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BACKGROUND: SIRT1 is a multifunctional protein, possibly essential in tumorigenesis pathways, which can act both as a tumor promoter and tumor suppressor depending on the oncogenes, specific to particular tumors. Pathogenesis of laryngeal cancer is multifactorial and the association of SIRT1 expression with the clinical characteristics and prognosis of LSCC has not been fully identified. OBJECTIVES: The study aimed to evaluate associations between single gene nucleotide polymorphisms (SNPs) of SIRT1 (rs3818292, rs3758391, and rs7895833), serum SIRT1 levels, and 5-year survival rate in patients with laryngeal squamous cell carcinoma (LSCC). METHODS: The study involved 302 patients with LSCC and 409 healthy control subjects. The genotyping of SNPs was performed using RT-PCR, and serum SIRT1 levels were determined by the ELISA method. RESULTS: Our study found significant differences in genotype distributions of SIRT1 rs3758391 polymorphisms between the study groups. SIRT1 rs3758391 T/T genotype was associated with the increased LSCC development odds (OR = 1.960 95% CI = 1.028–3.737; p= 0.041). Carriers of SIRT1 rs3758391 T/T genotype had statistically significantly increased odds of LSCC development into advanced stages under the codominant and recessive genetic models (OR = 2.387 95% CI = 1.091–5.222; p= 0.029 and OR = 2.287 95% CI = 1.070–4.888; p= 0.033, respectively). There were no statistically significant differences in serum SIRT1 levels between the LSCC and control groups. However, LSCC patients with SIRT1 rs3818292 AG genotype demonstrated a tendency to significantly lower SIRT1 serum levels than controls (p= 0.034). No statistically significant associations between SIRT1 (rs3818292, rs3758391, and rs7895833) SNPs and the 5-year survival rate of LSCC patients were found. CONCLUSION: The present study indicated a statistically significant association between the SIRT1 rs3758391 T/T genotype and increased LSCC development odds. LSCC patients with SIRT1 rs3818292 AG genotype showed a tendency to manifest with lower SIRT1 serum levels. No associations between SIRT1 SNPs and the 5-year survival rate of LSCC patients were detected.

In 2020, 2.3 million females identified with breast cancer, and it is the second most frequent cancer among females. As a result, there is severe requirement of an accurate procedure to recognize breast cancer. In accordance with breast cancer organization the breast cancer is divided into two types one is invasive and another one is non-invasive. In Indian cities like Delhi, Kolkata and Mumbai have the highest death rate for female due to breast cancer. Unusual alteration in genes is the prime reason for breast cancer. Our paper contains metabric dataset related to 1905 patients along with 31 clinical characteristics and 331 genes. The novelty of this paper is to find out genes which are highly responsible for death from breast cancer with foremost clinical features and implementation of a hybrid method which is a combination of genetic algorithm and artificial neural network to get the best accuracy with the help of machine learning as this can preserve life of females. For attribute scaling standard scaler is used which range data in between 0 and 1. Attribute selection is performed with the help of ANOVA which is a statistical appliance. With this tool 6 leading clinical attributes are examined. In our research 12 genes gsk3b, kmt2c, map4, tsc2, tnk2, pdgfb, ncoa3, akt1, afdn, sdc4,map2k2 and tubb4b which are extremely responsible for death in our dataset are recognized and our hybrid method implementation gives the perfection of 90.57%.

Attention deficit hyperactivity disorder (ADHD) is a polygenic neurodevelopmental disorder that affects 8-12 % of children and4 % of adults. Environmental factors are believed to interact with genetic predispositions to increase susceptibility to ADHD. No existing rodent model captures all aspects of ADHD, but several show promise. The main genetic models are the spontaneous hypertensive rat, dopamine transporter knock-out (KO) mice, dopamine receptor subtype KO mice, Snap-25 KO mice, guanylyl cyclase-c KO mice, and latrophilin-3 KO mice and rats. Environmental factors thought to contribute to ADHD include ethanol, nicotine, PCBs, lead (Pb), ionizing irradiation, 6-hydroxydopamine, neonatal hypoxia, some pesticides, and organic pollutants. Model validation criteria are outlined, and current genetic models evaluated against these criteria. Future research should explore induced multiple gene KOs given that ADHD is polygenic and epigenetic contributions. Furthermore, genetic models should be combined with environmental agents to test for interactions.

Bipolar disorder (BPD) is a psychiatric disease, characterized by the cycles of mania and depression. Several genetic studies investigated BDNF gene Val66Met polymorphism as risk factor for BPD, but results were inconclusive. Therefore, present meta-analysis was performed to reevaluate the BDNF Val66Met polymorphism and BPD association. Four databases (Pubmed, Springer Link, Science Direct and Google Scholar) were searched for eligible studies up to March 31,2018. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated to estimate the strength of the association. All statistical analyses were done by MetaAnalyst and Mix program. Forty studies with a total of 28,787 subjects (10,085 cases and 18,702 controls) were included in this meta-analysis. Overall, pooled analysis indicated that there was no significant association between BDNF Val66Met polymorphism and BPD risk under all five genetic models (ORA vs.G =0.99, 95%CI= 0.94-1.03, p=0.49; ORAG vs. GG= 0.1.02, 95%CI= 0.95-1.07, p= 0.57; ORAA vs. GG = 0.98, 95%CI=0.89-1.08, p=0.75; ORAA+AG vs. GG= 1.0, 95%CI= 0.94-1.06, p= 0.89;ORAA vs. AG+GG= 0.96, 95%CI= 0.89-1.05, p= 0.47). Similarly, no significant association was observed in ethnicity based subgroup analysis in both Asian and Caucasian population. However, significant association was found in subtype analysis between BDNF Val66Met and BPDII (ORAA+AG vs. GG= 1.21, 95%CI= 1.06-1.37, p= 0.003) but not with BPDI. These findings suggested that the BDNF Val66Met polymorphism confer no genetic susceptibility to BPD I but risk for BPDII.

In rodents and humans, the major cellular events at spermatogenesis include self-renewal of spermatogonial stem cells and undifferentiated spermatogonia via mitosis, commitment of spermatogonia to differentiation and transformation to spermatocytes, meiosis, spermiogenesis, and the release of spermatozoa at spermiation. While details of the morphological changes during these cellular events have been delineated, knowledge gap exists between the morphological changes in the seminiferous epithelium and the underlying molecular mechanism(s) that regulate these cellular events. Even though many of the regulatory proteins and biomolecules that modulate spermatogenesis are known based on studies using genetic models, the underlying regulatory mechanism(s), in particular signaling pathways/proteins, remain unexplored since much of the information regarding the signaling regulation is unknown. Studies in the past decade, however, have unequivocally demonstrated that the testis is using several signaling proteins and/or pathways to regulate multiple cellular events to modulate spermatogenesis. These include mTORC1/rpS6/Akt1/2 and p-FAK-Y407. While selective inhibitors and/or agonists and antagonists are available to examine some of these signaling proteins, their use have limitations due to their specificities and also potential systemic cytotoxicity. On the other hand, the use of genetic models has had profound implications for our understanding of the molecular regulation of spermatogenesis, and these knockout (null) models have also revealed the factors that are critical for spermatogenesis. Nonetheless, additional studies using in vitro and in vivo models are necessary to unravel the signaling pathways involved in regulating seminiferous epithelial cycle. Emerging data from studies, such as the use of the adjudin pharmaceutical/toxicant model, have illustrated that this non-hormonal male contraceptive drug is utilizing specific signaling pathways/proteins to induce specific defects in spermatogenesis, yielding mechanistic insights on the regulation of spermatogenesis. We sought to review these recent data in this article, highlighting an interesting approach that can be considered for future studies.

Objectives: The present study was designed to evaluate the association of transporters associated with antigen processing (TAP2) polymorphisms TAP2-379Ile > Val (rs1800454), TAP2-665Thr > Ala (rs241447) and TAP2-565Ala > Thr (rs2228396) as a candidate gene with susceptibility to the Systemic Lupus Erythematosus (SLE). Methods: To analyze these three polymorphic variants, 88 patients with SLE and 100 healthy controls from northeastern Iran were enrolled from May 2018 to July 2019. Genomic DNA polymorphisms were performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. Data were analyzed by SPSS software. Results: In this cross-sectional study, there was a stratification between patients and controls. The distribution of the frequency of Ala73 (41.5%) allele at TAP2/665 and Ile 19 (10.8%) allele at TAP2/379 was higher in patients. Additionally, the Ala/Ala 13(14.8%) and Ala/Thr 49(55.7%) genotypes distributions at 665 positions were higher in SLE patients compared to the controls. Furthermore, frequencies of TAP2*H allele significantly increased in SLE patients 10(5.71%) (P=0.01). Frequency of TAP2*A allele in the control group was 120(60%) (p=0.06) due to the dominant genetic model. This allele has a protective effect against SLE. There was no relationship between TAP2*D, TAP2*E, TAP2*F and TAP2*G alleles with the outbreak of SLE. Conclusions: Our data indicated that genetic variants in TAP2 gene may be associated with SLE disease. A correlation between Ala allele at TAP2/665 and Ile allele at TAP2/379 polymorphisms and pathogenesis of SLE was observed.

Congenital long QT syndrome (LQTS) is a familial cardiac ion channelopathy first described over sixty years ago. It is characterised by prolonged ventricular repolarization (long QT on ECG), ventricular arrhythmias and associated syncope or sudden cardiac death. As the most closely studied cardiac channelopathy, over the decades we have gained a deep appreciation of the complex genetic model of LQTS. Variability in genetic expression and incomplete penetrance leads to a heterogenous phenotype that can be challenging to clinically classify. In recent times, progress has been made in diagnostic method, risk stratification and treatment options. This review has been written as a guide for the general cardiologist to understand the basic pathophysiology, diagnosis, and management priorities for the most encountered LQTS subtypes: LQT1, LQT2 and LQT3. This article is protected by copyright. All rights reserved.

In the last years, the field of inheritable ventricular arrhythmia disease modelling has changed significantly with a push towards the use of novel cellular cardiomyocyte based models. However, there is a growing need for new in vivo models to study the disease pathology at the tissue and organ level. Zebrafish provide an excellent opportunity for in vivo modelling of inheritable ventricular arrhythmia syndromes due to the remarkable similarity between their cardiac electrophysiology and that of humans. Additionally, many state-of-the-art methods in gene editing and electrophysiological phenotyping are available for zebrafish research. In this review, we give a comprehensive overview of the published zebrafish genetic models for primary electrical disorders and arrhythmogenic cardiomyopathy. We summarise and discuss the strengths and weaknesses of the different technical approaches for the generation of genetically modified zebrafish disease models, as well as the electrophysiological approaches in zebrafish phenotyping. By providing this detailed overview, we aim to draw attention to the potential of the zebrafish model for studying arrhythmia syndromes at the organ level and as a platform for personalised medicine and drug testing.

Background. MicroRNA-423 (miR-423) rs6505162 polymorphism is found to be associated with breast cancer (BC) risk. However, the results were inconsistent. This study meta-analyzed the literature on possible association between rs6505162 polymorphism and BC risk. Methods. PubMed, Embase, Google Scholar, and the Chinese National Knowledge Infrastructure (CNKI) databases were systematically searched to identify relevant studies. Meta-analyses were performed to examine the association between rs6505162 polymorphism and BC. Results. None of the five genetic models suggested a significant association between rs6505162 polymorphism and BC risk: allelic model, OR 1.02, 95% CI 0.18–1.28, P = 0.85 ; recessive model, OR 0.99, 95% CI 0.72–1.38, P = 0.97 ; dominant model, OR 0.93, 95% CI 0.72–1.21, P = 0.60 ; homozygous model, OR 1.04, 95% CI 0.66–1.65, P = 0.87 ; and heterozygous model, OR 1.07, 95% CI 0.90–1.28, P = 0.45 . Similar results were obtained in subgroup analyses of Asian, Chinese, and Caucasian patients. Conclusion. The available evidence suggests no significant association between rs6505162 polymorphism and BC risk. These conclusions should be verified in large, well-designed studies.

Background: Steroid-induced osteonecrosis of the femoral head (ONFH) is aseptic necrosis of the femoral head caused by glucocorticoid use. Once necrotic femoral head necrosis occurs, it irreversibly affects the quality of life seriously. Studies have shown that the susceptibility to steroid-induced ONFH is likely to be related to the variation of miRNA-coding genes. Therefore, this study aimed was to investigate the effect of MIR3142HG on steroid-induced ONFH. Methods: Agena MassARRAY was used to genotype MIR3142HG gene rs1582417, rs2431689, rs7727155, and rs17057846 in 199 patients and 725 healthy people. A genetic model and haplotype analysis were used to evaluate the relationship between the MIR3142HG polymorphism and the risk of steroid-induced ONFH. The odds ratio and 95% confidence intervals were obtained through logistic regression to assess the influence of gene polymorphisms on the occurrence of steroid-induced ONFH. Results: The consequences show that rs7727115 is a protective factor, it could reduce the risk of steroid-induced ONFH, and rs1582417 could increase the risk of steroid-induced ONFH. In the genetic model, rs1582417 was associated with increased risk of alcohol-induced ONFH in dominant model and log-additive model. rs7727115 showed a decreased risk in codominant model, dominant model, and log-additive model. In addition, rs2431689 is related to HDL-C (p = 0.012) and ApoA1 (p = 0.010) levels, and rs17057846 (p = 0.024) is related to ApoB levels. Thelinkage analysis indicated 3 single-nucleotide polymorphisms (rs2431689, rs7727115, and rs17057846) in MIR3142HG with significant chain imbalance. In addition, haplotype “GGG” of MIR3142HG was found out and is harmful for steroid-induced ONFH. Conclusion: Our results first confirm that the genetic polymorphism of MIR3142HG is associated with steroid-induced ONFH susceptibility in Chinese Han population.

Plateau essential hypertension is a common chronic harmful disease of permanent residents in plateau areas. Studies have shown some single nucleotide polymorphisms (SNPs) associations with hypertension, but few have been verified in plateau area-lived people. In this paper, we examined some hypertension-related gene loci to analyze the relationship between risk SNPs and plateau essential hypertension in residents in Qinghai-Tibet plateau area. We screened hypertension-related SNPs from the literature, Clinvar database, GHR database, GTR database, and GWAS database, and then selected 101 susceptible SNPs for detection. Illumina MiSeq NGS platform was used to perform DNA sequencing on the blood samples from 185 Tibetan dwellings of Qinghai, and bioinformatic tools were used to make genotyping. Genetic models adjusted by gender and age were used to calculate the risk effects of genotypes. Four known SNPs as well as a new locus were found associated with PHE, which were rs2493134 (AGT), rs9349379 (PHACTR1), rs1371182 (CYP2C56P-PRPS1P1), rs567481079 (CYP2C56P-PRPS1P1), and chr14:61734822 (HIF1A). Among them, genotypes of rs2493134, rs9349379, and rs567481079 were risk factors, genotypes of rs1371182 and chr14:61734822 were protective factors. The rs2493134 in AGT was found associated with an increased risk of the plateau essential hypertension by 3.24-, 3.24-, and 2.06-fold in co-dominant, dominant, and Log-additive models, respectively. The rs9349379 in PHACTR1 is associated with a 2.61-fold increased risk of plateau essential hypertension according to the dominant model. This study reveals that the alleles of AGT, HIF1A, and PHACTR1 are closely related to plateau essential hypertension risk in the plateau Tibetan population.

Both clinical and genetic factors drive the risk of venous thromboembolism. However, whether clinically recorded risk factors and genetic variants can be combined into a clinically applicable predictive score remains unknown. Using Cox proportional-hazard models, we analyzed the association of risk factors with the likelihood of venous thromboembolism in U.K. Biobank, a large prospective cohort. We then created a polygenic risk score of 36 single nucleotide polymorphisms and a clinical score determined by age, sex, body mass index, previous cancer diagnosis, smoking status, and fracture in the last 5 years. Participants were at significantly increased risk of venous thromboembolism if they were at high clinical risk (subhazard ratio, 4.37 [95% CI, 3.85–4.97]) or high genetic risk (subhazard ratio, 3.02 [95% CI, 2.63–3.47]) relative to participants at low clinical or genetic risk, respectively. The combined model, consisting of clinical and genetic components, was significantly better than either the clinical or the genetic model alone (P

David Corredor-Orlandelli,1,* Santiago Sambracos-Parrado,1,* Santiago Mantilla-García,1 Josué Tovar-Tirado,1 Valentina Vega-Ramírez,1 Santiago David Mendoza-Ayús,1 Laura Catalina Peña,1 María Fernanda Leal,1 Juliana Rodríguez-Carrillo,1 Juanita León-Torres,1 Juan Mauricio Pardo-Oviedo,2 Katherine Parra Abaunza,3 Nora Contreras Contreras Bravo,1 Oscar Ortega-Recalde,1 Dora Janeth Fonseca Mendoza1 1Center for Research in Genetics and Genomics – CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad Del Rosario, Bogotá, Colombia; 2School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia; 3Hospital Universitario Mayor – Méderi, Universidad del Rosario, Bogotá, Colombia*These authors contributed equally to this workCorrespondence: Dora Janeth Fonseca MendozaCenter for Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Cra 24 # 63C69, Bogotá, 112111, ColombiaTel/Fax +57 12920200Email dora.fonseca@urosario.edu.coBackground: Paraoxonase-1 (PON1), a glycoprotein associated with serum high-density lipoprotein (HDL), has a central role in metabolizing lipid peroxides, exhibiting antiatherogenic properties. The polymorphism p.Q192R has been previously associated with coronary artery disease (CAD) susceptibility and clopidogrel response.Purpose: We aimed at investigating the association of PON1 p.Q192R with CAD and clopidogrel response in Colombian population.Patients and Methods: The study was conducted among 163 patients diagnosed with CAD and treated with clopidogrel. The allele frequencies for the PON1 192Q and 192R alleles were determined in cases and Latin-American controls obtained from the public database gnomAD (n = 17,711). Response to clopidogrel was determined by assessing the platelet function using the INNOVANCE PFA-200 System. We determined the association between PON1 p.Q192R polymorphism, increased susceptibility to CAD and high on-treatment platelet reactivity (HPR) by using odds ratio (OR) and 95% confidence interval (CI) on four genetic models.Results: The allele frequencies for the PON1 192Q and 192R alleles were 0.60 and 0.40, respectively. The allele distribution was found to be statistically different from the control group and other ethnic groups. The allele 192R was positively associated with decreased susceptibility to CAD under a dominant model (OR, 0.58; 95% CI, 0.42– 0.8; P < 0.01). We found no association between the polymorphism and HPR.Conclusion: We propose that PON1 p.Q192R is a potentially useful marker for CAD susceptibility in the Colombian population and lacks association with HPR under clopidogrel treatment.Keywords: PON1, genetic risk, cardiovascular disease susceptibility, platelet reactivity, clopidogrel

The cytochrome P450 family 17 (CYP17) is associated with hyperandrogenism in women, and the association between CYP17 gene polymorphism and the risk of polycystic ovary syndrome (PCOS) is not definitive. In order to determine whether the CYP17 T/C (rs74357) gene polymorphism is an exposure risk for PCOS, a comprehensive meta-analysis summarizing 19 studies was performed. The pooled odds ratio (OR) and the corresponding 95% CI were measured under five genetic models, and the stratified analyses by ethnicity, Hardy–Weinberg equilibrium, testosterone levels and BMI in controls were carried out to identify the causes of substantial heterogeneity. The overall results validated that the CYP17 T/C (rs74357) gene polymorphism was significantly associated with PCOS risk in four genetic models. Moreover, the outcomes of subgroup analysis by ethnicity indicated that the frequencies of the C allele of CYP17 T/C (rs74357) polymorphism were markedly higher in women from Asia than in Caucasians (T vs C: OR 0.85, 95% CI = 0.74–0.99, P < 0.05). Therefore, these findings suggested that the CYP17 T/C (rs74357) gene polymorphism played an indispensable part in increasing the susceptibility of PCOS when carrying the C allele, which proposed that the polymorphism of the CYP17 gene may be a predictive factor for the risk of PCOS or an important pathway in PCOS-associated metabolic and hormonal dysregulation.

Genes related to human longevity have not been studied so far, and need to be investigated thoroughly. This study aims to explore the relationship among ABO gene variants, lipid levels, and longevity phenotype in individuals (≥90yrs old) without adverse outcomes. A genotype-phenotype study was performed based on 5803 longevity subjects and 7026 younger controls from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Four ABO gene variants associated with healthy longevity (rs8176719 C, rs687621 G, rs643434 A, and rs505922 C) were identified and replicated in the CLHLS GWAS data analysis and found significantly higher in longevity individuals than controls. The Bonferroni adjusted p-value and OR range were 0.013-0.020 and 1.126-1.151, respectively. According to the results of linkage disequilibrium (LD) analysis, the above four variants formed a block on the ABO gene (D'=1, r2range = 0.585-0.995). The carriers with genotypes rs687621 GG, rs643434 AX, or rs505922 CX (prange = 2.728 x 10-107-5.940 x 10-14; ORrange = 1.004-4.354) and haplotype CGAC/XGXX (p = 2.557 x 10-27; OR = 2.255) had a substantial connection with longevity, according to the results of genetic model analysis. Following the genotype and metabolic phenotype analysis, it has been shown that the longevity individuals with rs687621 GG, rs643434 AX, and rs505922 CX had a positive association with HDL-c, LDL-c, TC, TG (prange = 2.200 x 10-5-0.036, ORrange = 1.546-1.709), and BMI normal level (prange = 2.690 x 10-4-0.026, ORrange = 1.530-1.997). Finally, two pathways involving vWF/ADAMTS13 and the inflammatory markers (sE-selectin/ICAM1) that co-regulated lipid levels by glycosylation and effects on each other were speculated. In conclusion, the association between the identified longevity-associated ABO variants and better health lipid profile was elucidated, thus the findings can help in maintaining normal lipid metabolic phenotypes in the longevity population.

Background: Genetic factors were suggested to have influence on the development of post-traumatic stress disorder (PTSD). The possible association between catechol-O-methyltransferase (COMT) Val158Met polymorphism and PTSD has been evaluated in several studies. But the results were still controversial. Therefore, we conduct this meta-analysis to address these issues. Methods: The PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched for eligible studies. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to estimate the association between COMT Val158Met polymorphism and PTSD. Results: Five articles including 6 studies with 893 cases and 968 controls were finally included in the present meta-analysis. The pooled analyses did not demonstrate a significant association between the COMT Val158Met polymorphism and PTSD in any of the selected genetic models: allele model (OR = 1.13, 95% CI: 0.97–1.31), dominant model (OR = 1.17, 95% CI: 0.93–1.46), recessive model (OR = 1.44, 95% CI: 0.78–2.66), and additive model (OR = 1.54, 95% CI: 0.85–2.80). Subgroup analyses suggested that the Hardy-Weinberg equilibrium status of genotype distributions could influence the relationship of COMT Val158Met polymorphism and PTSD. Conclusions: The present meta-analysis suggested that the COMT Val158Met polymorphism may not be associated with the PTSD risk. Further large-scale and population-representative studies are warranted to evaluate the impact of the COMT Val158Met polymorphism on the risk of PTSD.

Background: Colorectal cancer (CRC) is one of the common malignant tumors, with high mortality and poor prognosis. Our study aimed to determine the association between the long noncoding RNA (LncRNA) C5orf66 polymorphism and CRC risk in southern Chinese Han population. Method: Using the experimental design of “case-control” study (512 cases and 513 controls), we selected 4 candidate single-nucleotide polymorphisms (SNPs) of C5orf66. All candidate SNPs were genotyped by Agena MassARRAY. Logistic regression was used to analyze the association between SNPs and CRC risk. Then, we used false-positive report probability analysis to detect whether the significant result is just a chance or noteworthy observation. Multi-factor dimensionality reduction was used to analyze the interaction of “SNP-SNP” in CRC risk. Results: Our results showed that C5orf66 SNPs rs4976270 (odds ratio [OR] = 1.69, p = 0.021) and rs639933 (OR = 1.67, p = 0.024) were, respectively, associated with increasing CRC risk in the southern Chinese Han population. Stratified analysis showed that rs4976270 and rs639933 were significantly associated with an increased risk of CRC in subgroups (>60 years, body mass index ≤24 and drinking) under multiple genetic models. In addition, rs254563 and rs647161 also had potential association with CRC risk in subgroups (BMI ≤24 and drinking). Finally, haplotype analysis results showed that haplotype “TA” was significantly associated with increased CRC risk (OR = 1.21, confidence interval = 1.47–2.02, p = 0.043). Conclusion: Our study provides a new idea for the risk assessment of CRC. LncRNA C5orf66 SNPs have a certain association with CRC risk in the southern Chinese Han population.

Changes in pro-inflammatory cytokines are key mechanisms leading to kidney fibrosis. Among microRNAs, miR146 is well studied for its diverse roles in modulating immune responses and inflammation. This paper aims to study the prevalence of three functional miR146a gene polymorphisms (rs2910164 C/G, rs57095329 A/G, and rs6864584 T/C) in diabetic and non-diabetic patients with chronic kidney disease (CKD). One hundred fifty CKD patients (73 men, 77 women, mean age 52.17 years) and 150 healthy controls participated in this case–control study. CKD patients were divided into a diabetic nephropathy group and a non-diabetic group. Genotyping was performed by PCR–RFLP and allele-specific-PCR techniques. We found that rs2910164 C/G and rs57095329 A/G polymorphisms significantly enhanced the risk of CKD under different genetic models. Besides, these variations were associated with increased CKD risk in diabetic and non-diabetic patients. On the contrary, the rs6864584 T/C variant was associated with a decreased risk of CKD in non-diabetic patients. There were no notable changes in p-values after adjustment for age, sex, and body mass index. Although no strong linkage was found between the studied variants. In the meantime, different haplotypes of miR146a polymorphisms were associated with enhanced risk of CKD. In summary, our findings provided evidence for the association of miR146a gene polymorphisms with CKD risk in both diabetic and non-diabetic patients. Further studies on different races with larger sample sizes are needed to confirm the current results.

Background The Spontaneously Hypertensive Rat (SHR) Colony was established in 1963 and is the most commonly used rodent model for studying heart failure (HF). Ideally, animal models should recapitulate the clinical disease as closely as possible. Any drift in a genetic model may create a new model that no longer adequately represents the human pathology. Further, instability overtime may lead to conflicting data between laboratories and/or irreproducible results. While systolic blood pressure (SBP) is closely monitored during inbreeding, the sequelae of HF (e.g., cardiac hypertrophy) are not. Thus, the object of this review was to investigate whether the hypertension-induced sequelae of HF in the SHR have remained stable after decades of inbreeding. Methods A systematic review was performed to evaluate indices of cardiovascular health in the SHR over the past 60 years. For post hoc statistical analyses, studies were separated into 2 cohorts: Initial (mid to late 1900s) and Current (early 2000s to present) Colony SHRs. Wistar-Kyoto rats (WKY) were used as controls. Results SBP was consistent between Initial and Current Colony SHRs. However, Current Colony SHRs presented with increased concentric hypertrophy (i.e., elevated heart weight and posterior wall thickness) while cardiac output remained consistent. Since these changes were not observed in the WKY controls, cardiac-derived changes in Current Colony SHRs were unlikely due to differences in environmental conditions. Conclusions Together, these data firmly establish a cardiac-based phenotypic shift in the SHR model and provide important insights into the beneficial function of concentric hypertrophy in hypertension-induced HF.

Summary Introduction There is a relationship between macro-nutrient-intakes and the genes implicated in lipid metabolism. In this study, we assessed the association between macro-and micro-nutrients dietary intakes with rs2241883 genetic variants of the FABP1 gene. Methods For this cross-sectional study 2737 subjects (including 2203 subjects with dyslipidemia and 534 healthy volunteers) were enrolled as part of the Mashhad Stroke and Heart Atherosclerotic Disorder (MASHAD) study cohort. Dyslipidemia was defined based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). A NanoDrop®-1000 instrument was used to do the quantitation of DNA. The rs2241883 polymorphisms were genotyped using double ARMs PCR reactions. Genotyping reagents were obtained from Applied Biosystems. Dietary intake was evaluated using a food frequency questionnaire (FFQ) and validated by 2 consecutive 24-h food recalls. Results The results showed no significant association between subjects with and without dyslipidemia (P > 0.05), except for the zinc to copper ratio, the value for which was higher in the subjects with dyslipidemia (4.78 (1.62)) when compared to subjects without dyslipidemia (4.68 (1.82)) (p = 0.05). Using different genetic models we found that zinc and copper were significantly different in the additive (p = 0.01) and dominant (p = 0.01) genetic models. Although, this association was no longer significant after adjusting for confounding factors. Conclusions There were no associations between macro-and micro-nutrient dietary intakes with rs2241883 genetic variants after adjusting for confounding factors in the MASHAD study population.

Introduction Breast cancer (BC) is a prevalent malignant tumor among women. Numerous studies have been reported that long noncoding RNAs (lncRNAs) were associated with various human diseases. Materials and Methods In the current study, 681 patients with BC and 680 unrelated controls were recruited to investigate the correlation between lncRNA cancer susceptibility candidate 15 (CASC15) polymorphisms and BC risk in Chinese Han women. We performed single-nucleotide polymorphism genotyping using the Agena MassARRAY platform. The relationship between lncRNA CASC15 polymorphisms and the risk of BC were evaluated through odds ratios and 95% confidence intervals. Results Our results suggested that the lncRNA CASC15 rs7740084 “G/G” genotype and rs1928168 “T/C” genotype significantly reduced BC risk in different genetic models (P = .045, P = .029, and P = .047, respectively). However, rs9393266 “C/T” and “C/T-T/T” genotypes were correlated with the risk of BC (P = .021 and P = .048). In addition, we also observed that rs1928168 was related to the risk of BC in patients with age > 50 years (P = .025), body mass index > 24 (P = .006), and tumor size (P = .035). For rs9393266, it was revealed that the “C/T” and “C/T-T/T” genotypes were related to BC risk in people with age ≤ 50 years (P = .005) and body mass index > 24 (P = .023). Conclusion In summary, our results revealed a potential interaction between lncRNA CASC15 polymorphisms and BC susceptibility. The results provided an important insight into lncRNA CASC15 function in the development of BC.

Background IL6 is an important candidate gene implicated in the pathogenesis of glaucoma. The present study assessed the genetic association of −174G > C and −572G > C polymorphisms in the IL6 promoter region with primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) in a north Indian Punjabi cohort. Methods 910 subjects (313 POAG, 148 PACG cases and 449 controls) were recruited. Genotyping was done by TaqMan assays. Genetic association was tested under different genetic models using Plink. Diplotype and linkage disequilibrium (LD) analysis was done through Haploview. Association of clinical parameters with the genotypes was assessed by one-way ANOVA. Adjustment for potential confounding variables was done by binary logistic regression. IL6 levels were measured in POAG patients and controls. Results 572G > C variant showed marginal difference in genotype frequency between pooled cases and POAG subgroup with respect to controls (p = 0.042; OR = 1.33; and p = 0.041; OR = 1.37). The GC genotype conferred 1.37-fold protection under codominant model in POAG cases (p = 0.034, OR = 1.37, 95% CI = 1.02–1.85; pcorr = 0.025, OR = 1.45, 95% CI = 1.04–2.02). The mean value for IOP was elevated among cases having ‘CC’ genotype at the −572G > C locus (p = 0.037). Lower levels of IL6 were detected in POAG patients in plasma samples (p = 0.0001). Conclusion The study reports suggestive evidence for −572G > C variant in IL6 in affecting genetic susceptibility to POAG in the targeted North Indian Punjabi cohort. A correlation of IL6 levels in aqueous humor (AH) and systemic circulation in POAG was observed, the functional and diagnostic relevance of which may be further investigated.

Background Dilated cardiomyopathy (DCM) is one of the most common types of cardiomyopathies. Various genes have been verified to be related to DCM, but the pathogenesis remains unclear. Cyclin-dependent-kinase 8 (CDK8), encoded by the CDK8 gene, is a transcriptional factor that regulates the phosphorylation of RNA polymerase II. It plays an important role in the transcription process and different signaling pathways. This study aimed to investigate the potential role of CDK8 gene polymorphisms in DCM susceptibility and prognosis in a Chinese Han population. Methods Two single nucleotide polymorphisms (SNPs) of CDK8, rs17083838 (A/G) and rs7992670 (A/G), were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 341 DCM patients and 381 healthy controls. Survival analysis was performed using Kaplan-Meier curves and Cox regression analysis. Results The frequencies of allele A of both SNPs rs17083838 and rs7992670 were increased in DCM patients compared to healthy controls (P

Background and objectives The etiology of schizophrenia (SCZ) is not yet known, but the genetic factor has an essential role. Its heritability is estimated up to 85 percent. This study aimed to determine whether the selected brain-derived neurotropic factor (BDNF) gene variant (rs6265) is associated with SCZ, its psychopathology and intelligence quotient (IQ). Methods Rs6265 was genotyped in 159 participants, including 71 unrelated patients with SCZ (males = 40 [56%]) and 88 healthy controls (males = 35 [40%]). Psychopathology assessment was done by using positive and negative symptoms scale (PANSS), and IQ was measured by Wechsler adult intelligence scale (WAIS). COCAPHASE and CLUMP22 softwares were used to compare allele and genotype frequencies respectively. Two-way multivariate ANOVA was done using SPSS22 to evaluate the effects of the group (patients and healthy control) and the genotype on the test scores, including PANSS and WAIS scores, considering sex and smoking status as covariates. Results The study showed that the BDNF rs6265 C allele and CC genotypes, psychopathology, including PANSS scores, and also IQ were significantly different in all, male and female patients compared to healthy participants. For rs6265, we found significantly higher frequencies of the C allele (P = 0.04) in all participants with SCZ. The findings also revealed that BDNF polymorphism (rs6265) increased significantly the risk of SCZ in different genetic models. Conclusion The results showed that the BDNF rs6265 may be associated with the risk of SCZ development in an Iranian group of patients with SCZ. These results may be helpful in better understanding the role of the BDNF gene in the pathogenesis of the disorder.

Migraine is a neurological disorder which impairs the patient’s quality of life. Several association studies investigating the association between MTHFR gene C677T and A1298C polymorphisms and susceptibility to migraine were published. But the results were conflicting, so authors performed a meta-analysis of published case control studies to find out the exact association between MTHFR polymorphism and migraine susceptibility. Four databases were searched for suitable studies up to December, 2018. Odds ratios (OR) with 95% confidence intervals (CI) was calculated adopting additive, homozygote, co-dominant, dominant, and recessive genetic models. Results of MTHFR C677T polymorphism studies meta-analysis showed significant association with migraine risk using allele contrast, homozygote, dominant and recessive genetic models (T vs. C: OR = 1.18, 95% CI = 1.00–1.26, p = 0.05; TT vs. CC: OR = 1.24, 95% CI = 1.0–1.5, p = 0.04; CT vs. CC: OR = 1.08, 95% CI = 0.97–1.07, p = 0.25; TT + CT vs. CC: OR = 1.15, 95% CI = 1.0–1.29, p = 0.04; TT vs. CT + CC: OR = 1.97, 95% CI = 1.28–3.42, p = 0.002). However, results of MTHFR A1298 polymorphism studies meta-analysis did not show any association with migraine. Subgroup analysis based on ethnicity and migraine types i.e. migraine with aura (MA) and without aura (MO) were also performed. Results of present meta-analysis indicate overall association between MTHFR C677T polymorphism with migraine in total 24 studies, in Asian population and in MA cases but did not show any association with Caucasian population and MO cases.

Alzheimer’s disease(AD) is an age-associated neurodegenerative disease that results in deterioration of memory and cognitive function. As a currently untreatable disorder, AD has emerged as one of the defining biomedical challenges of our time. Thus, new approaches that can examine the cellular and molecular mechanisms underlying age-related AD pathology are sorely needed. One of the hallmarks of Alzheimer’s disease is the hyperphosphorylation of the tau protein. Caenorhabditis elegans have been previously used to study the genetic pathways impacted by tau proteotoxic stress; however, currently, available C. elegans tau models express the human protein solely in neurons, which are unresponsive to global RNA interference (RNAi). This limits powerful RNAi screening methods from being utilized effectively in these disease models. Our goal was to develop a C. elegans tau model that has pronounced tau-induced disease phenotypes in cells that can be modified by feeding RNAi methods. Towards this end, we generated a novel C. elegans transgenic line with codon-optimized human 0N4R V337M tau expressed in the body wall muscle under the myo-3 promoter. Immunoblotting experiments revealed that the expressed tau is phosphorylated on epitopes canonically associated with human AD pathology. The tau line has significantly reduced health metrics, including egg laying, growth rate, paralysis, thrashing frequency, crawling speed, and lifespan. These defects are suppressed by RNAi directed against the tau mRNA. Taken together, our results suggest that this alternative tau genetic model could be a useful tool for uncovering the mechanisms that influence the hyperphosphorylation and toxicity of human tau via RNAi screening and other approaches. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00436-9.

AIM: To explore the association of single nucleotide polymorphisms (SNPs) in the IL33/IL1RL1 gene region with the susceptibility to Behcet’s disease (BD) in a Chinese Han population. METHODS: A total of eight SNPs in the candidate gene region (rs11792633, rs7025417, rs10975519 and rs1048274 in IL33; rs2310220, rs12712142, rs13424006 and rs3821204 in IL1RL1) were genotyped in783 BD patients and 701 healthy controls by the Sequenom Mass Array iPLEX platform. RESULTS: A statistically significant association was observed between IL1RL1 rs12712142 and BD patients. The frequency of IL1RL1 rs12712142 variant allele A was significantly lower in BD patients than that in controls (OR=0.8, 95%CI: 0.69-0.94, Pc=0.039); the genotype distribution (Pc=0.043) and additive and dominant genetic model analyses (OR=0.8, 95%CI: 0.69-0.94, Pc=0.040 and OR=0.72, 95%CI: 0.58-0.88, Pc=0.011) also indicated a strong association between rs12712142 and BD patients. CONCLUSION: This is the first study to reveal the association between IL1RL1 rs12712142 variant allele A and the decreased risk of BD in the Chinese Han population, indicating a protective role of IL1RL1 in the pathogenesis of BD.

How neural correlates of self‐concept are influenced by environmental versus genetic factors is currently not fully understood. We investigated heritability estimates of behavioral and neural correlates of self‐concept in middle childhood since this phase is an important time window for taking on new social roles in academic and social contexts. To do so, a validated self‐concept fMRI task was applied in a twin sample of 345 participants aged between 7 and 9 years. In the self‐concept condition, participants were asked to indicate whether academic and social traits applied to them whereas the control condition required trait categorization. The self‐processing activation analyses (n = 234) revealed stronger medial prefrontal cortex (mPFC) activation for self than for control conditions. This effect was more pronounced for social‐self than academic self‐traits, whereas stronger dorsolateral prefrontal cortex (DLPFC) activation was observed for academic versus social self‐evaluations. Behavioral genetic modeling (166 complete twin pairs) revealed that 25–52% of the variation in academic self‐evaluations was explained by genetic factors, whereas 16–49% of the variation in social self‐evaluations was explained by shared environmental factors. Neural genetic modeling (91 complete twin pairs) for variation in mPFC and anterior prefrontal cortex (PFC) activation for academic self‐evaluations confirmed genetic and unique environmental influences, whereas anterior PFC activation for social self‐evaluations was additionally influenced by shared environmental influences. This indicates that environmental context possibly has a larger impact on the behavioral and neural correlates of social self‐concept at a young age. This is the first study demonstrating in a young twin sample that self‐concept depends on both genetic and environmental factors, depending on the specific domain., We investigated heritability estimates of behavioral and neural correlates of self‐concept in middle childhood since this phase is an important time window for taking on new social roles in academic and social contexts. To do so, a validated self‐concept fMRI task was applied in a twin sample of 345 participants aged between 7 and 9 years. This is the first study demonstrating in a young twin sample that self‐concept depends on both genetic and environmental factors, with stronger environmental influences in the social versus academic domain.

Zulipikaer Abudureheman,1,&ast; Li Li,2,&ast; XueMei Zhong,2,&ast; JingRan Xu,2 Hui Gong,1 Subinuer Yilamujiang,1 Jie Ren,2 ChengXin Xie,2 AiFang Zheng,2 Dilala Tuerxun,2 Ayiguzali Abudukadeer,2 Paierda Aini,2 AiMin Xu,3 XiaoGuang Zou2 1Department of Clinical Research Center of Infectious Diseases (Pulmonary Tuberculosis), First People’s Hospital of Kashi, Kashi, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, First People’s Hospital of Kashi, Kashi, People’s Republic of China; 3Department of Clinical Laboratory, First People’s Hospital of Kashi, Kashi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: AiMin Xu; XiaoGuang Zou Email 519202069@qq.com; ZXGKS11@yeah.netBackground: Kashi city is situated near the Taklamakan desert and has a high incidence rate of chronic obstructive pulmonary disease (COPD). In this study, we aimed to explore the relationship between the SNP of the SREK1 gene locus rs74794265 and the susceptibility to COPD among the Uyghur population in Kashi, XinJiang, China.Methods: A total of 541 patients with COPD and 534 control subjects were included in this study. Sanger sequencing was used to analyze the SNP of the SREK1 gene locus rs74794265 site. The distribution of genotypes in different genetic models between the case and control group were analyzed by logistic regression analysis after adjusting for age, sex, and smoking history.Results: The SREK1 gene SNP locus rs74794265 included two genotypes, namely, C/C and C/T, of which C/C was the wildtype; The risk of COPD was significantly lower in patients with heterozygous C/T in rs74794265 [p=0.0236, OR=0.3677 (0.1547– 0.8742)], and the allele frequency of T was also significantly lower in the patient group [p=0.0245, OR=0.3728 (0.1577– 0.8811)]. The heterozygous C/T of rs74794265 among non-smoking COPD patients was significantly lower than other COPD patients [p=0.0298, OR=0.3217 (0.1156– 0.8949)], and there was no significant correlation of the heterozygous C/T genotype in smokers.Conclusion: We found that the rs74794265 heterozygous C/T genotype significantly reduces the risk of COPD. The C/T genotype is likely a protective factor for COPD in the Kashi region. We speculate that the occurrence of COPD in this area is probably more related to desert climate condition and genetic factors than smoking status.Keywords: COPD, SREK1 gene polymorphism, rs74794265 locus, Uyghur population

Background Presently, whether X-ray repair cross complementing group 3 (XRCC3) Thr241Met polymorphism is correlated to leukemia risk remains controversial. Because of this reason, the objective of current study is to explore whether XRCC3 Thr241Met polymorphism confers risk to leukemia. Methods Two independent authors systematically and comprehensively searched Pubmed, Embase, the Cochrane library, Google academic, China National Knowledge Infrastructure (CNKI). Search time is from database foundation to March 2021. Results Overall, significant associations between leukemia risk and XRCC3 Thr241Met polymorphism were found in Caucasian population by allele contrast (T vs. C: OR 1.20, 95% CI 1.02–1.40), homozygote comparison (TT vs. CC: OR 1.35, 95% CI 1.05–1.73), and recessive genetic model (TT vs. TC/CC: OR 1.31, 95% CI 1.04–1.64). Conclusions The present meta-analysis suggests that the XRCC3 Thr241Met polymorphism may be a risk factor for leukemia in Caucasian population.

Background: Several studies have reported a possible association of miR-146a rs2910164 polymorphism with Breast Cancer (BC) development. However, the correlation between this polymorphism and susceptibility to BC is under debate. The current meta-analysis was designed and performed to more conclusively evaluate the miR-146a rs2910164 polymorphism and its potential link to BC. Methods: Our team has selected eligible studies (published up to October 2, 2020) from several electronic databases, including Web of Science, PubMed, Scopus and Google Scholar. A total number of 9,545 BC cases and 10,030 controls extracted from 26 eligible articles were included in this study. We utilized pooled Odds Ratios (ORs) as well as 95% confidence intervals (95% CIs) under five genetic models for quantitative estimation of any possible association between miR-146a rs2910164 polymorphism and BC. Results: Based on this meta-analysis, our findings suggest that there is no significant association between miR-146a rs2910164 polymorphism and BC risk. However, stratified analysis revealed that the rs2910164 polymorphism significantly increased the risk of BC in hospital-based studies using the homozygous genetic model (OR=1.37, 95%CI=1.01-1.86, p=0.043, CC vs. GG). Neither Asian nor Caucasian populations showed any significant association between rs2910164 polymorphism and BC susceptibility. Conclusion: In summary, our findings suggest that BC development is not associated with miR-146a rs2910164 polymorphism. However, larger ingenious future investigations might be needed for a more precise estimation of any association between miR-146a rs2910164 polymorphism and BC.

Hypertension is a complex disease which is mainly influenced by genetic factors. Recently, genome-wide association study (GWAS) found three novel endothelial dysfunction-related sites: Vascular endothelial growth factor A (VEGFA) rs9472135, Faciogenital dysplasia 5 (FGD5) rs11128722, Zinc Finger C3HC-type Containing 1 (ZC3HC1) rs11556924. Endothelial dysfunction is one of the early events in pathophysiology of essential hypertension. To investigate the association of endothelial dysfunction-related genes with essential hypertension, we conducted a case-control study of 431 patients with hypertension and 345 controls. The polymorphisms were detected using Taqman Probe. The alleles and genotypes of ZC3HC1 rs11556924 and VEGFA rs9472135 were not statistically different between the two groups, while the allele of FGD5 rs11128722 was different [P = 0.045, OR = 1.265, 95% CI = (1.009–1.586)], especially in the male [P = 0.035, OR = 1.496, 95% CI = (1.037–2.158)]. Analyzing the different of genotype distribution of 3 SNPs in the two groups under different genetic models, the genotypes of FGD5 rs11128722 showed difference in male under dominant model [P = 0.049, OR = 1.610, 95% CI = (1.018–2.544)]. The polymorphism of FGD5 rs11128722 had a significant difference in Body Mass Index (BMI) among different genotypes; In the additive genetic model, BMI of GA genotype was higher than that of GG (P = 0.038); GA + AA was higher than GG in the dominant genetic model (P = 0.011). In our study, we found that the polymorphisms of VEGFA rs9472135 and ZC3HC1 rs11556924 may not significantly associated with the risk of essential hypertension, and FGD5 rs11128722 may increase the risk of it, especially in elderly men.

A critical cell type participating in cardiac outflow tract development is a subpopulation of the neural crest cells, the cardiac neural crest cells (NCCs), whose defect causes a spectrum of cardiovascular abnormalities. Accumulating evidence indicates that mTOR, which belongs to the PI3K-related kinase family and impacts multiple signaling pathways in a variety of contexts, plays a pivotal role for NCC development. Here, we investigated functional roles of mTOR for cardiac neural crest development using several lines of mouse genetic models. We found that disruption of mTOR caused NCC defects and failure of cardiac outflow tract separation, which resulted in a spectrum of cardiac defects including persistent truncus arteriosus, ventricular septal defect and ventricular wall defect. Specifically, mutant neural crest cells showed reduced migration into the cardiac OFT and prematurely exited the cell cycle. A number of critical factors and fundamental signaling pathways, which are important for neural crest and cardiomyocyte development, were impaired. Moreover, actin dynamics was disrupted by mTOR deletion. Finally, by phenotyping the neural crest Rptor and Rictor knockout mice respectively, we demonstrate that mTOR acts principally through the mTORC1 pathway for cardiac neural crest cells. Altogether, these data established essential roles of mTOR for cardiac NCC development and imply that dysregulation of mTOR in NCCs may underline a spectrum of cardiac defects.

Although parasite-mediated selection is thought to be a major driver of host evolution, its influence on genetic variation for parasite resistance is not yet well understood. We monitored a large population of the planktonic crustacean Daphnia magna over eight years, as it underwent yearly epidemics of the bacterial pathogen Pasteuria ramosa. We observed a cyclical pattern of resistance evolution: resistant phenotypes increased in frequency throughout the epidemics, but susceptibility was restored each spring when hosts hatched from sexual resting stages, a phenomenon described as genetic slippage in response to sex. Collecting and hatching D. magna resting stages across multiple seasons showed that largely resistant host populations can produce susceptible offspring through recombination. Resting stages produced throughout the planktonic season accurately represent the hatching population cohort of the following spring. A genetic model of resistance developed for this host–parasite system, based on multiple loci and strong epistasis, is in partial agreement with these findings. Our results reveal that, despite strong selection for resistance in a natural host population, genetic slippage after sexual reproduction has the potential to maintain genetic diversity of host resistance.

Objective: Previous genome-wide studies have demonstrated significant pathogenic association between variants rs35934224 within TXNRD2 and rs6478746 near LMX1B in primary open-angle glaucoma. We investigated the association between these variants in primary angle-closure glaucoma (PACG) and pseudoexfoliation glaucoma (PXG) patients of Saudi origin. Methods: In a case-control study, DNA samples from 249 controls (135 men and 114 women), 100 PACG cases (44 men and 56 women), and 95 PXG cases (61 men and 34 women) were genotyped by TaqMan® based real-time PCR. Statistical tests were performed to evaluate genetic association with glaucoma types and related clinical indices. Results: The allele frequencies of rs35934224 and rs6478746 did not show significant variation in PACG and PXG than controls, except that the rs35934224[T] allele was found to be significantly low among PXG women (0.10) as compared to controls (0.21) (odds ratio = 0.38, 95% confidence interval = 0.16–0.94, p = 0.024). Rs35934224 genotypes showed a nominal-to-borderline protective association with PACG and PXG among women in different genetic models. However, except for the over-dominant model in PACG ( p = 0.0095), none of the effects survived Bonferroni’s correction ( p Conclusions: Variants rs35934224 in TXNRD2 and rs6478746 near LMX1B are not associated with PACG and PXG in the Saudi cohort, but rs35934224 may confer modest protection among women. Further population-based studies are needed to validate these results.

Glioma is a common and fatal primary malignant tumor of the central nervous system, and its prognosis is poor. To determine the susceptibility markers of gliomas in Chinese population we conducted a genome-wide association study (GWAS) of glioma in the Han Chinese population, with a total of 485 glioma cases and 485 controls. Genotyping was conducted using the Applied Biosystems Axiom Precision Medicine Diversity Array. Besides, we carried out imputation using IMPUTE 2.0 software, and the 1000 Genomes Phase 3 was used as the reference panel. The logistic regression model was used to analyze the association of each SNP with glioma risk, assuming an additive genetic model, which was implemented in PLINK version 1.9. Odds ratio (OR) and 95% confidence interval (CI) were estimated from logistic regression analysis with adjustment for age and gender. The results revealed that the SNP (rs688755) in the exon region of CYP4F12 at 19p13.12 reached genome-wide significance associated with gliomas (P = 2.35 × 10-8 , OR = 3.55, 95% CI = 2.20-5.74). Our findings provide deeper insight into the genetic contribution to glioma in different populations.

Mineral elements (copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), iron (Fe)) play important biological roles in enzymes, hormones, vitamins, and normal metabolism. The deficiency of mineral elements can lead to abnormal physiological functions. And some elements (such as lead (Pb)) are harmful to the body. We aim to identify genetic loci which can influence the serum levels of mineral elements (Cu, Zn, Ca, Mg, Fe, and Pb). Genotyping was performed using Applied Biosystems Axiom™ PMDA in 587 individuals, and 6,423,076 single-nucleotide polymorphisms (SNPs) were available for the genome-wide association study (GWAS) analysis. The association between genotype and phenotype was analyzed using mixed linear regression (additive genetic model) adjusting by age and gender combined with identical by descent (IBD) matrix. Genetic loci in BCHE-LOC105374194, DTX2P1-UPK3BP1-PMS2P11, VAT1L, LINC00908-LINC00683, LINC01310-NONE, and rs6747410 in VWA3B were identified to be associated with serum Cu element concentration (p < 5 × 10-6). ADAMTSL1 rs17229526 (p = 4.96 × 10-6) was significantly associated with serum Zn element levels. Genetic loci in LRP1B, PIGZ-MELTF, LINC01365-LINC02502, and HAPLN3 were related to serum Ca element levels (p < 5 ×1 0-6). Three SNPs in ALPK1, ASAP1-ADCY8 and IER3IP1-SKOR2 also achieved a significant association with Mg element levels (p < 5 × 10-6). TACSTD2-MYSM1, LRP1B, and ASAP1-ADCY8 showed suggestive associations with serum Fe element levels (p < 5 × 10-6). Moreover, the two most significant SNPs associated with Pb were rs304234 in CADPS-LINC00698 (p = 2.47 × 10-6) and rs12666460 in LOC101928211-GPR37 (p = 1.81 × 10-6). In summary, we reported 19 suggestive loci associated with serum mineral elements in the Chinese Han population. These findings provided new insights into the potential mechanisms regulating serum mineral elements levels.

Background A meta-analysis was performed by summarizing relevant researches to evaluate the relationship between miRNA-146a gene polymorphism rs2910164 and Behcet's disease (BD). Methods A systematic search of published studies was conducted in PubMed and Embase. Five eligible studies involving 1167 BD cases and 1662 controls were included in the current meta-analysis. Results The results suggested that the polymorphism rs2910164 was correlated with BD susceptibility in all genetic models. In subgroup analysis according to ethnicity, the relationship between this polymorphism and BD was more significant in Caucasians (allele model: OR = 0.49, 95% CI 0.39-0.61; heterozygote model: OR = 0.35, 95% CI 0.26-0.47; homozygote model: OR = 0.29, 95% CI 0.16-0.53; dominant model: OR = 0.34, 95% CI 0.25-0.45; recessive model: OR = 0.56, 95% CI 0.50-0.72) than that in Asians. Conclusion In conclusion, this meta-analysis indicates that miRNA-146a gene polymorphism rs2910164 G allele confers BD susceptibility, especially in Caucasians.

Background Enhancement of N-methyl-D-aspartate (NMDA) receptor function using glycine-site agonist D-cycloserine is known to facilitate fear extinction, providing a means to augment cognitive behavioral therapy in anxiety disorders. A novel class of glycine-site agonists has recently been identified, and we have found that the prototype, AICP, is more effective than D-cycloserine in modulating neuronal function. Methods Using novel glycine-site agonist AICP, local infusion studies, and genetic models, we elucidated the role of GluN2C-containing receptors in fear extinction. Results We tested the effect of intracerebroventricular injection of AICP on fear extinction and found a robust facilitation of fear extinction. This effect was dependent on GluN2C subunit, consistent with superagonist action of AICP at GluN2C-containing receptors. Local infusion studies in wild-type and GluN2C knockout mice suggested that AICP produces its effect via GluN2C-containing receptors in the basolateral amygdala (BLA). Furthermore, consistent with astrocytic expression of GluN2C subunit in the amygdala, we found that AICP did not facilitate fear extinction in mice with conditional deletion of obligatory GluN1 subunit from astrocytes. Importantly, chemogenetic activation of astrocytes in the basolateral amygdala facilitated fear extinction. Acutely, AICP was found to facilitate excitatory neurotransmission in the BLA via presynaptic GluN2C-dependent mechanism. Immunohistochemical studies suggest that AICP-mediated facilitation of fear extinction involves synaptic insertion of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor GluA1 subunit. Conclusion These results identify a unique role of astrocytic NMDA receptors composed of GluN2C subunit in extinction of conditioned fear memory and demonstrate that further development of recently identified superagonists of GluN2C-containing receptors may have utility for anxiety disorders.

Polymorphisms of the catechol-O-methyl transferase (COMT) or monoamine oxidase B (MAO-B) genes may affect the occurrence of dyskinesia in Parkinson’s disease (PD) patients. However, the findings are inconsistent. Thus, we performed a meta-analysis to assess whether COMT and MAO-B genetic variants are associated with an increased incidence of levodopa-induced dyskinesia (LID) in PD patients. A literature search of PubMed, Embase, and Cochrane Library was conducted to identify relevant studies published up to January 2021. The strength of the association between the polymorphisms and LID susceptibility was estimated by odds ratio (OR) and associated 95% confidence interval (CI). The pooled ORs were assessed in different genetic models. Ten studies involving 2385 PD patients were included in the meta-analysis. Analysis of pooled ORs and 95% CIs suggested that the AA genotype of COMT(rs4680) was associated with LID (OR = 1.39, 95%CI: 1.02–1.89, P = 0.039) in the recessive model, and this correlation was more obvious in Brazilian samples in the analysis stratified by ethnicity. For the AG genotype of MAO-B(rs1799836), the pooled OR was 1.66 (95% CI: 1.04–2.65, P = 0.03) in patients with LID versus those without LID in the heterozygote model. Our meta-analysis implicates the AA genotype of the COMT rs4680 polymorphism as potentially increasing the risk of LID in a recessive genetic model for PD patients. Furthermore, the AG genotype of the MAO-B rs1799836 polymorphism may influence the prevalence of LID in PD patients in the heterozygote model. However, further well-designed studies with larger PD patient cohorts are required to validate these results after adjusting for confounding factors.

Nonselective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson's disease and dystonia. Despite their efficacy in these and other central nervous system disorders, antimuscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the antiparkinsonian and antidystonic efficacy observed with the use of nonselective antimuscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of nonselective antimuscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here, we utilize genetic mAChR knockout animals in combination with nonselective mAChR antagonists to confirm that the M4 receptor activation is required for the locomotor-stimulating and antiparkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have antiparkinsonian and antidystonic efficacy in pharmacological and genetic models of movement disorders.

Objective: The potential correlation between the ε2/ε3/ε4 variants of the ApoE (Apolipoprotein E) gene and the odds of mesial temporal lobe epilepsy was investigated. Methods: The database searching for eligible studies was performed in October 2020. A series of pooling analyses were conducted. Results: We enrolled a total of twelve case-control studies for pooling. Within the pooling analysis of ε4, there was an in- creased risk of mesial temporal lobe epilepsy in cases under the models of carrier ε4 vs. ε3, ε3ε4 vs. ε3ε3, and ε3ε4+ε4ε4 vs. ε3ε3 [P < 0.05, odds ratio (OR) > 1], compared with controls. Moreover, we observed similar positive results in the subgroup analyses of “China” and “Population-based control” under the genetic models of ε4 (P < 0.05, OR > 1). Nevertheless, we did not detect the significant difference between the mesial temporal lobe epilepsy cases and controls in the pooling analyses of ε2 (all P > 0.05). Conclusion: The ε3ε4 genotype of ApoE seems to be linked to the risk of mesial temporal lobe epilepsy for patients in China. More sample sizes are required to confirm the potential role of ApoE isoforms in the susceptibility to diverse types of epilepsy from different origins. Keywords: Epilepsy; ApoE; isoforms; susceptibility.

Background The essential nutrient choline provides one-carbon units for metabolite synthesis and epigenetic regulation in tissues including brain. Dietary choline intake is often inadequate, and higher intakes are associated with improved cognitive function. Objective Choline supplements confer cognitive improvement for those diagnosed with fetal alcohol spectrum disorder (FASD), a common set of neurodevelopmental impairments; however, the effect sizes have been modest. In this retrospective analysis, we report that genetic polymorphisms affecting choline utilization are associated with cognitive improvement following choline intervention. Methods Fifty-two children from the upper midwestern United States and diagnosed with FASD, ages 2-5 y, were randomly assigned to receive choline (500 mg/d; n = 26) or placebo (n = 26) for 9 mo, and were genotyped for 384 choline-related single nucleotide polymorphisms (SNPs). Memory and cognition were assessed at enrollment, study terminus, and at 4-y follow-up for a subset. Results When stratified by intervention (choline vs. placebo), 14-16 SNPs within the cellular choline transporter gene solute carrier family 44 member 1 (SLC44A1) were significantly associated with performance in an elicited imitation sequential memory task, wherein the effect alleles were associated with the greatest pre-/postintervention improvement. Of these, rs3199966 is a structural variant (S644A) and rs2771040 is a single-nucleotide variant within the 3' untranslated region of the plasma membrane isoform. An additive genetic model best explained the genotype associations. Lesser associations were observed for cognitive outcome and polymorphisms in flavin monooxygenase-3 (FMO3), methylenetetrahydrofolate dehydrogenase-1 (MTHFD1), fatty acid desaturase-2 (FADS2), and adiponectin receptor 1 (ADIPOR1). Conclusions These SLC44A1 variants were previously associated with greater vulnerability to choline deficiency. Our data potentially support the use of choline supplements to improve cognitive function in individuals diagnosed with FASD who carry these effect alleles. Although these findings require replication in both retrospective and prospective confirmatory trials, they emphasize the need to incorporate similar genetic analyses of choline-related polymorphisms in other FASD-choline trials, and to test for similar associations within the general FASD population. This trial was registered at www.clinicaltrials.gov as NCT01149538.

Lipoprotein lipase (LPL) is an enzyme involved in lipid metabolism and distribution of fatty acids hence its role in the initiation and development of dyslipidemia and adiposity. Single nucleotide polymorphisms (SNPs) across the LPL gene have been associated with dyslipidemia, however, the association with obesity has been limited towards specific populations. This study examined the association between LPL gene polymorphisms with plasma lipid levels and body mass index (BMI) in the Kuwaiti population. We examined a total of 486 adults (303 and 183 females and males respectively) with plasma lipid levels and BMI. DNA samples were genotyped for two LPL gene polymorphisms (rs1534649 and rs28645722) using TaqMan allelic discrimination. The relationship between the genotypes with both plasma lipid levels and BMI were assessed using linear regression using “SNPassoc” package from R statistical software. Using an additive genetic model, linear regression analysis showed the T-allele of rs1534649 to be associated with increased BMI in a dose-dependent trend β = 2.13 (95% CI 1.33–2.94); p = 1.7 × 10−7. In addition, a borderline significance was observed between the T-allele and low levels of high density lipoprotein-cholesterol β = −0.04 (95% CI −0.08, −0.006); p = 0.02. There were no associations between rs28645722 and plasma lipid levels (p > 0.05). However, a trend was observed between the A-allele and increased BMI β = 1.75 (95% CI 0.14–3.35); p = 0.03. Our study shows intron one polymorphism rs1534649 to increase the risk of obesity and dyslipidemia. Our findings warrant further investigation of the mechanism of LPL on the development of obesity along with the role of intron one and its impact on LPL gene activity.

Summary Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31−6.73], p = 7.87 × 10−8). The HLA-DPB1∗02:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66−7.63], p = 2.28 × 10−9), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33−6.26], p = 3.03 × 10−8). A meta-analysis performed in the combined set revealed that the HLA-DPB1∗02:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89−5.93], p = 1.06 × 10−14). Individuals carrying the HLA-DPB1∗02:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed.

Background Recent studies identifying methylenetetrahydrofolate reductase (MTHFR) polymorphisms associated with breast cancer (BC), ovarian cancer (OC), cervical cancer, and endometrial cancer (EC) have reported conflicting results and been underpowered. To clarify the correlation between MTHFR mutations and these common female malignancies, we conducted a comprehensive meta-analysis incorporating all eligible publications. Methods Relevant reports published before January 20, 2020, were retrieved from PubMed, Embase, the Cochrane Library, and the China National Knowledge Infrastructure databases. The odds ratio and 95% confidence interval summaries for the MTHFR 677C/T and 1298A/C polymorphisms in BC, OC, cervical cancer, and EC were estimated. Results A total of 171 studies comprising 56,675 cancer cases and 67,559 controls were included. The results showed a markedly elevated risk of cancer susceptibility related to MTHFR 677C/T based on all genetic models. Similarly, we identified a significant correlation between 1298A/C mutation and cancer risk based on overall comparisons among all models, except the heterozygous model. Moreover, subgroup analysis by cancer type revealed a significantly increased risk of BC associated with 677C/T in the five models and of cervical cancer associated with 1298A/C in some models. Based on ethnicity, significant associations were observed between Asian, African, and mixed populations for 677C/T and the Asian population for 1298A/C. With regard to the sample type used for analysis, we detected a positive association between using blood as the DNA source and cancer risk for 677C/T in all genetic models and for 1298A/C in some genetic models. Further stratification of the results revealed that a notably increased risk was associated with the use of polymerase chain reaction-restriction fragment-length polymorphism or TaqMan as the genotyping method, as well as with the use of population-or hospital-based groups as the controls for 677C/T and 1298A/C, respectively. Conclusion This meta-analysis suggests that MTHFR 677C/T and 1298A/C polymorphisms correlate with the risk of common gynecological cancers, with these findings potentially applicable for overall comparisons of related data.