Association Of Single Nucleotide Polymorphisms Research Articles

Association of single nucleotide polymorphisms rs7459185 of the HSPβ1 gene and the risk of hematological toxicity in lung cancer.

Hematological toxicities (HTs) in lung cancer (LCa) may compromise the delivery of Radio-Chemotherapy (RTCT), and consequently affect the control of the disease. The aim of this study is to evaluate the association of Single nucleotide polymorphisms (SNPs) with HT. In this prospective multicentre study, 264 patients with primary LCa treated with RTCT between 2012 and 2018 were included. Genotyping analysis was performed on DNA isolated from peripheral blood samples by real-time polymerase chain reaction (PCR) using TaqMan. HTs were scored using the Common Toxicity Criteria (CTCAE) version 5.0. An increased risk of HT≥grade 2 was observed in patients with the GG genotype of the SNP rs7459185 (HSPβ1) with a hazard ratio (HR) of 1.462 (95%CI 1.054-2.029, p=0.007). Similarly, those patients had an increased risk of overall HT≥grade 3 with a HR of 1.531 (95%CI 1.016-2.30, p=0.007). The patients with the GG genotype experienced an acute lymphopenia≥Grade 3 (HR 1.590 [95%CI 1.004-2.517; p 0.045]) and acute anemia≥Grade 2 (HR 1.886 [95%CI 1.060-3.356; p 0.032]), compared to the GC/CC genotypes. Our findings show a relationship between the functional GG genotypic of the SNP rs7459185 (HSPβ1) and heightened risk the development of HT, including anemia and lymphopenia in patients with LCa. This genetic variant could be utilized as a predictive marker to tailor treatment intensity, contributing to the advancement of individualized therapeutic approaches.

Transcriptome-wide association study identifies genes associated with bladder cancer risk

Genome-wide association studies (GWAS) have detected several susceptibility variants for urinary bladder cancer, but how gene regulation affects disease development remains unclear. To extend GWAS findings, we conducted a transcriptome-wide association study (TWAS) using PrediXcan to predict gene expression levels in whole blood using genome-wide genotype data for 6180 bladder cancer cases and 5699 controls included in the database of Genotypes and Phenotypes (dbGaP). Logistic regression was used to estimate adjusted gene-level odds ratios (OR) per 1-standard deviation higher expression with 95% confidence intervals (CI) for bladder cancer risk. We further assessed associations for individual single-nucleotide polymorphisms (SNPs) used to predict expression levels and proximal loci for genes identified in gene-level analyses with false-discovery rate (FDR) correction. TWAS identified four genes for which expression levels were associated with bladder cancer risk: SLC39A3 (OR = 0.91, CI = 0.87–0.95, FDR = 0.015), ZNF737 (OR = 0.91, CI = 0.88–0.95, FDR = 0.016), FAM53A (OR = 1.09, CI = 1.05–1.14, FDR = 0.022), and PPP1R2 (OR = 1.09, CI = 1.05–1.13, FDR = 0.049). Findings from this TWAS enhance our understanding of how genetically-regulated gene expression affects bladder cancer development and point to potential prevention and treatment targets.

Investigation of GSTP1 and PTEN gene polymorphisms and their association with susceptibility to colorectal cancer

Abstract Background This study investigates the association of single nucleotide polymorphism in glutathione S transferase P1 (rs1695 and rs1138272) and phosphatase and TENsin homolog (rs701848 and rs2735343) with the risk of colorectal cancer (CRC). Patients and methods In this case-control study, 250 healthy controls and 200 CRC patients were enrolled. All subjects were divided into 3 groups: healthy control, patients, and overall (control + patients). Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The demographic information, including age, gender, location, smoking status, cancer stage, and node involvement, were collected. Results The allele frequencies of PTEN rs701848 in overall subjects were 0.78 for C and 0.22 for T. Similarly, in overall individuals, allele frequencies for PTEN rs2735343 were 0.65 and 0.35 for G and C alleles, respectively. The CC genotype or C allele of rs701848 and CG/GG genotype of rs2735343 were observed to be a risk factor for CRC. In overall individuals, a significant (p ≤ 0.05)) association was observed between rs701848 and rs2735343 polymorphisms CRC. Allele frequencies for GSTP1 rs1695 were 0.68 and 0.32 for the A and G alleles, respectively. Allele frequencies for GSTP1 rs1138272 were 0.68 and 0.32 for C and T alleles, respectively. However, a significant (p < 0.05) association was found in males for rs1695, while a non-significant difference was observed for the distribution of any genotypes or alleles at GSTP1 (rs1138272). Conclusions Both SNPs of PTEN rs701848 and rs2735343 polymorphisms were significantly associated with CRC. However, in GSTP1, rs1695 was significantly associated with CRC risk in males, and rs1138272 showed a non-significant association with colorectal cancer risk.

Association of walking pace and risk of stroke: A two- sample mendelian randomization study in a European ancestry cohort.

Walking pace (WP), a simple physiological indicator, has been found to be strongly associated with a variety of health outcomes in recent years. Among them, the relationship between walking pace and stroke is of particular interest. Given the high morbidity, disability and mortality associated with stroke, identifying modifiable indicators of health, such as walking pace, could help in stroke prevention strategies. However, the causal relationship between WP and stroke risk remains unclear. This study aims to determine the causal relationship between walking pace and risk of stroke using a two-sample Mendelian randomization approach in a European-ancestry population. In order to evaluate the potential for a causal relationship between WP and stroke in people of European heritage, a two-sample Mendelian randomization (MR) study was carried out. Statistics about the association of single nucleotide polymorphisms (SNPs) with stroke were taken from FinnGen (R8) (n = 284,040), while the UK Biobank genome-wide association studies (GWAS) provided the summary data on the association of SNPs with WP (n = 459,915). The inverse-variance weighted (IVW) method was utilised as the primary strategy to examine the causal connection between WP and stroke. Additionally, complementary analyses were conducted using the MR-Egger and weighted median. In order to identify the potential directional pleiotropy and heterogeneity, the MR-Egger intercept test, the MR-PRESSO test, and Cochran's Q statistic were all carried out. This connection was evaluated using OR with 95% confidence intervals (CIs). A total of 48 SNPs were identified as valid instrumental variables in our two-sample MR analysis. The result showed that a slower walking pace is associated with a higher risk of stroke (OR = 0.573; 95% CI, 0.383-0.858, P = 0.007). The "leave-one-out" analysis demonstrated that the absence of a single SNP did not affect the robustness of our results. The MR-Egger intercept test indicated that genetic pleiotropy did not introduce bias into the results [intercept = -2.9E-03, SE = 0.008, P = 0.719] and Cochran's Q test revealed no heterogeneity. Therefore, the sensitivity analyses yielded comparable results. Consequently, the results of the sensitivity analyses were consistent. Our MR study revealed that WP is inversely associated with risk of stroke. These results provided evidence that slower WP causally increased the risk of stroke, recommending that patients with lower WP should have a prompt physical examination and targeted interventions to reduce their risk of stroke and enhance their quality of life.

Associations of genetic polymorphisms with clinical response to tocilizumab in Chinese rheumatoid arthritis patients.

To examine the associations of single-nucleotide polymorphisms (SNPs) within interleukin-6 (IL6) and IL-6 receptor (IL6R) as well as several potential SNPs revealed in a genome-wide association study (GWAS) with clinical response to tocilizumab (TCZ) in Chinese rheumatoid arthritis (RA) patients. A total of 23 SNPs were genotyped in 68 RA patients receiving intravenous TCZ, who were prospectively followed for 6months to determine the clinical response based on several criteria, including clinical disease activity index (CDAI) low disease activity (LDA) and remission, disease activity score in 28 joint counts - erythrocyte sedimentation rate (DAS28-ESR) LDA and remission, European League Against Rheumatism (EULAR) good response and change in DAS28-ESR (ΔDAS28-ESR). The patients were on average 51.16 (13.23) years, and 55 were female (80.88%) and 47 were bDMARD-naïve (69.12%). After adjusting potential confounding factors, IL6R rs35717427 and GALNT18 rs4910008 were significantly associated with CDAI LDA, and IL6R rs11265621, rs6690230 were significantly associated with EULAR good response, DAS28-ESR LDA and remission. In addition, IL6 2069840 was found to be significantly associated with DAS28-ESR remission, and rs10108210, CLEC2D rs1560011 and KCNMB1 rs703505 were found to be significantly associated with ΔDAS28-ESR. Genetic polymorphisms hold the potential as predictive biomarkers for clinical response to TCZ, which might aid in individualized treatment with TCZ in Chinese patients with RA.

Association of single nucleotide polymorphisms of FASN and DGAT1 genes with live weight in beef cattle

The domestic Kalmyk cattle breed is considered unique and differs from all meat breeds bred in Russia. Animals of this breed are endowed with natural endurance and independence from climatic conditions, they are characterized by high adaptive ability, which makes it possible to breed them both in purity and in various schemes of crossing with other breeds in many regions and regions of our country. In addition, beef from animals of this breed has quite high quality and taste indicators. Given the increasing need for high-quality beef, the need for research aimed at increasing the meat productivity of cattle is an urgent task of agricultural science and practice.The aim of the work is to study the polymorphisms of the FASN and DGAT1 genes and their association with live weight in a population of Kalmyk bull calves bred in an extremely arid climatic and semi-arid ecological landscape zone of the Stavropol Territory. The studies were conducted in the conditions of SPK (kolkhozplemzavod) "Druzhba" (Druzhba collective farm) of Stavropol Krai on Kalmyk steers (n=156) at the age of 8 months. To study the polymorphisms of the FASN and DGAT1 genes, genotyping was performed by PCRPDRF using lyophilized ready-made GenPak ® PCR Core reaction mixtures using a pair of primers selected on the Primer-BLAST resource. It was found that animals carrying AG and GG genotypes in the replacement of g.17924A>G of the FASN gene had a live weight of 7.8 and 11.9% more than the AA genotype, as well as among the entire studied livestock for the two studied genes. Animals carrying the homozygous TT genotype of c.1416T > G polymorphism in the DGAT1 gene had a higher live weight among all animals studied for this gene by 5%.

Phenome-wide association network demonstrates close connection with individual disease trajectories from the HUNT study.

Disease networks offer a potential road map of connections between diseases. Several studies have created disease networks where diseases are connected either based on shared genes or Single Nucleotide Polymorphism (SNP) associations. However, it is still unclear to which degree SNP-based networks map to empirical, co-observed diseases within a different, general, adult study population spanning over a long time period. We created a SNP-based phenome-wide association network (PheNet) from a large population using the UK biobank phenome-wide association studies. Importantly, the SNP-associations are unbiased towards much studied diseases, adjusted for linkage disequilibrium, case/control imbalances, as well as relatedness. We map the PheNet to significantly co-occurring diseases in the Norwegian HUNT study population, and further, identify consecutively occurring diseases with significant ordering in occurrence, independent of age and gender in the PheNet. Our analysis reveals an overlap far larger than expected by chance between the two disease networks, with diseases typically connecting within their own category. Upon examining the sequential occurrence of diseases in the HUNT dataset, we find a giant component consisting of mostly cardiovascular disorders. This allows us to identify sequentially occurring diseases that are genetically linked and co-occur frequently, while also highlighting non-sequential diseases. Furthermore, we observe that survivors of severe cardiovascular diseases subsequently often face less severe conditions, but with a reduced time until their next fatal illness. The HUNT sub-PheNet showing both genetically and co-observed diseases offers an interesting framework to study groups of diseases and examine if they, in fact, are comorbidities. We find that the HUNT sub-PheNet offers the possibility to pinpoint exactly which mutation(s) constitute shared cause of the diseases. This could be of great benefit to both researchers and clinicians studying relationships between diseases.

Genetic variants in folate metabolism-related genes, serum folate and hepatocellular carcinoma survival: the Guangdong Liver Cancer Cohort study.

Folate metabolism is involved in the development and progression of various cancers. We investigated the association of single nucleotide polymorphisms (SNP) in folate-metabolising genes and their interactions with serum folate concentrations with overall survival (OS) and liver cancer-specific survival (LCSS) of newly diagnosed hepatocellular carcinoma (HCC) patients. We detected the genotypes of six SNPin three genes related to folate metabolism: methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). Cox proportional hazard models were used to calculate multivariable-adjusted hazard ratios (HR) and 95 % CI. This analysis included 970 HCC patients with genotypes of six SNP, and 864 of them had serum folate measurements. During a median follow-up of 722 d, 393 deaths occurred, with 360 attributed to HCC. In the fully-adjusted models, the MTRR rs1801394 polymorphism was significantly associated with OS in additive (per G allele: HR = 0·84, 95 % CI: 0·71, 0·99), co-dominant (AG v. AA: HR = 0·77; 95 % CI: 0·62, 0·96) and dominant (AG + GG v. AA: HR = 0·78; 95 % CI: 0·63, 0·96) models. Carrying increasing numbers of protective alleles was linked to better LCSS (HR10–12 v. 2–6 = 0·70; 95 % CI: 0·49, 1·00) and OS (HR10–12 v. 2–6 = 0·67; 95 % CI: 0·47, 0·95). Furthermore, we observed significant interactions on both multiplicative and additive scales between serum folate levels and MTRR rs1801394 polymorphism. Carrying the variant G allele of the MTRR rs1801394 is associated with better HCC prognosis and may enhance the favourable association between higher serum folate levels and improved survival among HCC patients.

Association of NLRP3 single nucleotide polymorphisms with juvenile idiopathic arthritis: a case-control study.

Although juvenile idiopathic arthritis (JIA) is one of the most common pediatric rheumatologic diseases, the exact etiology of JIA remains unclear. Genetic factors, including variations in the NLRP3 gene, have been implicated in the pathogenesis of autoimmune diseases. Therefore, we aimed to investigate the association between NLRP3 polymorphisms and JIA. We conducted a case-control study involving 51 JIA patients and 56 healthy controls from the Children's Medical Center Hospital. Genotyping of four NLRP3 single nucleotide polymorphisms (SNPs) (rs10754558, rs3806265, rs4612666, and rs35829419) was performed using real-time polymerase chain reaction (PCR). Statistical analysis was conducted to compare allele and genotype frequencies between cases and controls. Additionally, haplotype analysis and evaluation of information interaction between SNPs were performed. Allele and genotype frequencies of the investigated NLRP3 SNPs did not show significant differences between JIA cases and healthy controls. However, a notable difference in information interaction was observed at the rs4612666/rs3806265 SNPs (p-value = 0.000426). The CCCT haplotype was associated with increased odds of JIA with an odds ratio (OR) of 2.166 (95%CI:1.156-4.06), and contrariwise, the TCGT haplotype was associated with lower odds of JIA with an OR of 0.166 (95%CI:0.036-0.763). The NLRP3 gene could be involved in the pathogenesis of JIA. Further research with larger cohorts and functional studies is warranted to confirm these findings and elucidate the underlying biological mechanisms. Key Points • No significant difference was observed in the allelic and genotype distribution of NLRP3 SNPs (rs10754558, rs3806265, rs4612666, and rs35829419) between JIA cases and the control group. • A statistically significant difference in information interaction between cases and the control group was observed in rs4612666/rs3806265 SNPs. • The CCCT haplotype was associated with a higher risk of JIA, while the TCGT haplotype was associated with a lower risk.

Single-nucleotide polymorphism rs670 in the promoter region of the apolipoprotein A-I gene

Apolipoprotein A-I (Apo A-I) plays a central role in the function of high-density lipoprotein (HDL). The rs670 single-nucleotide polymorphism (SNP) was identified as a cytosine-to-thymine (C>T) transition in a cytosine–phosphate–guanine site within the promoter region of APOA1. Given its location, studies have hypothesized that this polymorphism may influence APOA1 expression, potentially impacting lipid and carbohydrate metabolism. The aim of this integrative review was to summarize all observational and experimental studies on the rs670 SNP available in the Scopus, ScienceDirect, dbSNP, and LitVar2 databases up to July 2024. In total, 162 articles were identified, of which 28 met the inclusion criteria. Most studies originated from Asia and were published between 2009 and 2023. Of the selected studies, 14 (50%) examined the association of the rs670 SNP with metabolic disorders. Among these, eight (28.57%) reported an association between the polymorphic allele and alterations in lipid profiles, proinflammatory markers, and insulin resistance. The remaining studies explored associations between the polymorphic allele and ischemic events, pharmacological therapies, diet, neurodegenerative diseases, pancreatitis, and breast cancer. The rs670 SNP occurs in more than 20% of the global population. Its position within the promoter region enables it to potentially regulate the APO cluster on chromosome 11. This review underscores the need for further investigation into the impact of this polymorphism on gene expression and its role in the pathogenesis of metabolic syndrome, cardiovascular disease, and cancer.

Association between Catechol-O-Methyltransferase (COMT) gene rs4680 SNP and rs165599 SNP and schizophrenia: A meta-analysis of case-control studies

The relationship between schizophrenia and single-nucleotide polymorphisms (SNPs) in the Catechol-O-MethylTransferase (COMT) gene has been investigated in numerous research, yielding varying conclusions. The investigation aimed to perform a meta-analysis for the purpose of determining the combined impact measure of the association of the COMT gene rs165599 SNP and ra4680 SNP with schizophrenia. The effect size used to assess the relationship between these two SNPs and schizophrenia was the odds ratio (OR). R studio was used to achieve the pooled ORs. Additionally, for the sake of assessing bias of publications, this paper utilize the Egger's test. Meta-analyses involving 19 independent studies have not revealed a statistically significant association between rs4680 and rs165599 SNPs and schizophrenia; however, the A versus A genetic model regarding rs4680 SNP has demonstrated a positive association with schizophrenia (OR=0.86,95% CI = 0.75-0.99, I= 42%,P= 0.04), which is dependent on two studies. According to this study, there may be no association between the COMT gene rs16599 SNP and rs4680 SNP and the risk of schizophrenia or its psychopathological symptoms.

Structural variants contribute to phenotypic variation in maize.

Comprehensively identifying the loci shaping trait variation has been challenging, in part because standard approaches often miss many types of genetic variants. Structural variants (SVs), especially transposable elements (TEs), are likely to affect phenotypic variation but we lack methods that can detect polymorphic structural variants and TEs using short-read sequencing data. Here, we used a whole genome alignment between two maize genotypes to identify polymorphic structural variants and then genotyped a large maize diversity panel for these variants using short-read sequencing data. After characterizing SV variation in the panel, we identified SV polymorphisms that are associated with life history traits and genotype-by-environment (GxE) interactions. While most of the SVs associated with traits contained TEs, only two of the SVs had boundaries that clearly matched TE breakpoints indicative of a TE insertion, while the other polymorphisms were likely caused by deletions. One of the SVs that appeared to be caused by a TE insertion had the most associations with gene expression compared to other trait-associated SVs. All of the SVs associated with traits were in linkage disequilibrium with nearby single nucleotide polymorphisms (SNPs), suggesting that the approach used here did not identify unique associations that would have been missed in a SNP association study. Overall, we have created a technique to genotype SV polymorphisms across a large diversity panel using support from genomic short-read sequencing alignments and connecting this presence/absence SV variation to diverse traits and GxE interactions.

Unveiling therapeutic targets for spinal stenosis from genetic insights: a Mendelian randomization analysis

Spinal stenosis is a commonly chronic spinal degenerative disease, which is a major cause of pain and dysfunction in the elderly. Mendelian randomization (MR) has been widely applied to repurpose licensed drugs and identify novel therapeutic targets. Consequently, we intended to identify new therapeutic targets for spinal stenosis and to analyze their possible mechanisms and potential side effects.We conducted the Mendelian randomization analysis to identify potential drug targets for the management of spinal stenosis. Cis-expressed quantitative trait loci (cis-eQTL) data as genetic instrumental variables were acquired from the eQTLGen consortium. The summary statistics for single nucleotide polymorphism (SNP) associations of spinal stenosis were obtained from the FinnGen study(20,807 cases and 294,770 controls). Co-localization analysis was performed to determine whether there was shared causal variation between the SNPs associated with spinal stenosis as well as the eQTL. Multiple external validations were performed to reinforce the reliability and stability of the findings utilizing the cis-eQTL from the GTEx portal, the Ferkingstad et al. pQTL dataset, and the Sun et al. pQTL dataset. The viability of the identified drug targets for future clinical applications was elucidated through the phenome-wide association study and drug candidate prediction. Three drug targets (BMP6, DLK1, and GFPT1) exhibited significant causal associations with spinal stenosis in the eQTLGen cohort by MR analysis, which was strongly supported by the results of the co-localization analysis. The causal association of DLK1 and GFPT1 with spinal stenosis remained remarkable with multiple external validations. Multivariate MR and phenome-wide association study analysis indicated that both targets were not associated with other traits. In addition, phenome-wide association study analysis and drug prediction analysis demonstrated the potential of these two targets for future clinical applications. In this study, DLK1 and GFPT1 were identified as promising novel therapeutic targets for spinal stenosis, providing initial genetic insights for drug development in spinal stenosis.

Lung cancer, platinum analog-based frontline treatment and pharmacogenetic limitations.

Lung cancer has the highest mortality rate among all the highly prevalent neoplasia globally. The major concern with its frontline treatment-cisplatin, is the rapid progression of chemoresistance and multi-organ-based toxicities including hearing loss and tinnitus, nephrotoxicity, hepatotoxicity and myelosuppression including anemia and neutropenia. In this review, studies concluding the association of single nucleotide polymorphisms (SNP) in disparate genes with aforementioned toxicity points are summarized to observe the pharmacogenomic pattern. Especially, SNPs in ATP7B, ERCC-1, ERCC-2, MATE-1, OCT-2, ABCB-1, ABCC-1, ABCG-2, ABCC-2, SLC22A, ERCC-5, BRCA-1, GSTM-3, GSTM-4 and GSTM-5 genes appear to be associated with the therapeutic response and/or adverse effects of cisplatin. We recommend utilizing this information to minimize the risk of treatment failure due to chemoresistance and adverse effects on other organs.

Association of IL1RN VNTR and NKG2A polymorphisms with hepatitis E infection, a case study from western India.

Interleukin 1 receptor antagonist (IL1RN) is a competitive inhibitor of interleukin 1 (IL-1). Natural killer cells (NK cells) contribute to the elimination of viruses by their antiviral effector function, which depends on a balance between inhibitory and activating receptor genes such as NKG2D and NKG2A. Using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assays, the association of intronic single-nucleotide polymorphisms (SNPs) in these genes with viral infection were assessed in 111 patients with hepatitis E virus (HEV) infection and 222 HEV-naive healthy controls. An SNP in the IL1RN (VNTR) gene revealed allele 2 to be associated with protection against HEV infection (IL1RN *1/*1 vs. IL1RN *2/*2, OR = 0.26, 95% CI = 0.14-0.47, p < 0.001). Similarly, a polymorphism in the intronic region of NKG2A revealed an association with protection in a co-dominant model (A/A vs. A/G: OR = 0.40; 95% CI = 0.24-0.67; A/A vs. G/G: OR = 0.25; 95% CI = 0.10-0.57; p < 0.05) and an association with susceptibility in a dominant model (A/A + A/G vs. G/G: OR = 2.28; 95% CI = 1.06-4.93; p < 0.05) and a recessive model (AA vs. AG + GG: OR = 2.71; 95% CI = 1.66-4.48; p < 0.001). Our data suggest that genetic polymorphisms in host NKG2A and IL1RN have both protective and detrimental roles in HEV infection, although their impact on disease outcome remains unknown.

Association of a non-synonymous variant of MLH3 gene involved in meiotic recombination with conception rate of Japanese Black cattle

Context Conception rate, which is an important parameter to evaluate female fertility, has been gradually decreasing in Japanese Black cattle during the past decades. Meiosis is an essential biological process in gamete formation and meiotic failure could be a cause of infertility or reduced fertility in mammals. Of note, single nucleotide polymorphisms (SNPs) in the MLH3 gene involved in meiotic recombination were reported to affect the genome-wide recombination rate of meiosis in cattle. Aims The present study was conducted to investigate the association of SNPs in the MLH3 gene with conception rate in Japanese Black cattle. Methods On the basis of the reproductive data of 2045 Japanese Black cattle born from 1990 to 2009, we selected two groups of the reproductive females with high conception rate (n = 103) and low conception rate (n = 109). Then, we genotyped the SNPs in MLH3 gene in both reproductive groups by sequencing and polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). The significant association of SNPs with conception rate in Japanese Black cattle was estimated by Fisher’s exact test, by using R commander. Key results We found the presence of five SNPs of MLH3 gene in Japanese Black cattle, including non-synonymous variants of MLH3 N408S that has been reported to be involved in meiotic recombination rate and MLH3 S591G newly identified in the present study. Comparison of genotype distributions and allele frequencies of the MLH3 N408S between high and low conception-rate groups indicated a significant difference between these groups, suggesting that this SNP is associated with conception rate. However, there is no significant difference between MLH3 S591G with conception rate in Japanese Black cattle. Conclusions We found a significant association between a non-synonymous variant of MLH3 N408S and conception rate, suggesting that this SNP can be a potential marker for selecting the Japanese Black cattle for improving fertility. We also identified a novel non-synonymous variant of MLH3 S591G in Japanese Black cattle. Implications These findings will be informative for future marker-assisted selection to improve the fertility of Japanese Black cattle. This is the first report of a genetic variant implicated in meiotic recombination being linked to female fertility in cattle.

Genetic association of the kynurenine pathway to suicidal behavior

Suicidal behavior has been associated with dysfunctions in the kynurenine pathway, including alterations in the levels of neuroprotective and neurotoxic metabolites. Changes in the catalytic activity of enzymes within the pathway may contribute significantly. Variations in the genes encoding enzymes within the pathway can significantly affect their catalytic activity, playing a crucial role in the process. To explore this possibility, we hypothesized that these genetic variations would occur more frequently in patients with a history of suicidal behavior compared to non-suicidal individuals. Thus, we investigated the relationship between a history of suicide attempts and five single nucleotide polymorphisms (SNPs) within genes involved in the kynurenine pathway: IDO1 (rs7820268), IDO2 (rs10109853), KMO (rs1053230), KAT1 (rs10988134), and ACSMD (rs2121337). Our sample comprised 849 subjects: 325 individuals who had attempted suicide in their lifetime (SAs), 99 individuals with a history of major depression disorder but no previous suicide attempts (non-SAs), and 425 non-psychiatric controls (CTRL). We performed SNP association analyses using codominant, dominant, and recessive models. Adjustment for sex and multiple comparisons was applied. After adjustment, the analysis revealed that SAs showed a significantly higher frequency of T alleles and TT genotypes of the rs1053230 SNP compared to CTRL across nearly all models. Furthermore, in the recessive model, non-SAs displayed a higher prevalence of the TT genotype of the rs10109853 SNP compared to CTRL.The rs1053230 and rs10109853 SNPs could play a role in the previously observed metabolic dysregulation among SAs and non-SAs, respectively. To validate our findings, it is crucial to conduct functional analyses to investigate the impact of rs10109853 and rs1053230 SNPs on the expression and/or catalytic activity of the corresponding enzymes.

EPCO-53. CHARACTERIZING THE FUNCTIONAL IMPACT OF GERMLINE-INHERITED RISK ALLELES IN GLIOMA EVOLUTION

Abstract Efforts to understand etiology of glioma led researchers to investigate associated genetic factors. Genome Wide Association Studies (GWAS) conducted to that end, uncovered an association of various single nucleotide polymorphisms (SNP) among hallmark oncogenes and tumor suppressors as risk variants in glioma incidence. Here, we perform in vitro modeling of four risk alleles/SNPs((rs723527 (EGFR), rs55705857 (MYC), rs7572263 (IDH1), rs78378222 (TP53)) mapped to non-coding regulatory regions of the genome, to assess their causal contribution to glioma evolution. To model the aforementioned risk alleles in an in-vitro system, we used a CRISPR-knock in strategy in human induced pluripotent stem cells (hiPSCs) and verified by Sanger sequencing. To study the effects of the risk alleles on brain cell types, we generated a cerebral organoid model from the edited and control lines and subjected them to downstream morphological and transcriptomic analyses. While we did not see morphological changes in the histological sections relative to controls at the early 14-day timepoint, we observed increased differentiation in both control and risk cohorts, along with an absence of neural rosettes, at the late 90-day timepoint. Bulk RNA-seq of the organoids at 14-days resulted in positive enrichment of oncogenic signaling pathways and negative enrichment of DNA repair pathways in the risk allele cohorts. Furthermore, single cell RNA seq of 14 and 90-day samples revealed a sharp decrease in neural stem cell clusters in both IDH and TP53 cohorts, while control organoids demonstrated robust production of immature neurons at 90 days. Overall, we observed a significant increase in differentiation into mature cell clusters in the control, relative to the risk allele organoids. Ongoing efforts are aimed at understanding this apparent differentiation block in the IDH and TP53 compartments, relative to control. Further analysis will lead to addressing key understudied areas of glioma etiology and associated mechanisms of risk incidence.

E-cadherin Single Nucleotide Variants Are Associated with Increasing Susceptibility to Periodontitis.

To investigate the association of E-cadherin single nucleotide polymorphisms (SNPs) with periodontitis and the potential of these SNPs for identifying susceptibility to periodontitis. Periodontal clinical parameters were recorded followed by collecting venous blood for DNA extraction. Polymerase chain reaction was used to amplify target segments of the E-cadherin gene. Determination of the genotype and allele frequencies was performed using Sanger sequencing. All statistical analyses were performed using GraphPad Prism (version 9) using a statistically significant difference of p < 0.05. A total of 207 participants were recruited into two groups of healthy controls (n = 105) and cases diagnosed with periodontitis stage 2 or 3, grade B or C (n = 102). Analyses indicated that the genotypes and alleles of rs3743674 and rs5030625 E-cadherin SNPs were significantly associated with periodontitis. Results from a binary regression model suggested that the presence of these SNPs may indicate susceptibility to periodontitis and increase the rate of progression. Linkage disequilibrium analysis indicated that E-cadherin variants rs3743674 and rs5030625, and rs10272115 and rs16260 were correlated in a nonrandom manner (r 2 = 0.638 and 0.495, respectively). E-cadherin gene variants, rs3743674 and rs5030625, were associated with the periodontitis phenotype. These biomarkers may identify individuals susceptible to periodontitis and the rate of disease progression.

Association of ACE2 Gene Variants with Adverse Perinatal Outcomes in COVID-19 Infected Pregnant Women in Kazakhstan.

SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptors located on membranes to enter host cells. Nevertheless, the ACE2 gene primarily encodes for a zinc metalloproteinase, which is a part of the renin-angiotensin system (RAS). ACE2 downregulation results in the deregulation of RAS in favor of pro-fibrosis, pro-apoptosis, oxidative stress, pro-inflammation, aldosterone production and release, and blood vessel contraction axis. ACE2 is highly expressed in the placenta. There are both axes of the RAS system in the placenta. This study aims to assess the perinatal outcomes with ACE2 receptor polymorphisms in pregnant women infected with SARS-CoV-2 during pregnancy. The case-control study was conducted to determine the association of ACE2 single-nucleotide polymorphisms in 171 COVID-19-positive pregnant subjects and 112 control subjects. The recessive mutations of rs2158082 and rs4830974 were associated with an increased risk of low birthweight and preterm birth, whereas the dominant mutation of rs2285666 (CT + TT) was associated with decreased odds of low birthweight. COVID-19 was not a significant factor contributing to the adverse perinatal outcomes in our sampling. These findings may help to clarify the controversy regarding the increased risk of adverse perinatal outcomes observed during COVID-19 as well as provide new perspectives for research on the genetic factors associated with a higher risk of adverse perinatal outcomes.