant of ZHX2 predicts response to pegylated interferon α therapy in HBeAg-positive chronic hepatitis B patients

ZHX2 plays a crucial role in host immunity and modulates hepatitis B virus (HBV) replication. However, its correlation with immunomodulator-related treatment, i.g., pegylated interferon α(PegIFNα), for HBV remains uncertain. To explore the link between single nucleotide polymorphisms (SNPs) in ZHX2 and response to PegIFNα therapy for chronic hepatitis B (CHB) patients, we conducted a retrospective study in 945 hepatitis B e antigen (HBeAg)-positive CHB patients with at least 48 weeks of PegIFNα treatment and 24 weeks of follow-up from two phase-IV, multicenter trials (Cohort 1, n = 238; Cohort 2, n = 707). Thirty-eight tag SNPs were selected across the whole ZHX2 gene region. A polygenic score (PGS) was constructed by integrating multiple SNPs. The associations of ZHX2 SNPs and PGS with treatment response were assessed in both cohorts and their combination. Among the 38 tag SNPs, ZHX2_rs17289471 (T>C) was significantly associated with combined response (CR, i.e., HBeAg seroconversion and HBV DNA level <3.3log10IU/mL) at week 72 in both cohorts. The CR rate at week 72 increased steadily from rs17289471 TT to CT and CC genotype carriers in both Cohort 1 (P = 0.002) and Cohort 2 (P = 0.025) as well as Cohort 1 + 2 (P = 3.50 × 10−4). Moreover, a PGS integrating ZHX2_rs17289471 and five other previously identified SNPs was further significantly associated with CR rate at week 72 in Cohort 1 (P = 2.38 × 10−6), Cohort 2 (P = 1.04 × 10−7) and Cohort 1 + 2 (P = 9.37 × 10−13). Overall, ZHX2_rs17289471 and PGS have the potential to predict response to PegIFNα treatment of HBeAg-positive CHB patients.

Functional variants of the chitinase 3-like 1 gene are associated with clinicopathologic outcomes and progression of prostate cancer.

Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in advanced stages of several cancer types, including prostate cancer (PCa). Impacts of genetic variants of CHI3L1 on PCa development have not yet been investigated. The most common well-studied genetic variations are single-nucleotide polymorphisms (SNPs). Therefore, the objective of this study was to explore associations of CHI3L1 SNPs with both the susceptibility to PCa and its clinicopathological development. Three promoter SNPs, rs6691378 (-1371, G>A), rs10399805 (-247, G>A) and rs4950928 (-131, C>G), and one non-synonymous SNP, rs880633 (+2950, T>C), were analysed using a TaqMan allelic discrimination assay for genotyping in a cohort of 701 PCa patients and 701 healthy controls. Results indicated that there were no significant associations of PCa susceptibility with these four CHI3L1 SNPs. However, among elderly PCa patients (aged >65 years), it was observed that polymorphic variants (GA + AA) of CHI3L1 rs6691378 and 10399805 were significantly linked to reduced risks of several clinicopathological characteristics, including a high Gleason grade, advanced pathologic T stage and tumour cell invasion. Moreover, analyses of The Cancer Genome Atlas database revealed that CHI3L1 expression levels were elevated in PCa tissues compared with normal tissues. Interestingly, higher CHI3L1 expression levels were found to be associated with longer progression-free survival rates in PCa patients. Our findings indicated that levels of CHI3L1 may influence the progression of PCa, and the rs6691378 and 10399805 SNP genetic variants of CHI3L1 are linked to the clinicopathological development of PCa within a Taiwanese population.

Association of Single-Nucleotide Polymorphisms in Capecitabine Bioactivation Pathway with Adjuvant Therapy Safety in Colorectal Cancer Patients.

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is part of the standard treatment of colorectal cancer (CRC). Severe adverse dose limiting reactions that impair treatment safety and lead to treatment suspension remain a relevant concern. Single-nucleotide polymorphisms (SNPs) in genes involved in the activation of capecitabine may alter the bioavailability of 5-FU and thereby affect therapy outcomes. The aim of this study was to evaluate the association of these SNPs with severe toxicity and treatment suspension in patients with CRC treated with capecitabine-based therapy. An ambispective cohort study was conducted, including 161 patients with CRC. SNPs were analyzed using real-time PCR with TaqMan® probes. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0. CES1 rs71647871-A was associated with a severe hand-foot syndrome (p = 0.030; OR = 11.92; 95% CI = 1.46-73.47; GG vs. A). CDA rs1048977-CC (p = 0.030; OR = 2.30; 95% CI 1.09-5.00; T vs. CC) and capecitabine monotherapy (p = 0.003; OR = 3.13; 95% CI 1.49-6.81) were associated with treatment suspension due to toxicity. SNPs CES1 rs71647871 and CDA rs1048977 may act as potential predictive biomarkers of safety in patients with CRC under capecitabine-based adjuvant therapy.

The association of interleukin-10 single nucleotide polymorphisms (rs1800871) and serum levels in Iraqi patients with celiac disease: A case-control study

BackgroundCeliac disease is one of the autoimmune diseases resulting from ingesting gluten, in addition to the diverse microbiota in the gut, micronutrient deficiencies, and genetic predisposition. Several immunological factors impact celiac disease pathogenesis; interleukin-10 is one of these immunological factors that have a role in disease development. MethodsThe present study was designed to examine the genotypes and alleles frequency of IL10 rs1800871in celiac disease patients compared to the healthy control volunteers using allele-specific primers-polymerase chain reaction technique. Fifty celiac disease patients volunteered to participate in the current study (age mean ± SD was 23.5 ± 11.88 years) who enrolled during the period from November 2021–February 2022, compared with 50 healthy volunteers (age mean ± SD was 23.5 ± 11.88 years). ResultsThe genetic variations of IL-10 SNPs rs1800871 results showed that the TT genotype and T allele were more frequent than the other genotypes and allele C in the patients' group (58.0% and 73.0% vs 30.0%, 12.0% and 27.0%, respectively). Also, the TT genotype and T allele have higher OR values than the CC, CT genotypes and C allele in the patients' group (15.88 and 7.70 vs 0.11, 0.76 and 0.13, respectively). These findings might be due to the risk of TT and T in the disease development than CC, CT/C genotypes/allele. ConclusionFrom the obtained results, the present study concluded that the TT/T genotype/allele might be associated with autoimmune disease development, such as celiac disease, more than the other genotypes.

Association of ABCC4 G559T single nucleotide polymorphism with arsenic-induced precancerous hyperkeratosis

Association of ABCC4 G559T single nucleotide polymorphism with arsenic-induced precancerous hyperkeratosis

Association of single nucleotide polymorphism miRNA-146a (rs2910164) with increased predisposition to oral squamous cell carcinoma in central India population.

miRNAs play a crucial role in the genesis of cancer, either as tumor suppressor genes or as oncogenes. Single Nucleotide Polymorphisms (SNPs) in the seed region of microRNAs (miRNAs) can dysregulate their levels in the tissues and thereby affect carcinogenesis. The association of SNP in miR-146a (rs2910164) with the risk of oral squamous cell carcinoma (OSCC) has not been understood. In the present study, we have determined the association and functional significance of miR-146a (rs2910164) SNP with susceptibility to OSCC predisposition. In the present case-control study, we enrolled 430 subjects from central India (215 OSCC cases and 215 healthy controls). We performed genotyping by Kompetitive Allele Specific PCR (KASP), and their correlation with OSCC susceptibility was analyzed. miRNA expression profiling in tumor tissues and adjacent normal tissues from six OSCC patients was done by a NanoString n-Counter-based assay. Subsequently, gene ontology and pathway analysis were performed with FunRich version 3.13. The CC genotype of rs2910164 miR-146a was significantly associated with the increased risk for OSCC (CC vs GC, OR = 2.62; 95% CI: 1.48-4.66; p value = 0.001). However, the GC genotype was protective with GC vs CC (OR = 0.38, 95%CI =0.21-0.67, p-value = 0.001), and GC vs GG (OR = 0.58, 95%CI = 0.37-0.89, p-value = 0.01). Our finding suggests that SNP rs2910164 of miR-146a may be a genetic risk factor for OSCC susceptibility in the Central India population. However, more extensive multicenter studies are required to validate these findings.

Matrix Gla protein polymorphism rs1800802 is associated with atheroma plaque progression and with cardiovascular events in a chronic kidney disease cohort.

Chronic kidney disease (CKD) is associated with increased atherosclerotic burden and higher risk for cardiovascular events (CVE). Atherosclerosis has a significant genetic component and, in CKD, it is influenced by mineral metabolism alterations. Therefore, genetic modifications of mineral metabolism-related proteins could affect atherosclerosis in CKD patients. In the present study we investigated the role of single nucleotide polymorphisms (SNPs) of the matrix gamma-carboxy glutamic acid protein (MGP) on atherosclerosis progression and CVE in a CKD cohort. A total of 2187 CKD patients from the Observatorio Nacional de Aterosclerosis en Nefrologia (NEFRONA) study were genotyped for SNPs present in the matrix gamma-carboxy glutamic acid (Gla) protein (MGP) gene. Atheromatosis was detected by vascular ultrasound. Progression of atheromatosis, defined as an increase in territories with plaque, was assessed after 24 months. Patients were followed for 48 months for CVE. Association of SNPs with plaque progression was assessed by logistic regression and their capacity to predict CVE by Cox regression. Three SNPs of the MGP gene were analyzed. No association of the rs4236 or the rs1800801 SNPs was detected with any of the outcomes. However, patients homozygotes for the minor allele of the rs1800802 SNP showed higher adjusted risk for plaque progression [odds ratio 2.3 (95% confidence interval 1.06-4.9)] and higher risk of suffering a CVE [hazard ratio 2.16 (95% confidence interval 1.13-4.12)] compared with the rest of genotypes. No association of the SNP with total or dp-ucMGP levels was found in a subsample. The rs1800802 polymorphism of MGP is associated with plaque progression and CVE in CKD patients.

Allelic variation in TUSC1 gene: rs1462218557 is associated with male infertility and azoospermia

BackgroundMale infertility is rapidly growing, and single nucleotide polymorphism (SNP) association studies are of critical importance. Tumor suppressor candidate 1 (TUSC1) gene is associated with azoospermia. We investigated association between rs1462218557 in TUSC1 with azoospermia.MethodsWe performed tetra-ARMS PCR analysis and sequencing on healthy and infertile individuals.ResultsTetra-ARMS PCR results revealed that the allele frequency of the SNP for T alleles was 0.66, while the same value for C allele was 0.36. It was different from the previous reports of the other countries because they reported the allele C as the frequent allele and it was considered an ancestral allele. The genotype frequencies obtained showed that 67% of the samples were heterozygotes (T/C), while 33% were homozygotes (TT). SNP-STAT analysis showed a significant association (p = 0.04) with the studied SNP and azoospermia in Iranian samples.ConclusionsThe present study reports a new allele frequency of rs1462218557 in TUSC1 gene, which may be associated with azoospermia in Iranian people. Moreover, no association was observed between neighboring sequences/SNPs with male infertility.

Hipofizės adenoma: literatūros apžvalga ir sąsajos su TAS2R16 (rs978739, rs1357949) geno polimorfizmais

The pituitary gland is the primary regulatory gland in the endocrine system transmitting signals from the hypothalamus to target organs through hormone release. Through the release of hormones, the pituitary gland regulates vital physiological functions: growth, reproduction, metabolism, and the stress response. Disorders in the pituitary gland can cause damage, such as pituitary adenomas (PA). PA is the most common benign tumor arising from epithelial cells of the anterior pituitary gland. PA is one of the most common tumors of the central nervous system. PA is differentiated by hormone secretion into non-secretory (non- functional) and secretory (functionally active). Excess hormones secreted by PA can cause clinical syndromes, such as hyperprolactinemia (caused by excessive secretion of prolactin), acromegaly (due to excess growth hormone), and Cushing’s syndrome (due to excessive production of the adrenocorticotropic hormone ACTH)). Studies show that the prevalence of adenomas in the population is approximately 80/100,000. The occurrence of PA is influenced not only by somatic or germ cell defects but also by environmental factors. The exact cause of PA is still unclear, but it is known that a small part (~5%) of PA due to hereditary syndromes is caused by gene changes. Considering the influence of environmental factors and genetic alterations that affect the occurrence of PA, new genetic markers can be searched to detect this disease. One of the risk factors contributing to the development of PA and its aggressiveness is alcohol consumption. Excessive alcohol consumption affects not only the development of PA but also the manifestation of other cancers. A recent study has investigated the association of TAS2R16 gene single nucleotide polymorphisms (SNPs) with colon cancer, as SNPs in this gene have been found to increase alcohol dependence. Based on the association of TAS2R16 SNPs with cancer, we decided to investigate the association of TAS2R16 gene (rs978739, rs1357949) polymorphisms with PA.

Genetic Associations With Acceleration, Change of Direction, Jump Height, and Speed in English Academy Football Players.

McAuley, ABT, Hughes, DC, Tsaprouni, LG, Varley, I, Suraci, B, Bradley, B, Baker, J, Herbert, AJ, and Kelly, AL. Genetic associations with acceleration, change of direction, jump height, and speed in English academy football players. J Strength Cond Res 38(2): 350-359, 2024-High-intensity movements and explosive actions are commonly assessed during athlete development in football (soccer). Although many environmental factors underpin these power-orientated traits, research suggests that there is also a sizeable genetic component. Therefore, this study examined the association of 22 single-nucleotide polymorphisms (SNPs) with acceleration, change of direction, jump height, and speed in academy football players. One hundred and forty-nine, male, under-12 to under-23 football players from 4 English academies were examined. Subjects performed 5-, 10-, 20-, and 30-m sprints, countermovement jumps (CMJs), and the 5-0-5 agility test. Simple linear regression was used to analyze individual SNP associations, whereas both unweighted and weighted total genotype scores (TGS; TWGS) were computed to measure the combined influence of all SNPs. To control for multiple testing, a Benjamini-Hochberg false discovery rate of 0.05 was applied to all genotype model comparisons. In isolation, the GALNT13 (rs10196189) G allele and IL6 (rs1800795) G/G genotype were associated with faster (∼4%) 5-, 10-, and 20-m sprints and higher (∼16%) CMJs, respectively (p < 0.001). Furthermore, the TGS and TWGS significantly correlated with all performance assessments, explaining between 6 and 33% of the variance (p < 0.001). This study demonstrates that some genetic variants are associated with power-orientated phenotypes in youth football players and may add value toward a future polygenic profile of physical performance.

Allelic and Genotypic Analysis of LncRNA ANRIL rs4977574 A/G Mutations in Oral Squamous Cell Carcinoma Patients: Insights into Tumor Characteristics and Genotypic Correlations.

Long noncoding RNAs (lncRNA) ANRIL and its genetic polymorphisms are shown to be associated with the risk of several cancers. However, the single nucleotide polymorphisms (SNPs) of lncRNA ANRIL are not thoroughly assessed in oral squamous cell carcinoma (OSCC) which is the most prevalent cancer in the head and neck area. Thus, this study aimed to assess the association of SNP of lncRNA ANRIL rs4977574 in patients with OSCC. 106 blood samples from the patients with OSCC were obtained with a gender- and age-matched control group to evaluate the SNP of rs4977574 of lncRNA ANRIL. The DNA was extracted using the salt-out technique and DNA genotyping was undertaken using specific primer pairs in the tetra-primer ARMS-PCR technique. Eventually, the frequency of wild-type (A) and the mutated allele (G), as well as the genotypes were estimated between the groups of patients with OSCC and healthy individuals. The results of our study indicated no statistically significant difference in the frequency of rs4977574 A/G of lncRNA ANRIL among the patients with OSCC and healthy individuals (p > 0.05). Likewise, no significant difference was found in the genotypes' frequencies (p > 0.05). Nevertheless, the marked association of GG with smaller tumor size and the high level of differentiation of OSCC cells in the presence of AA or AG genotypes were interesting outcomes of this study (p < 0.05). Similarly, all the genotypes AA, AG, and GG were correlated with the site of the occurrence of OSCC. Furthermore, the association of the genotypes with the lymph node metastasis and the tumors stage was not found to be significant (p > 0.05). The results of our study indicate that rs4977574 A/G and its genotypes do not have any direct correlation with the presence of OSCC; however, its association with the smaller tumor size and the level of the cancer cells differentiation could imply its possible indirect role.

Susceptibility to hypertension based on MTHFR rs1801133 single nucleotide polymorphism and MTHFR promoter methylation.

The aetio-pathologenesis of hypertension is multifactorial, encompassing genetic, epigenetic, and environmental factors. The combined effect of genetic and epigenetic changes on hypertension is not known. We evaluated the independent and interactive association of MTHFR rs1801133 single nucleotide polymorphism (SNP) and MTHFR promoter methylation with hypertension among Taiwanese adults. We retrieved data including, MTHFR promoter methylation, MTHFR rs1801133 genotypes (CC, CT, and TT), basic demography, personal lifestyle habits, and disease history of 1,238 individuals from the Taiwan Biobank (TWB). The distributions of hypertension and MTHFR promoter methylation quartiles (β < 0.1338, 0.1338 ≤ β < 0.1385, 0.1385 ≤ β < 0.1423, and β ≥ 0.1423 corresponding to <Q1, Q1-Q2, Q2-Q3, and ≥Q3) among individuals with the rs1801133 genotypes (CC, CT, and TT) were significantly different (P < 0.05). The risk of hypertension was significantly higher among individuals with the TT genotype compared to the reference genotype (CC): odds ratio (OR); 95% confidence interval (CI) = 2.718; 1.503-4.914. The trend of the association of the CT and TT genotypes with hypertension was dose-dependent (P-trend = 0.0041). MTHFR promoter methylation (lower quartiles compared to ≥Q3) was not significantly associated with hypertension. However, its interaction with MTHFR rs1801133 was significant (P = 0.0323). After stratification by rs1801133 genotypes, lower MTHFR promoter methylation quartiles (<Q1, Q1-Q2, Q2-Q3) compared to ≥Q3 were significantly associated with a higher risk of hypertension among individuals carrying the CC genotype: ORs (95% CIs) = 3.225 (1.140-9.124), 4.177 (1.424-12.247), and 8.645 (2.513-29.739) for Q2-Q3, Q1-Q2, and <Q1, respectively. The trend test was significant (P-trend = 0.0009). Independently, rs1801133 TT was associated with a higher risk of hypertension, but methylation was not. Based on genotypes, lower methylation was dose-dependently associated with a higher risk of hypertension in individuals with the CC genotype. Our findings suggest that MTHFR rs1801133 and MTHFR promoter methylation could jointly influence hypertension susceptibility.

Treatment resistance NMDA receptor pathway polygenic score is associated with brain glutamate in schizophrenia.

Dysfunction of glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia and may be particularly relevant in severe, treatment-resistant symptoms. The underlying mechanism may involve hypofunction of the NMDA receptor. We investigated whether schizophrenia-related pathway polygenic scores, composed of genetic variants within NMDA receptor encoding genes, are associated with cortical glutamate in schizophrenia. Anterior cingulate cortex (ACC) glutamate was measured in 70 participants across 4 research sites using Proton Magnetic Resonance Spectroscopy (1H-MRS). Two NMDA receptor gene sets were sourced from the Molecular Signatories Database and NMDA receptor pathway polygenic scores were constructed using PRSet. The NMDA receptor pathway polygenic scores were weighted by single nucleotide polymorphism (SNP) associations with treatment-resistant schizophrenia, and associations with ACC glutamate were tested. We then tested whether NMDA receptor pathway polygenic scores with SNPs weighted by associations with non-treatment-resistant schizophrenia were associated with ACC glutamate. A higher NMDA receptor complex pathway polygenic score was significantly associated with lower ACC glutamate (β=-0.25, 95% CI=-0.49, -0.02, competitive p=0.03). When SNPs were weighted by associations with non-treatment-resistant schizophrenia, there was no association between the NMDA receptor complex pathway polygenic score and ACC glutamate (β=0.05, 95% CI=-0.18, 0.27, competitive p=0.79). These results provide initial evidence of an association between common genetic variation implicated in NMDA receptor function and ACC glutamate levels in schizophrenia. This association was specific to when the NMDA receptor complex pathway polygenic score was weighted by SNP associations with treatment-resistant schizophrenia.