Significant Differences In Allele Frequencies Research Articles

Identification of genetic variants by using a whole exome sequencing approach in Taiwanese patients with Brugada Syndrome

Abstract Background Brugada Syndrome (BrS) is a life-threatening arrhythmia disease primarily affecting young men. Many genetic studies have been conducted mainly in Caucasian BrS patients to identify potential genetic drivers. SCN5A mutations are less common in Asian BrS patients (around 10%) compared to Caucasian patients (20-30%). This means the pathogenic process of more than 70% of BrS patients remains unclear. With the advancement in NGS technologies, we can conduct genome-wide screening of DNA variants in BrS patients efficiently. Purpose Since less than 30% of the BrS patients have known genetic drivers for the disease, we aimed to identify more DNA variants in BrS patients by using the whole exome sequencing (WES) approach. Furthermore, we evaluated the landscape of DNA variants in the two groups of BrS patients according to whether they have SCN5A mutations or not. Methods A total of 201 BrS patients were recruited for the WES experiments. After obtaining the raw sequencing data, we performed the quality check procedures using the multiQC and Trimmomatic softwares (Figure 1). For reads passing the quality check, the BWA algorithm was used for the alignment. Next, the samtools, bamtools, and Picard methods were used to remove duplicates and perform the sorting. Subsequently, those sorted sequencing files were used to call the DNA variants by using the GATK approach and annotate them using the ANNOVAR method. The 201 BrS patients were classified into two different groups based on their mutation status of SCN5A, presentation of sudden cardiac death (SCD), and SCD along with syncope. The gene-based algorithm, SKAT, was used to analyze the summarized effects of DNA variants located in a single gene. For each DNA variant, Fisher's exact test was used to compare the allele frequency in the BrS patients under their groupings. Results The WES approach in the 201 BrS patients revealed a total of 205,454 variants, which were further categorized into two groups, common variants (51,867) and rare variants (153,587), based on their allele frequencies (5%). The SKAT algorithm was performed in the 30 genes that have been previously reported to be associated with BrS. No significant differences were observed in any gene in BrS patients for the common variants. Intriguingly, KCNJ8, SCN1B, ZFPM2, MAPRE2, and KCNE5 showed significant differences in allele frequencies between the SCN5A+ and SCN5A- patients (Figure 2). Fisher's exact test further revealed that three DNA variants (chr19:35524980, chr12:21926440, chr6:126210346) were significantly enriched in SCN5A+ patients. The 5 DNA variants located in ZFPM2 showed a linkage disequilibrium block and were enriched in SCN5A+ patients. Conclusions The WES approach in BrS patients revealed DNA variants that were reported in previous studies. Several DNA variants were significantly enriched in SCN5A+ patients, suggesting that the genome-wide mutation landscape was different in SCN5A+ and SCN5A- BrS patients.Figure 1Figure 2

Investigating Leptin Gene Variants and Methylation Status in Relation to Breastfeeding and Preventing Obesity

Objective: We investigated whether the results of leptin gene (LEP) 2548G/A (rs7799039) and leptin receptor gene (LEPR) 668 A/G (rs1137101) variants, as well as the methylation analysis of CpG regions at nucleotides −31 and −51 of the LEP gene, showed any differences between breastfed and non-breastfed children in this study. Materials and Methods: The cross-sectional study included 100 children aged 2–5 years who were attending nursery and kindergarten and had been accepted to the Department of General Paediatrics. Infants who were exclusively breastfed for the first six months after birth constituted the study group, and those who were not only breastfeed constituted the control group. Methylation percentages at CpG islands of the LEP gene were compared between exclusively breastfed and non-exclusively breastfed infants, and the statistical significance was analyzed by looking for changes in LEP −31 and −51 nt methylation and LEP 2548G/A ve LEPR 668 A/G variants. Results: Both groups were compared by feeding, and the association of LEPR and LEP gene polymorphisms and −51 nt and −31 nt methylations were analyzed. There were no significant differences between the groups regarding genotype and allele frequency for the LEPR 668 A/G, LEP 2548 G/A gene variant, −31 nt methylation, and −51 nt methylation status. Similarly, there was no significant difference in genotype and allele frequency for the LEPR 668 A/G gene variant in terms of duration of exclusive breastfeeding, total breastfeeding, body mass index, family obesity, and satiety status. However, maternal support from family elders and physical activity increased the 51 nt methylation, but this methylation was not significantly affected by BMI, age, or satiety status. Conclusions: Maternal support from family elders and physical activity were associated with increased 51 nt methylation, but this methylation was not significantly affected by BMI, age, or satiety status. However, there are not enough studies in this area to reach a definitive conclusion, and further research is needed.

Genomic association of SNPs rs4077582 of CYP11A1 and rs700519 of CYP19A1 genes with polycystic ovarian syndrome.

Polycystic Ovarian Syndrome (PCOS) is a complex endocrine disorder that affects women of reproductive age. Several candidate genes have been shown to be associated with PCOS. Previous studies have shown that variations in CYP11A1 and CYP19A1 genes are associated with hormonal dysregulation associated with PCOS in different ethnic populations. This study aims to investigate the genomic association between SNPs rs4077582 of CYP11A1 and rs700519 of CYP19A1 and the development of PCOS in Pakistani population. A total of 280 subjects were recruited for the study, including 142 PCOS cases diagnosed based on Rotterdam criteria and 138 age-matched controls. The anthropometric, hormonal and biochemical parameters of all subjects were analyzed. Genomic DNA was extracted and genotyping of the selected SNPs was performed using Sanger sequencing. Further, we also examined the genotypic-phenotypic correlation analysis for various clinical and biochemical parameters for SNP rs4077582 of CYP11A1. We found significant differences in allele frequency (OR = 0.42, 95% CI = 0.30-0.60, χ2 = 16.3693, p = 0.000052) and genotypic frequency (χ2 = 26.4376, p = 0.00001) between PCOS women and controls for SNP rs4077582 of CYP11A1. Genotype-phenotype correlation analysis showed a significant difference in FAI (p = 0.005), testosterone (p = 0.001), androstenedione (p = 0.005) and urea (p = 0.049) levels between the three genotypes. No association between SNP rs700519 of CYP19A1 and PCOS was observed. Our results suggest the role of SNP rs4077582 of CYP11A1 gene in the clinical manifestation of PCOS in Pakistani women.

Genotype distribution and allele frequency of thioester-containing protein 1(Tep1) and its effect on development of Plasmodium oocyst in populations of Anopheles arabiensis in Ethiopia.

Thioester-containing protein 1 (TEP1) is a crucial component of mosquitoes' natural resistance to parasites. To effectively combat malaria, there is a need to better understand how TEP1 polymorphism affects phenotypic traits during infections. Therefore, the purpose of this study was to determine the Tep1 genotype frequency in malaria vector populations from south-western Ethiopia and investigate its effect on Plasmodium oocyst development in Anopheles arabiensis populations. Using standard dippers, Anopheles mosquito larvae were collected from aquatic habitats in Asendabo, Arjo Dedessa, and Gambella in 2019 and 2020. Collected larvae were reared to adults and identified morphologically. Female An. gambiae s.l. were allowed to feed on infected blood containing the same number of gametocytes obtained from P. falciparum and P. vivax gametocyte-positive individuals using indirect membrane feeding methods. Polymerase Chain Reaction (PCR) was used to identify An. gambiae s.l. sibling species. Three hundred thirty An. gambiae s.l. were genotyped using Restricted Fragment Length Polymorphism (RFLP) PCR and sub samples were sequenced to validate the TEP1 genotyping. Among the 330 samples genotyped, two TEP1 alleles, TEP1*S1 (82% frequency) and TEP1*R1 (18% frequency), were identified. Three equivalent genotypes, TEP1*S1/S1, TEP1*R1/R1, and TEP1*S1/R1, had mean frequencies of 65.15%, 2.12%, and 32.73%, respectively. The nucleotide diversity was ranging from 0.36554 to 0. 46751 while haplotype diversity ranged from 0.48871 to 0.63161, across all loci. All sample sites had positive Tajima's D and Fu's Fs values. There was a significant difference in the TEP1 allele frequency and genotype frequency among mosquito populations (p < 0.05), except populations of Anopheles arabiensis from Asendabo and Gambella (p > 0.05). In addition, mosquitoes with the TEP1 *RR genotype were susceptible and produced fewer Plasmodium oocysts than mosquitoes with the TEP1 *SR and TEP1 *SS genotypes. The alleles identified in populations of An. arabiensis were TEP1*R1 and TEP1*S1. There was no significant variation in TEP1*R1 allele frequency between the high and low transmission areas. Furthermore, An. arabiensis carrying the TEP1*R1 allele was susceptible to Plasmodium infection. Further studies on vector-parasite interactions, particularly on the TEP1 gene, are required for vector control techniques.

Advancing pharmacogenomic research in US Hmong populations: prevalence of key single nucleotide variations in California Hmong.

In collaboration with the Minnesota Hmong community, we have previously discovered significant differences in allele frequencies for key Single Nucleotide Variations (SNVs) within Very Important Pharmacogenes (VIPs) between Hmong and East Asians. Recognizing the potential clinical implications of these observed differences, we sought to validate these observations in a Hmong cohort residing in California, the state with the largest Hmong population in the US. Robust validation of these differences would affect motivation for clinicians treating individuals who identify as Hmong to consider pharmacogenomic (PGx) testing as a means to improve clinical decision making when using therapeutic agents in this unique population. Guided by California Hmong community leaders and utilizing the basic approach of community-based participatory research, demographic, clinical information and a buccal swab was obtained from Hmong adults residing in California. A commercial PGx testing panel was performed on these samples and specific allele frequencies of interest were compared between California and Minnesota Hmong. Allele frequency differences between California Hmong, East Asians and Europeans, were also compared. Return-of-PGx-results and presentations of group data were made to members of the Hmong along with PGx educational sessions to help interpret the observations. In 118 California Hmong who completed the study, the allele frequencies for SNV's were similar to previous Minnesota Hmong results. Furthermore, out of the 18 SNVs that were not previously reported in Hmong, allele frequencies were statistically different in 38% (7/18) of SNVs comparing California Hmong to East Asians, and in 77.8% (14/18) SNVs comparing California Hmong to Europeans. These results validate the original study's findings that Hmong people living in different US locations have similar allele frequencies for key PGx genes. Further, for many of these PGx genes, their allele frequencies are significantly different compared to either East Asians or Europeans. Clinicians should consider these important differences when prescribing medications for people who identify as Hmong.

Molecular characteristics of NPM1 mutations in AML patients using targeted NGS

ABSTRACT Background Acute myeloid leukemia (AML) is a clonal hematopoietic stem cell malignancy characterized by the accumulation of myeloid progenitor cells with arrested differentiation, leading to the suppression of normal hematopoiesis. The disease exhibits significant heterogeneity, with less than 30% five-year overall survival. Nucleophosmin 1 (NPM1) is the most commonly mutated gene in adult AML, found in approximately 25–35% of patients, and is recognized as a distinct subtype by the WHO. Methods The mutational status of NPM1 was assessed using the Oncomine Myeloid research panel on the Ion5S NGS platform (Thermo Fisher Scientific, USA). Results In our AML cohort, NPM1 was the most frequently mutated gene (75%). Indel mutations in the NPM1 gene, frequently resulting in frameshift consequences, show a statistically significant difference in variant allele frequency (VAF) compared to other mutation types. Specifically, NPM1-mutated cases exhibit a VAF that is positively correlated with initial bone marrow (BM) blast counts. Univariate logistic regression analysis reveals that a high VAF is significantly associated with non-complete remission (Non-CR), while a low VAF is significantly associated with complete remission (CR), indicating a statistically significant difference in outcomes (p = 0.012). Conclusion Targeted NGS technology enables the simultaneous analysis of multiple AML-relevant genes, offering a comprehensive mutational profile that supports risk stratification, diagnosis, and personalized treatment. Our findings highlight the significant impact of NPM1 mutations on patient outcomes, revealing their molecular characteristics and their correlation with different clinical parameters.

MiR-146a rs2910164 (G/C) variant may predict morbid obesity risk in adults

Obesity is a common public health problem associated with serious, life-threatening complications. MicroRNAs (miRs) have modulating roles in the immune and inflammatory systems. Therefore, this study aimed to analyze the relationship between miR-146a and morbid obesity (MO) in a Turkish population. In this study, a total of 258 subjects (110 patients with MO and 148 controls) were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze miR-146a rs2910164. Then, we examined the patients as males and females separately. The results of the analyses were evaluated for statistical significance. There was a significant difference in genotype and allele frequencies of miR-146a rs2910164 between patients with MO and control individuals. miR-146a rs2910164 CC genotype and C allele were shown to increase in the MO patients’ group compared to the control group (p = 0.000, p = 0.000, respectively). Also, the C allele was higher in both female and male patients compared to controls (p = 0.000, p = 0.000, respectively). High differences were also observed when the patients and the controls were compared according to CC versus GG + GC and GG versus GC + CC (p = 0.000, p = 0.000, respectively). A significant difference was found between the female/male patients and the female/male controls in terms of GG + GC versus CC (p = 0.000, p = 0.000, respectively). To the best of our knowledge, this is the first study to investigate the relationship between this variant and MO in Turkey. Our results showed that miR-146a rs2910164 is a valuable biomarker that can be used to distinguish between patients with MO and the healthy population. The findings can be extended by increasing the sample sizes with diverse ethnicities.

Association of VEGFR1, VEGFR2 and VEGFR3 polymorphisms with esophageal cancer risk: a case–control study

BackgroundEsophageal cancer is the eleventh most common cancer and is the seventh leading cause of mortality worldwide. Vascular endothelial growth factor (VEGF) and its receptors pathway are a key regulator of angiogenesis and play an important role in carcinogenesis. The aim of current study was to evaluate the association of five VEGFR polymorphisms with esophageal cancer risk in patients from Punjab, North-west India.MethodsThis case–control study included 310 esophageal cancer patients and 325 age and gender matched healthy controls. VEGFR1-710C/T, VEGFR2-604 T/C (rs2071559), VEGFR2 1192 G/A (rs2305948), VEGFR2 1719A/T (rs1870377) and VEGFR3 (rs72816988) polymorphisms were genotyped by using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method. Restriction digestion products were analyzed on 2.4% agarose gel and genotype was assigned to each sample on the basis of fragments obtained after digestion. Randomly 10% samples were repeated by Sanger sequencing to revalidate the results.ResultsThere was a significant association of CT genotype (OR = 0.28; 95%CI, 0.10–0.76; p = 0.01) and T allele (OR = 0.28; 95%CI, 0.10–0.77; p = 0.01) of VEGFR1-710C/T polymorphism with decreased risk of esophageal cancer. TC genotype of VEGFR2-604 T/C (OR = 0.66; 95%CI, 0.44–0.97; p = 0.03) and GA genotype of VEGFR2 1192G/A (OR = 0.54; 95%CI, 0.31–0.95; p = 0.03) polymorphisms were significantly associated with decreased risk of esophageal cancer. There was no significant difference in allele and genotype frequency of VEGFR2 1719A/T and VEGFR3 (rs72816988) polymorphisms between esophageal cancer patients and controls (p > 0.05). Haplotype analysis revealed that haplotype C-604A1719A1192 was significantly associated with the decreased esophageal cancer risk (OR = 0.44; 95%CI, 0.23–0.84; p = 0.01).ConclusionVEGFR1-710C/T, VEGFR2-604 T/C and VEGFR2 1192G/A polymorphisms were associated with the decreased risk of esophageal cancer in patients from Punjab, North-west India.Graphical abstract

Association between angiotensin-converting enzyme gene insertion/deletion polymorphism and cognition impairment in patients with schizophrenia.

Several lines of evidence indicate that an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) gene may be involved in the pathogenesis of schizophrenia and cognitive impairment. However, the relationship between ACE I/D polymorphism and cognitive impairment in patients with schizophrenia remains unclear. The aim of this study was to examine whether ACE gene I/D polymorphism contributed to cognitive impairment in Chinese patients with schizophrenia, and whether the association between clinical symptoms and cognitive impairment depended on different ACE genotypes. The ACE I/D polymorphism was genotyped in 928 schizophrenia patients and 325 healthy controls using a case-control design. The severity of psychopathological symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive functioning was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). There were significant differences in genotype and allele frequencies of the ACE I/D polymorphism between patients and healthy controls (both P < 0.01). After controlling for demographic characteristics, patients who are homozygous carriers of D and I performed worse on the RBANS attention index than heterozygous carriers (P = 0.009). In addition, attention index score was negatively correlated with PANSS negative symptom score in patients of all genotypes (all P < 0.05), and positively correlated with positive symptom score only in the I/I genotype (P = 0.005). These findings suggest that ACE I/D gene variants play a role in susceptibility to schizophrenia, specific cognitive impairment and the association between clinical symptoms and cognitive impairment in schizophrenia patients.

Worldwide genetic variability of the rs1861868 SNP in the FTO gene associated with obesity

Introduction: genetic predisposition to obesity is linked to an imbalance between food intake and energy expenditure, regulated by the nervous and endocrine systems. The FTO gene variants significantly impact obesity susceptibility in different populations. The objective of the research was to analyze the genetic variability of the SNP rs1861868 in the FTO gene and its association with obesity in various populations.Method: genotype data from 1000 Genomes and allele frequencies from ALFRED were analyzed. Moran's I assessed spatial autocorrelation, Hardy-Weinberg equilibrium was tested using VCFtools, and ANOVA compared risk allele frequencies across continents.Results: Moran's I indicated no significant spatial autocorrelation globally, but higher concentrations of the risk allele were observed in Europe. ANOVA showed significant differences in risk allele frequencies among continents, with Europe having the highest frequency. Hardy-Weinberg equilibrium was observed within macro populations but not globally.Conclusions: regional variations significantly impact the distribution of the rs1861868 (T) risk allele. Evolutionary, historical, and demographic are candidate factors that shaped the genetic landscape of the FTO gene related to obesity

The Effect of Genetic Variants of SLC22A2 (rs662301 and rs315978) on the response to Metformin in type 2 Saudi diabetic patients

PurposeTo investigate the allelic and genotypic frequencies of the two genetic variations, NC_000006.12: g.160275887C > T (rs662301) and NC_000006.12:g.160231826 T > C (rs315978), in the SLC22A2 gene among the Saudi population. The primary goal is to elucidate potential associations with these genetic variations and the response to metformin therapy over 6 months to enhance our knowledge of the genetic basis of Type 2 Diabetes Mellitus (T2DM) and its clinical management in the Saudi population. Materials/Methods76 newly diagnosed T2DM patients, aged 30 to 60, of both sexes and Saudi origin, were treated with metformin monotherapy. Blood samples were collected before and after 6 months of therapy,80 healthy individuals were included as controls. Genomic DNA was extracted. Genotyping of the SLC22A2 genetic variations was performed using TaqMan® SNP Genotyping Assays. Binary logistic regression was utilized to evaluate how certain clinical parameters influence T2DM concerning the presence of SLC22A2 gene variants. ResultsAmong these patients, 73.3 % were responders, and 26.7 % were non-responders. For these variants, no statistically significant differences in genotype or allele frequencies were observed between responders and non-responders (p = 0.375 and p = 0.384 for rs662301; p = 0.473 and p = 0.481 for rs315978, respectively). For the SLC22A2 variant rs662301, the C/C genotype was significantly associated with increased T2DM risk with age and elevated HbA1c levels. Similarly, rs315978 revealed higher T2DM susceptibility and HbA1c elevation in C/C genotype carriers, specifically with advancing age compared to individuals with C/T and T/T genotypes. ConclusionThe study offers insights into the genetic landscape of T2DM in Saudi Arabia. Despite the absence of significant associations with treatment response, the study suggests potential age-specific associations, this highlights the complexity of the disease. This research underscores the necessity for expanded research, considering diverse populations and genetic factors, to develop personalized treatment approaches. This study serves as a foundation for future investigations into the Saudi population, recognizing the need for a larger sample size.

Neuregulin 2 Is a Candidate Gene for Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with heterogeneous and complex genetic underpinnings. Our previous microarray gene expression profiling identified significantly different neuregulin-2 gene (NRG2) expression between ASD patients and controls. Thus, we aimed to clarify whether NRG2 is a candidate gene associated with ASD. The study consisted of two stages. First, we used real-time quantitative PCR in 20 ASDs and 20 controls to confirm the microarray gene expression profiling results. The average NRG2 gene expression level in patients with ASD (3.23 ± 2.80) was significantly lower than that in the controls (9.27 ± 4.78, p < 0.001). Next, we conducted resequencing of all the exons of NRG2 in a sample of 349 individuals with ASD, aiming to identify variants of the NRG2 associated with ASD. We identified three variants, including two single nucleotide variants (SNVs), IVS3 + 13A > G (rs889022) and IVS10 + 32T > A (rs182642591), and one small deletion at exon 11 of NRG2 (delGCCCGG, rs933769137). Using data from the Taiwan Biobank as the controls, we found no significant differences in allele frequencies of rs889022 and rs182642591 between two groups. However, there is a significant difference in the genotype and allele frequency distribution of rs933769137 between ASDs and controls (p < 0.0001). The small deletion is located in the EGF-like domain at the C-terminal of the NRG2 precursor protein. Our findings suggest that NRG2 might be a susceptibility gene for ASD.

MMP-1, MMP-8, and MMP-13 Gene Polymorphisms and Haplotype Is a Risk Factor for Dupuytren Contracture: A Case-Control Study.

There is an increased tissue expression of matrix metalloproteinases (MMPs) on Dupuytren contracture (DC). Genetic polymorphisms (single nucleotide polymorphism [SNPs]) in genes of these enzymes may individually influence these transcriptions. Haplotype analysis, which is the observation of a group of alleles, could be more useful to identify the association between SNPs and DC. The purpose of this study was to evaluate the influence of MMP-1 g.-1607 G>GG (rs1799750), MMP-8 g.-799 C>T (rs11225395), and MMP-13 g.-77 A>G (rs2252070) SNPs individually and in haplotype on DC. A total of 60 patients with a clinical diagnosis of DC were evaluated and matched, according to age and gender, with the control group of 100 patients without this clinical diagnosis. Genomic DNA was extracted from saliva samples, and genotypes were obtained by polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis of the results included Mann-Whitney U test, Chi-squared test, and PHASE and R software, with a significance level of 5%. The 3 SNPs studied showed significant differences in allele and genotype frequencies between the groups: 2G in MMP-1 (P = .018; odds ratio [OR] 1.80 (95% confidence interval [CI], 1.13-2.88)), T in MMP-8 (P = .015; OR 0.53 (95% CI, 0.33-0.88)), and A in MMP-13 (rs2252070) SNPs (P = .040, OR 0.54 (95% CI, 0.33-0.90)) are risk alleles. The global haplotype analysis indicated a significant difference between both groups. In conclusion, MMP-1 g.-1607 G>GG (rs1799750), MMP-8 g.-799 C>T (rs11225395), and MMP-13 g.-77 A>G (rs2252070) SNPs, individually and in haplotype, are a risk factor for DC, indicating that these SNPs may be a potential diagnostic and prognostic factor for DC.

The Relationship Between CYP46A1 Polymorphism and Suicide Risk: A Preliminary Investigation.

Suicide is a global public health issue, with a particularly high incidence in individuals suffering from Major Depressive Disorder (MDD). The role of cholesterol in suicide risk remains controversial, prompting investigations into genetic markers that may be implicated. This study examines the association between CYP46A1 polymorphisms, specifically SNPs rs754203 and rs4900442, and suicide risk in a Mexican MDD patient cohort. Our study involved 188 unrelated suicide death victims, 126 MDD patients, and 144 non-suicidal controls. Genotypic and allelic frequencies were assessed using the Real Time-polymerase chain reaction method, and associations with suicide risk were evaluated using chi-square tests. The study revealed significant differences in allelic and genotypic frequencies in rs754203 SNP between suicide death and controls. The CYP46A1 rs754203 genotype G/G was significantly linked with suicide, and the G allele was associated with a higher risk of suicide (OR = 1.370, 95% CI = 1.002-1.873). However, we did not observe any significant differences in genotype distribution or allele frequencies of CYP46A1 rs4900442. Our study suggests that carriers of the CYP46A1 rs754203 G allele (A/G + G/G) may play a role in suicidal behavior, especially in males. Our findings support that the CYP46A1 gene may be involved in susceptibility to suicide, which has not been investigated previously. These results underscore the importance of further research in different populations to elucidate the genetic underpinnings of the role of CYP46A1 in suicide risk and to develop targeted interventions for at-risk populations.

CYP2C8 rs11572080 and CYP3A4 rs2740574 risk genotypes in paclitaxel-treated premenopausal breast cancer patients

Breast cancer (BC) is the most prevalent malignancy in women globally. At time of diagnosis, premenopausal BC is considered more aggressive and harder to treat than postmenopausal cases. Cytochrome P450 (CYP) enzymes are responsible for phase I of estrogen metabolism and thus, they are prominently involved in the pathogenesis of BC. Moreover, CYP subfamily 2C and 3A play a pivotal role in the metabolism of taxane anticancer agents. To understand genetic risk factors that may have a role in pre-menopausal BC we studied the genotypic variants of CYP2C8, rs11572080 and CYP3A4, rs2740574 in female BC patients on taxane-based therapy and their association with menopausal status. Our study comprised 105 female patients with histologically proven BC on paclitaxel-therapy. They were stratified into pre-menopausal (n = 52, 49.5%) and post-menopausal (n = 53, 50.5%) groups. Genotyping was done using TaqMan assays and employed on Quantstudio 12 K flex real-time platform. Significant increased frequencies of rs11572080 heterozygous CT genotype and variant T allele were established in pre-menopausal group compared to post-menopausal group (p = 0.023, 0.01, respectively). Moreover, logistic regression analysis revealed a significant association between rs11572080 CT genotype and premenopausal BC. However, regarding rs2740574, no significant differences in genotypes and allele frequencies between both groups were detected. We reported a significant association between CYP2C8 genotypic variants and premenopausal BC risk in Egyptian females. Further studies on larger sample sizes are still needed to evaluate its importance in early prediction of BC in young women and its effect on treatment outcome.

Association between polymorphisms of IL33 and IL37 and atopic dermatitis

Atopic dermatitis (AD) is a chronic recurrent inflammatory disease accompanied by severe itching. One of the leading mechanisms underlying the development of AD is an imbalance of the Th1/Th2 cells immune response, which leads to an increased production of inflammatory mediators, including IL-1 family. The IL-1 family includes the recently discovered IL-33 and IL-37, and their role in the pathogenesis of AD has been actively studied. IL-33 functions as an alarmin that can induce IL-31 production, thereby leading to skin barrier impairment, pruritus and scratching. Having both immunomodulatory and immunosuppressive properties, IL-37 suppresses leukocyte infiltration of the affected skin and reduces the activity of proinflammatory cytokines. The aim of our study was to search for associations between gene polymorphisms of IL33, IL37 genes, and risk of AD. A total of 98 patients with moderate and severe AD were included in the study. The control group included 72 healthy volunteers. Polymorphic markers were determined in peripheral blood. After extraction of total RNA, polymorphic markers rs7019575 in the IL33 gene, rs3811046 and rs3811047 in the IL37 gene were analyzed using RT-PCR. There was no statistically significant difference in allele frequency and genotype distribution of rs7019575 (IL33) and rs3811047 (IL37). Studying the rs3811046 polymorphic marker in the IL37 gene showed that the risk of AD was almost 2 times lower for the G allele carriers and more than 2-fold higher for TT homozygous carriers. The haplotype analysis revealed that the GTAA and TTGG haplotypes of IL37 were associated with AD, thus increasing the risk of AD development by 2 and 10 times, respectively. In conclusion, SNP markers identified in this study can be used to predict the risk of AD development in the subjects with a positive family history of atopic diseases.

Research on the Correlation Between rs2110385 Polymorphisms of the Visfatin Gene and Nonproliferative Diabetic Retinopathy

Objective: To investigate the association between rs2110385 polymorphisms of the visfatin gene and the risk of type 2 diabetic retinopathy (DR). Methods: 172 Han subjects were selected from Xi’an Shaanxi Province；140 patients with type 2 diabetes mellitus (T2DM) and 32 normal controls (NC) were selected from our hospital. Patients with diabetes were divided into a non-DR group (T2DM) (n = 69) and a nonproliferative diabetic retinopathy Group (DR) (n =71) after dilated fundus photography and fundus fluorescein angiography. rs2110385/Alu Ⅰ genotypes were detected by standardized polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the differences in the detection rates of different genotypes in the above populations were compared. Results: 1) The visfatin level in the DR Group was significantly higher than that in the NC and T2DM groups (P &lt; 0.05). 2) The frequency of GG genotype and G allele of rs2110385 in the DR Group were higher than those in the T2DM and NC groups (80.3, 69.6, 50.0, 86.6, 79, 65.6, P &lt; 0.05). 3) There were significant differences in allele frequency and genotype frequency distribution of rs2110385 between the DR Group and the NC group (P &lt; 0.01). Conclusion: Visfatin increased in the nonproliferative diabetic retinopathy group and could be a potential indicator for the clinical prediction of DR. The G allele of the rs2110385 polymorphic site may be related to the risk of DR.

Analysis of CHIP-Related Mutation and Risk of Cardio-Cerebrovasculars Events in Patients with Myeloproliferative Neoplasms

To analyze the mutant spectrum of clonal hematopoiesis of indeterminate potential (CHIP) related mutations and clinical characteristics and to explore the correlation and the possible mechanism between CHIP-related mutations and cardio-cerebrovasculars events (CCEs) in patients with myeloproliferative neoplasms (MPNs). The clinical data and next-generation sequencing results of 73 MPN patients in Beijing Anzhen Hospital from August 2019 to July 2022 were retrospectively analyzed. Statistical analyses were conducted by multivariate logistic regression for the effects of CHIP-related mutations and inflammatory cytokines on CCEs for MPNs patients. Fifty-five cases of MPN (75.3%) showed positive in CHIP-related genes. There was no significant difference in variant allele frequency of CHIP-related gene between essential thrombocythemia (ET) and polycythemia vera (PV). CHIP-related gene mutations were mainly single gene mutations, with mutation rate from high to low as JAK2V617F (63.0%, 46/73), ASXL1 (16.4%, 12/73), TET2 (11.0%, 8/73), DNMT3A (9.6%, 7/73), SRSF2 (6.9%, 5/73), SF3B1 (4.1%, 3/73), TP53(1.4%, 1/73) and PPM1D (1.4%, 1/73). The mutation rate of CHIP-related genes in MPN patients >60 years old was significantly higher than that in the patients ≤60 years old ［91.7%(33/36) vs 59.5%(22/37)］. CCEs occurred in 27 MPNs patients (37.0%, MPNs/CCEs), and 5 had recurrent CCEs, all of which were arterial events. Age (62.8±12.8 years vs 53.9±15.8 years, P =0.015), IL-1β level (17.7±26.0 vs 4.3±8.6, P =0.012), IL-8 level (360.7±598.6 vs 108.3±317.0, P =0.045), the proportion of the patients with thrombosis history (29.6% vs 2.2%, P =0.020), and the detection rate of CHIP-related mutations (88.9% vs 67.4%, P =0.040) in the group with CCEs were higher than those in the group without CCEs. Multivariate Logistic regression analysis showed that age（OR =0.917， 95%CI ：0.843-0.999, P =0.047）, thrombosis history (OR =34.148， 95%CI ：2.392-487.535, P =0.009), any CHIP-related mutations(OR =16.065， 95%CI ：1.217-212.024， P =0.035), and elevated level of IL-1β (OR =0.929， 95%CI ：0.870-0.992， P =0.027) were independent risk factors for MPNs/CCEs. CHIP-related gene mutations were not associated with CCEs in MPN patients, but DNMT3A (OR =88.717， 95%CI ：2.690-292.482， P =0.012) and ASXL1 (OR =7.941， 95%CI ：1.045-60.353， P =0.045) were independent risk factors for CCEs in PV. There is a higher mutation rate of CHIP-related genes in MPN patients, especially those over 60 years old. Older age, thrombosis history, CHIP-related mutations and IL-1β elevated levels are independent risk factors for CCEs in MPN. DNMT3A and ASXL1 mutations are independent risk factors for CCEs in PV patients. CHIP-related gene mutations and inflammatory cytokine IL-1 β elevated levels may be the novel risk factors for CCEs in MPN.

Genetic insights into endurance athlete status: A meta-analysis of ACVR1B, AGT, FTO, IL-6, and NRF2 gene polymorphisms.

The aim of this meta-analysis was to analyze allele and genotype pattern frequencies of five different gene polymorphisms associated with endurance athlete status. Endurance sports require prolonged physical performance, and it is well known that physiological and genetic characteristics play a prominent role in this performance. In recent years, research on the impact of genetic factors on endurance athlete status has been on the rise, suggesting that various gene polymorphisms may be associated with physical performance. Specifically, the gene polymorphisms, activin receptor type-1B (A9CVR1B) rs2854464, angiotensinogen (AGT) rs699, fat mass and obesity-associated (FTO) rs9939609, interleukin-6 (IL-6) rs1800795, and nuclear factor erythroid 2 (NRF2) rs12594956, are thought to be related to endurance athlete status. Each of these genes plays a part in different biological processes, such as muscle development, energy metabolism, inflammation, and antioxidant defense mechanisms. For example, the NRF2 gene is a critical player in the regulation of cellular stress responses and may contribute to adaptive responses that enhance performance in endurance athletes. This meta-analysis included a total of 20 articles published between 2009 and 2023. The specific gene polymorphisms explored in this study, i.e., ACVR1B rs2854464, AGT rs699, FTO rs9939609, IL-6 rs1800795, and NRF2 rs12594956, were selected due to their reported associations with physical performance and endurance. A comprehensive search was conducted in the Web of Science and PubMed databases using specific keywords, preliminarily identifying 329 articles. Upon analysis of the abstracts, and full texts, 20 articles were deemed eligible for inclusion in this meta-analysis. Articles lacking control and endurance athlete groups or clear allele/genotype data were excluded. The findings indicated no significant differences in allele and genotype frequencies for ACVR1B, AGT, FTO, and IL-6 gene polymorphisms between endurance athletes and control groups. However, the NRF2 rs12594956 gene polymorphism showed a significantly higher frequency of the major allele (A) and the AA genotype in endurance athletes than in controls. In conclusion, the NRF2 rs12594956 polymorphism may be a genetic variant of interest in determining the status of endurance athletes. These findings highlight the potential clinical implications for genetic screening and personalized training programs in sport genetics. More extensive studies with larger cohorts are needed to further confirm these associations.

Association between TRAF1/C5 Gene Polymorphisms and IgA Vasculitis in Chinese Children

ABSTRACT Objective To investigate the association between loci rs3761847 and rs10818488 of tumor necrosis factor receptor-associated factor 1/complement C5 (TRAF1/C5) gene and the susceptibility to IgAV. Methods 100 blood samples of children with IgAV and 100 blood samples of healthy children were collected from the Third Xiangya Hospital of Central South University from June 2017 to June 2019. The target gene fragment was amplified by polymerase chain reaction (PCR), and the single nucleic acid gene polymorphism of the gene loci was detected by PCR sequencing based typing technique. The association between gene polymorphism of each locus and susceptibility to IgAV was analyzed. Results There were significant differences in both genotype (P < .05) and allele frequencies （P < .05) of rs3761847 of TRAF1/C5 gene between the IgAV group and the control group.Besides, the risks of developing IgAV in children with the TT genotype was 0.495 times and in children with the C allele was 1.627 times of that in children with other genotypes and alleles, respectively (P < .05). For IgAV patients, renal involvement risk in children with CC genotype was 5.859 times of that in children with other genotypes (P < .05). There were no significant differences in genotype (P > .05) and allele frequencies (P > .05) of rs10818488 of TRAF1/C5 gene between the IgAV group and the control group. IgAV patients with TT genotype had a 3.2 times higher risk of renal involvement than those with other genotypes (P < .05). Conclusions There is an association between locus rs3761847 of TRAF1/C5 gene single nucleotide polymorphisms and susceptibility to IgAV. The T allele at locus rs3761847 of TRAF1/C5 gene may be a protective factor for IgAV. The C allele at locus rs3761847 and the T allele at locus rs10818488 of TRAF1/C5 gene may be associated with kidney injury in IgAV.