Functional Genetic Polymorphisms Research Articles

MEG3 rs7158663 genetic polymorphism is associated with the risk of hepatocellular carcinoma

Recently, a meta-analysis has shown that a potentially functional genetic polymorphism (rs7158663 A > G) on the cancer-associated lncRNA MEG3 is associated with the risk of many types of cancer. Given the important role of MEG3 in the development of hepatocellular carcinoma (HCC), the current study evaluated the association of the rs7158663 genetic polymorphism with HCC risk. A total of 271 HCC patients and 267 healthy individuals were included in the current case-control study. Direct sequencing was used to detect the rs7158663 locus genotype of the included individuals. The case-control study showed that the MEG3 rs7158663 genetic polymorphism was associated with the increased risk of developing HCC [GA vs. GG: OR = 1.63, 95% CI = 1.14–2.34, p = 0.009; AA vs. GG: OR = 2.10, 95% CI = 1.10–4.08, p = 0.03; (GA + AA) vs. GG: OR = 1.70, 95% CI = 1.21–2.40, p = 0.003; A vs. G: OR = 1.53, 95% CI = 1.17–2.00, p = 0.002]. In addition, the genotype-tissue expression showed that the rs7158663 AA or GA genotype was associated with reduced MEG3 expression. Bioinformatic analysis showed that the rs7158663 genetic polymorphism not only affects the binding of transcription factors but also interacts with multiple genes through chromatin loops. In summary, the current findings suggest that the rs7158663 genetic polymorphism affecting MEG3 expression is associated with HCC risk and may serve as a marker of genetic susceptibility to HCC. However, the specific molecular mechanisms of the rs7158663 genetic polymorphism in the development of HCC need to be further revealed.

The HSP90AA1 gene is involved in heat stress responses and its functional genetic polymorphisms are associated with heat tolerance in Holstein cows

As the stress-inducible isoform of the heat-shock protein 90 (HSP90), the HSP90AA1 gene encodes HSP90α and plays an important role in heat stress (HS) response. Therefore, this study aimed to investigate the role of the HSP90AA1 gene in cellular responses during HS and to identify functional SNPs associated with thermotolerance in Holstein cattle. For the in vitro validation experiment of acute HS, cells from the Madin-Darby bovine kidney cell line were exposed to 42°C for 1 h, and various parameters were assessed, including cell apoptosis, cell autophagy, and the cellular functions of HSP90α by using its inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). Furthermore, the polymorphisms identified in the HSP90AA1 gene and their functions related to HS were validated in vitro. Acute HS exposure induced cell apoptosis, cell autophagy, and upregulated expression of the HSP90AA1 gene. Inhibition of HSP90α by 17-AAG treatment had a significant effect on the expression of the HSP90α protein and increased cell apoptosis. However, autophagy decreased in comparison to the control treatment when cells were exposed to 42°C for 1 h. Five SNPs identified in the HSP90AA1 gene were significantly associated with rectal temperature and respiration score in Holstein cows, in which the rs109256957 SNP is located in the 3' untranslated region (3' UTR). Furthermore, we demonstrated that the 3' UTR of HSP90AA1 is a direct target of bta-miR-1224 by cell transfection with exogenous microRNA (miRNA) mimic and inhibitor. The luciferase assays revealed that the SNP rs109256957 affects the regulation of bta-miR-1224 binding activity and alters the expression of the HSP90AA1 gene. Heat stress-induced HSP90AA1 expression maintains cell survival by inhibiting cell apoptosis and increasing cell autophagy. The rs109256957 located in the 3' UTR region is a functional variation and it affects the HSP90AA1 expression by altering its binding activity with bta-miR-1224, thereby associating with the physiological parameters of Holstein cows.

Smoke and Spike: Benzo[a]pyrene Enhances SARS-CoV-2 Infection by Boosting NR4A2-Induced ACE2 and TMPRSS2 Expression.

Cigarette smoke aggravates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the underlying mechanisms remain unclear. Here, they show that benzo[a]pyrene in cigarette smoke extract facilitates SARS-CoV-2 infection via upregulating angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Benzo[a]pyrene trans-activates the promoters of ACE2 and TMPRSS2 by upregulating nuclear receptor subfamily 4 A number 2 (NR4A2) and promoting its binding of NR4A2 to their promoters, which is independent of functional genetic polymorphisms in ACE2 and TMPRSS2. Benzo[a]pyrene increases the susceptibility of lung epithelial cells to SARS-CoV-2 pseudoviruses and facilitates the infection of authentic Omicron BA.5 in primary human alveolar type II cells, lung organoids, and lung and testis of hamsters. Increased expression of Nr4a2, Ace2, and Tmprss2, as well as decreased methylation of CpG islands at the Nr4a2 promoter are observed in aged mice compared to their younger counterparts. NR4A2 knockdown orinterferon-λ2/λ3 stimulationdownregulates the expression of NR4A2, ACE2, and TMPRSS2, thereby inhibiting the infection. In conclusion, benzo[a]pyrene enhances SARS-CoV-2 infection by boosting NR4A2-induced ACE2 and TMPRSS2 expression. This study elucidates the mechanisms underlying the detrimental effects of cigarette smoking on SARS-CoV-2 infection and provides prophylactic options for coronavirus disease 2019, particularly for the elderly population.

The relationship between rs968697 genetic polymorphism and gastric cancer susceptibility, TNM stage and survival prognosis

Background HMGA2 can promote the development of multiple malignancies. This study aimed to determine whether a putative functional genetic polymorphism (rs968697 T>C) in the HMGA2 gene promoter region was associated with malignancy susceptibility in the Chinese population. Methods The rs968697 genetic polymorphism was genotyped using the SNaPshot method in the case-control study. The odds ratios and 95% confidence intervals were calculated using a logistic regression model. STATA software was used to conduct the meta-analysis. Results The rs968697 genetic polymorphism was associated not only with susceptibility to malignant tumors [CC versus TT: OR = 0.45, 95%CI = 0.28–0.73, p = .001; CC versus (CT + TT): OR = 0.47, 95%CI = 0.29–0.75, p = .003] including gastric cancer (GC), but also with TNM stage and survival prognosis of GC patients. Genotype-tissue expression analysis, luciferase assay and bioinformatics analysis revealed that the rs968697 genetic polymorphism might affect the binding of transcription factors, especially POLR2A, which in turn regulate the expression of HMGA2. Conclusions The current research suggests that the rs968697 genetic polymorphism may be used as a biomarker for malignancy susceptibility and GC prognosis in the Chinese population.

Abstract 1404: A functional genetic polymorphism of mitochondrion-associated DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma

Abstract Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease worldwide and may progress to nonalcoholic steatohepatitis (NASH). Although emerging evidence suggests that NASH would be an important driver of hepatocellular carcinoma (HCC), molecularly what drives the transition of NAFLD to NASH and then HCC has not been clearly defined. Since NASH is a mitochondrial disease, we aimed to determine genetic variants associated with mitochondrial dysfunction linked to NASH and NASH-related HCC. We performed an integrative genomics analysis by analyzing a large-scale genome-wide association study of the body fat distribution-related variants in 344,369 individuals from multiple ancestries. And we linked these results to the top 24 significant variants to NASH and NASH-related HCC in 1,009 individuals from the NCI-UMD cohort. We also performed the expression quantitative trait loci (eQTL) analysis on candidate variants. We analyzed the 3D genome architecture especially chromatin topology based on UCSC Genome Browser that influences the expression of candidate variants. As a result, we identified rs3747579-TT, an eQTL to a mitochondrial chaperone Hsp40, also known as DNAJA3 rather than a coding variant, as a risk allele linked to NASH-related HCC. HCC patients with rs3747579-TT variant had a poor prognosis compared to HCC patients with rs3747579-CT or CC variant. We confirmed that HCC with rs3747579-TT had a reduced expression of DNAJA3, encoding a protein that maintains mitochondrial homeostasis. Consistently, HCC patients with low DNAJA3 expression had a poor prognosis. We found a specific site based on chromatin topology that may influence rs3747579 to regulate the expression of DNAJA3. In summary, we identified rs3747579-TT as a functional polymorphic variant of DNAJA3 that may be responsible for the development of NASH and NASH-related HCC. Citation Format: Yuto Shiode, Ching-Wen Chang, Xin Wei Wang. A functional genetic polymorphism of mitochondrion-associated DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1404.

Emotional, inflammatory, and genetic factors of resilience and vulnerability to depression in patients with premenopausal breast cancer: A longitudinal study protocol.

Psychosocial stress and depressive disorder have been associated with cancer as putative contributors to worse prognosis. On the other hand, cancer diagnosis is a recognised life event that can contribute to distress and depressive states. Humoral and cellular inflammation can promote depressive disorder by means of decreased monoamine synthesis, glutamate neurotoxicity, neurogenesis and neuroplasticity, dysregulated hypothalamic-pituitary-adrenal axis, and glucocorticoid resistance. This protocol objectives are to observe the interactions between psychosocial variables and biochemical and immunological biomarkers in a longitudinal, prospective design; to identify inflammation-related depression endophenotypes in breast cancer patients and to understand if early diagnosed and treated depression in this population will translate in better inflammation status and better global prognosis. Prospective observational cohort, composed by 100 consecutive premenopausal patients, diagnosed with non-distant metastatic breast carcinoma and with no history of major psychopathology or other organic illness. The participants will have an in-person assessment in three different moments, along illness treatment and follow-up, with respect to cytometric, immunologic, and psychosocial parameters and will be tested for depression vulnerability and resilience inflammation-related functional genetic polymorphisms. Additionally, at years 5 and 10 post enrollment, patients`medical records will be assessed. As a control cohort, all patients excluded due to psychiatric history or past psychiatric treatments will have their clinical records assessed at years 5 and 10 after admission. All the data will be managed with the SPSS® software. This study is an original longitudinal cohort of breast cancer premenopausal patients, with a comprehensive approach to psychosocial, clinical, inflammatory, and genetic variables. It expects to provide evidence regarding the links between genetic, cytometric, immunologic, and psychosocial factors, their potential contribution to the pathophysiology of depressive disorder, breast cancer course, progression, and prognosis. It may further contribute with data to better efficacy of the psycho-oncological interventions. National Commission of Data Protection (CNPD) 13413/2017; Ethics Committee of IPOP project code CI-IPOP81/2017.

Automated warfarin dose prediction for Asian, American, and Caucasian populations using a deep neural network

Existing warfarin dose prediction algorithms based on pharmacogenetics and clinical parameters have not been used clinically due to the absence of external validation, lack of assessment for clinical utility, and high risk of bias. Moreover, given the high degree of heterogeneity across different datasets used to develop these algorithms, it is unsurprising that prediction errors remain high, and dosing accuracy is dependent on specific ethnic populations. To circumvent these challenges, deep neural models are increasingly used to improve the precision and accuracy of warfarin dose predictions. Hence, this study sought to develop a deep learning-based model using a well-established curated dataset of over 6000 patients from the International Warfarin Pharmacogenomics Consortium (IWPC). Clinically-relevant input data such as physical attributes, medical conditions, concomitant medications, genotype status of functional warfarin genetic polymorphisms, and therapeutic INR were entered followed by applying a unique and robust training and validation method. The deep model yielded a low average mean absolute error (MAE) of 7.6 mg/week and a relatively low mean percentage of error of 40.9% in Asians, 14.2 mg/week MAE and 36.9% in African Americans, and 12.7 mg/week MAE and 45.4% mean percentage of error in White Caucasians. This model also resulted in 36.4% of all patients with a predicted dose within 20% of the administered dose. Hence, our proposed deep model provides an alternative to predicting warfarin dose in the clinical setting upon validation in ethnically-similar datasets.

TERT genetic polymorphism rs2736100 is associated with an aggressive manifestation of papillary thyroid carcinoma.

TERT rs2736100 genetic polymorphism is commonly found in human malignancies, indicating its key role in cancer cell transformation. The aim of this study is to investigate the effects of the functional TERT rs2736100 genetic polymorphism on the outcomes of papillary thyroid carcinoma (PTC) patients. We performed a retrospective study on the relationship between rs2736100 and clinicopathological outcomes of PTC in 500 patients (378 females and 122 males) aged 43.8 ± 11.4 years (range 15-74 years) with a median follow-up of 60 months (range, 1-455 months). TERT rs2736100 genetic polymorphism (TG/GG vs. TT) was significantly associated with several high-risk clinicopathological features such as tumor spread, extrathyroidal extension, central/lateral lymph node metastases, and Stage T III or IV disease. However, in Kaplan-Meier survival analyses, the rs2736100 mutation was unrelated to overall disease-free survival with a log-rank value of p > 0.05. In Cox-regression analyses, the overall survival rate of recurrence/neo-metastasis was related to a larger tumor size, younger age, and tumor spread but unrelated to the rs2736100 mutation. TERT rs2736100 genetic polymorphism mutation is more likely to manifest with aggressive clinicopathological characteristics but cannot worsen prognosis in PTC.

TP73-AS1 rs3737589 Polymorphism is Associated With the Clinical Stage of Colorectal Cancer.

TP73-AS1 can promote the occurrence and development of a variety of tumors, including colorectal cancer (CRC). The current study aimed to investigate the association between a potentially functional genetic polymorphism (rs3737589 T > C) on the TP73-AS1 gene and the susceptibility and clinical stage of CRC in a Chinese Han population. The polymorphic genotyping was performed by the SNaPshot method. The real-time quantitative PCR method and the luciferase assay were used separately to explore genotype-tissue expression and the function of the genetic polymorphism. A total of 576 CRC patients and 896 healthy controls were included in the current study. The rs3737589 polymorphism was not associated with CRC susceptibility but was associated with the CRC stage (CC vs. TT: OR = 0.25, 95% CI = 0.12 - 0.54, P=0.0003; C vs. T: OR = 0.69, 95% CI = 0.53-0.89, P=0.006; and CC vs. (TC + TT): OR = 0.26, 95% CI = 0.12-0.56, P=0.0004). CRC patients carrying the rs3737589 CC genotype or C allele were less likely to have stage III/IV tumors than those carrying the rs3737589 TT genotype or T allele. The expression of TP73-AS1 was lower in CRC tissues with the rs3737589 CC genotype compared to those with the TT genotype. Bioinformatics analysis and the luciferase assay revealed that the C allele could promote the binding of miR-3166 and miR-4771 to TP73-AS1. The TP73-AS1 gene rs3737589 polymorphism affecting miRNAs binding is associated with the CRC stage and may serve as a biomarker for predicting CRC progression.

A functional polymorphism in the poly(ADP-ribose) polymerase-1 gene increases the risk of endometrial carcinoma

The aim of this study was to investigate the effects of two functional genetic polymorphisms in the poly(ADP-ribose) polymerase-1 (PARP-1) gene on the risk of endometrial carcinoma (EC). Genotypes of the rs1136410 and rs8679 polymorphisms were determined by polymerase chain reaction and ligase detection reaction in 327 EC patients and 329 controls. The results showed that there were significant differences in the genotype distributions of rs1136410 between cases and controls. Women carrying the rs1136410 CC genotype had a significantly increased risk of EC compared to those with the rs1136410 TT genotype (OR = 1.73, 95% CI = 1.10–2.72, p = .018). After adjustment for clinical characteristics, the rs1136410 CC genotype still significantly increased the risk of EC (adjusted OR = 1.83, 95% CI = 1.09–3.07, p = .021). However, no significant difference was observed in the genotype frequencies of rs8679 between cases and controls. This study indicated that rs1136410 was related to the risk of developing EC, and the CC genotype of rs1136410 may be a risk factor for EC in the northern Chinese population. IMPACT STATEMENT What is already known on this subject? Genetic variations in the PARP-1 gene may affect protein function and hence reduce DNA repair capacity, leading to the accumulation of DNA damage and a subsequent increased probability of tumorigenesis. Previous studies have shown that polymorphisms of the PARP-1 gene are associated with the risk of various carcinomas, including breast cancer, lung cancer, thyroid cancer, colorectal cancer, and oral squamous cell carcinoma. What do the results of this study add? Our results suggest that the rs1136410 polymorphism of PARP-1 was related to the risk of developing endometrial carcinoma, and the CC genotype of rs1136410 may be a risk factor for endometrial carcinoma in the northern Chinese population. What are the implications of these findings for clinical practice and/or further research? The new genetic marker may help to identify genetic basis of endometrial carcinoma, and develop gene-targeted therapies for endometrial carcinoma.

Recognition of functional genetic polymorphism using ESE motif definition: a conservative evolutionary approach to CYP2D6/CYP2C19 gene variants.

Although predicting the effects of variants near intron-exon boundaries is relatively straightforward, predicting the functional Exon Splicing Enhancers (ESEs) and the possible effects of variants within ESEs remains a challenge. Considering the essential role of CYP2D6/CYP2C19 genes in drug metabolism, we attempted to identify variants that are most likely to disrupt splicing through their effect on these ESEs. ESEs were predicted in these two genes using ESEfinder 3.0, incorporating a series of filters (increased threshold and evolutionary conservation). Finally, reported mutations were evaluated for their potential to disrupt splicing by affecting these ESEs. Initially, 169 and 243 ESEs were predicted for CYP2C19/CYP2D6, respectively. However, applying the filters, the number of predicted ESEs was reduced to 26 and 19 in CYP2C19/CYP2D6, respectively. Comparing prioritized predicted ESEs with known sequence variants in CYP2C19/CYP2D6 genes highlights 18 variations within conserved ESEs for each gene. We found good agreement in cases where such predictions could be compared to experimental evidence. In total, we prioritized a subset of mutational changes in CYP2C19/CYP2D6 genes that may affect the function of these genes and lead to altered drug responses. Clinical studies and functional analysis for investigating detailed functional consequences of the mentioned mutations and their phenotypic outcomes is mostly recommended.

Predictors of Chronic Fatigue Syndrome and Mood Disturbance After Acute Infection.

Prospective cohort studies following individuals from acute infections have documented a prevalent post-infective fatigue state meeting diagnostic criteria for chronic fatigue syndrome (CFS) – that is, a post-infective fatigue syndrome (PIFS). The Dubbo Infection Outcomes Study (DIOS) was a prospective cohort following individuals from acute infection with Epstein-Barr virus (EBV), Ross River virus (RRV), or Q fever through to assessment of caseness for CFS designated by physician and psychiatrist assessments at 6 months. Previous studies in DIOS have revealed that functional genetic polymorphisms in both immunological (pro- and anti-inflammatory cytokines) and neurological (the purinergic receptor, P2X7) genes are associated with both the severity of the acute infection and subsequent prolonged illness. Principal components analysis was applied to self-report data from DIOS to describe the severity and course of both the overall illness and concurrent mood disturbance. Associations between demographics and acute infection characteristics, with prolonged illness course as well as the PIFS outcome were examined using multivariable statistics. Genetic haplotype-driven functional variations in the neuropeptide Y (NPY) gene previously shown to be associated with brain responses to stress, and to trait anxiety were also examined as predictors. The sample included 484 subjects (51% female, median age 32, IQR 19–44), of whom 90 (19%) met diagnostic criteria for CFS at 6 months. Participants with greater overall illness severity and concurrent mood disturbance in the acute illness had a more prolonged illness severity (HR = 0.39, 95% CI: 0.34–0.46, p < 0.001) and mood disturbance (HR = 0.36, 95% CI: 0.30–0.42, p < 0.001), respectively. Baseline illness severity and RRV infection were associated with delayed recovery. Female gender and mood disturbance in the acute illness were associated with prolonged mood disturbance. Logistic regression showed that the odds of an individual being diagnosed with PIFS increased with greater baseline illness severity (OR = 2.24, 95% CI: 1.71–2.94, p < 0.001). There was no association between the NPY haplotypes with overall illness severity or mood disturbance either during the acute illness phase or with prolonged illness (p > 0.05). Severe acute infective illnesses predicted prolonged illness, prolonged mood disturbance and PIFS. These factors may facilitate early intervention to manage both PIFS and mood disturbances.

Association of third molar agenesis and microdontia with genetic polymorphisms in vitamin-D-related genes

The present study aimed to evaluate if functional genetic polymorphisms in vitamin-D-related genes are associated with third molar agenesis and third molar microdontia in German orthodontic patients. Pre-orthodontic and follow-up treatment records were evaluated for phenotype definition. Saliva samples were collected for DNA extraction. Eight potential functional genetic polymorphisms in VDR [rs731236 (TaqI), rs7975232 (ApaI), rs2228570 (FokI), and rs1544410 (BsmI)], CYP27B1 (rs4646536), CYP24A1 (rs927650), GC (rs4588), and SEC23A (rs8018720) were evaluated using real-time PCR. Comparison among the groups were performed (third molar anomaly vs. control; third molar agenesis vs. control; and third molar microdontia vs. control) with an alpha of 5%. A total of 164 patients were analyzed. Forty-nine (29.9%) patients had at least one third molar anomaly. In the haplotype analysis, genetic polymorphisms in VDR and CYP27B1 were associated with third molar anomalies (p < 0.05). The G allele in rs8018720 (SEC23A) was more frequent in microdontia cases. In the genotype distribution analysis, rs8018720 in SEC23A was associated with third molar microdontia in the co-dominant (p = 0.034; Prevalence Ratio [PR]=5.91, 95% Confidence Interval [CI]= 1.14–30.66) and in the recessive (p = 0.038; PR=5.29; 95% CI= 1.09–25.65) models. In conclusion, vitamin D-related genes could be involved in third molar anomalies.

TLR Signaling Pathway Gene Polymorphisms, Gene-Gene and Gene-Environment Interactions in Allergic Rhinitis.

ABSTRACTBackgroundAllergic rhinitis (AR) is a nasal inflammatory disease resulting from a complex interplay between genetic and environmental factors. The association between Toll-like receptor (TLR) signaling pathway and environmental factors in AR pathogenesis remains to be explored. This study aims to assess the genetic association of AR with single nucleotide polymorphisms (SNPs) in TLR signaling pathway, and investigate the roles of gene–gene and gene–environment interactions in AR.MethodsA total of 452 AR patients and 495 healthy controls from eastern China were enrolled in this hospital-based case–control study. We evaluated putatively functional genetic polymorphisms in TLR2, TLR4 and CD14 genes for their association with susceptibility to AR and related clinical phenotypes. Interactions between environmental factors (such as traffic pollution, residence, pet keeping) and polymorphisms with AR were examined using logistic regression. Models were stratified by genotype and interaction terms, and tested for the significance of gene–gene and gene–environment interactions.ResultsIn the single-locus analysis, two SNPs in CD14, rs2563298 (A/C) and rs2569191 (C/T) were associated with a significantly decreased risk of AR. Compared with the GG genotype, the GT and GT/TT genotypes of TLR2 rs7656411 (G/T) were associated with a significantly increased risk of AR. Gene–gene interactions (eg, TLR2 rs7656411, TLR4 rs1927914, and CD14 rs2563298) was associated with AR. Gene–environment interactions (eg, TLR4 or CD14 polymorphisms and certain environmental exposures) were found in AR cases, but they were not significant after Bonferroni correction.ConclusionThe genetic polymorphisms of TLR2 and CD14 and gene–gene interactions in TLR signaling pathway were associated with susceptibility to AR in this Han Chinese population. However, the present results were limited to support the association between gene–environment interactions and AR.

Glutathione Peroxidase GPX1 and Its Dichotomous Roles in Cancer.

Simple SummaryGlutathione peroxidase 1 (GPX1), as one of the most important antioxidant enzymes, maintains cellular redox balance by regulating reactive oxygen species levels. In this review, we summarize and discuss the relationship between GPX1 genetic polymorphisms and cancer susceptibility, as well as the dichotomous roles of GPX1 aberrant expressions in the occurrence and development of human malignancies via various biological mechanisms. Our work may deepen the understanding of the critical clinical values and future directions of GPX1 as a potential prognostic biomarker and novel cancer therapeutic target.As the first identified selenoprotein, glutathione peroxidase 1 (GPX1) is a widely and abundantly expressed antioxidant enzyme. GPX1 utilizes glutathione as a substrate to catalyze hydrogen peroxide, lipid peroxide, and peroxynitrite, thereby reducing intracellular oxidative stress. The GPX1 gene is regulated at transcriptional, post-transcriptional, and translational levels. Numerous case-control studies and meta-analyses have assessed the association between a functional genetic polymorphism of the GPX1 gene, named Pro198Leu (rs1050450 C>T), and cancer susceptibility in different populations. GPX1 polymorphism has type-specific effects as a candidate marker for cancer risk, but the association between GPX1 variants and cancer susceptibility remains controversial in different studies. GPX1 is abnormally elevated in most types of cancer but has complex dichotomous roles as tumor suppressor and promoter in different cancers. GPX1 can participate in various signaling pathways to regulate tumor biological behaviors, including cell proliferation, apoptosis, invasion, immune response, and chemoresistance. In this review, we comprehensively summarize the controversial associations between GPX1 polymorphism and cancer risks and further discuss the relationships between the aberrant expressions of GPX1 and tumorigenesis. Further studies are needed to elucidate the clinical significance of GPX1 as a potential prognostic biomarker and novel therapeutic target in various malignancies.

Associations between Omega-3 Index, Dopaminergic Genetic Variants and Aggressive and Metacognitive Traits: A Study in Adult Male Prisoners.

Omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are critical for cell membrane structure and function. Human beings have a limited ability to synthesise docosahexaenoic acid (DHA), the main n-3 LCPUFA required for neurological development. Inadequate levels of n-3 LCPUFA can affect the dopaminergic system in the brain and, when combined with genetic and other factors, increase the risk of developing aggression, inattention and impulse-control disorders. In this study, male prisoners were administered questionnaires assessing aggressive behaviour and executive functions. Participants also produced blood sampling for the measurement of the Omega-3 Index and the genotyping of dopaminergic genetic variants. Significant associations were found between functional genetic polymorphism in DBH rs1611115 and verbal aggression and between DRD2 rs4274224 and executive functions. However, the Omega-3 Index was not significantly associated with the tested dopaminergic polymorphisms. Although previous interactions between specific genotypes and n-3 LCPUFA were previously reported, they remain limited and poorly understood. We did not find any association between n-3 LCPUFA and dopaminergic polymorphisms in adult male prisoners; however, we confirmed the importance of genetic predisposition for dopaminergic genes (DBH and DRD2) in aggressive behaviour, memory dysfunction and attention-deficit disorder.

Genetic Variants of Matrix Metalloproteinase and Sepsis: The Need Speed Study.

Many causal mechanisms in sepsis susceptibility are largely unknown and the functional genetic polymorphisms (GP) of matrix metalloproteinases (MMPs) and their natural tissue inhibitor of MMPs (TIMP1) could play a role in its development. GPs of MMPs and TIMP (namely MMP-1 rs1799750, MMP-3 rs3025058, MMP-8 rs11225395, MMP-9 rs2234681, and TIMP-1 rs4898) have been compared in 1058 patients with suspected sepsis to assess the association with susceptibility and etiology of sepsis. Prevalence of MMP8 rs11225395 G/G genotype was higher in sepsis patients than in those with non-infective Systemic Inflammatory Reaction Syndrome (35.6 vs. 26%, hazard ratio, HR 1.56, 95% C.I. 1.04–2.42, p = 0.032). G/G patients developed less hyperthermia (p = 0.041), even after stratification for disease severity (p = 0.003). Patients carrying the 6A allele in MMP3 rs3025058 had a higher probability of microbiologically-proven sepsis (HR 1.4. 95%C.I. 1.01–1.94, p = 0.044), particularly when due to virus (H.R. 2.14, 95% C.I. 1.06–4.31, p = 0.046), while MMP-1 G/G genotype patients carried a higher risk for intracellular bacteria (Chlamydia, Mycoplasma, and Legionella, H.R. 6.46, 95% C.I. 1.58–26.41, p = 0.003). Neither severity of sepsis at presentation, nor 30-day mortality were influenced by the investigated variants or their haplotype. MMP8 rs11225395 G/G carriers have lower temperature at presentation and a more than 50% increased susceptibility to sepsis. Among patients with sepsis, carriers of MMP1 rs1799750 G/G have an increased susceptibility for intracellular pathogen infections, while virus serology is more often positive in those with the MMP3 rs3025058 A/A genotype.

Association of interleukin-12B gene polymorphisms and mRNA expression with preeclampsia

ObjectiveTo explore the effects of functional genetic polymorphisms of the interleukin-12B (IL-12B) gene on the susceptibility to preeclampsia in northern Chinese women. Study DesignMaternal peripheral blood from 306 preeclamptic women and 310 control women and the placentas from 52 preeclamptic and 55 control women were collected. Two polymorphisms (rs17860508 and rs3212227) of the IL-12B gene were genotyped by polymerase chain reaction (PCR) with a direct sequencing method. The mRNA expression of IL-12B in the placentas was measured by quantitative real-time PCR (qRT-PCR). ResultsSignificant differences were observed between preeclamptic women and the control group in the genotype frequencies of rs17860508 (P = 0.017). Compared with the TTAGAG/TTAGAG genotype of rs17860508, the GC/GC genotype were associated with a higher risk of preeclampsia (adjusted OR: 1.95; 95% CI = 1.18–3.22; P = 0.009), especially the early-onset preeclampsia (adjusted OR: 2.40; 95% CI = 1.23–4.68; P = 0.010). The qRT-PCR results showed that the mRNA levels of IL-12B were significantly higher in the placentas of preeclampsia patients than that in the placentas of controls (P = 0.001). Moreover, the expression of IL-12B mRNA was significantly higher in the placentas of patients carrying the GC/GC genotype than in those carrying the TTAGAG/GC (P = 0.007) and TTAGAG/TTAGAG (P = 0.005) genotypes. ConclusionThe GC/GC genotype of rs17860508 polymorphism may be a risk factor for the early-onset preeclampsia by upregulating the expression of IL-12B in northern Chinese women.

Genetic polymorphisms of vitamin B12 and folate transporter proteins and depression in postpartum period: A case-control study

• First study to explore association of vitamin B12 and folate transporter protein polymorphisms (TCN-2 C776G and RFC-1 G80A) with depression in postpartum period. • No association was observed between TCN-2 C776G and RFC-1 G80A & postpartum. • TCN2 C776G CG genotype was associated with lower 5-methylTHF and SAM levels. • RFC-1 G80A GA genotype was associated with lower vitamin B12 levels. • Observations suggest the role of transporter genotype on vitamin B12 and folate homoeostasis. Vitamin B12 and folate deficiency have been linked to the susceptibility of developing depression in the postpartum period. Transcobalamin-2 (TCN-2) and reduced folate carrier (RFC-1) are essential for the cellular uptake of vitamin B12 and folate respectively. Therefore, functional genetic polymorphism of both may lead to the intracellular deficiency of vitamin B12 & folate. We observed the association of TCN-2 C776G and RFC-1 G80A polymorphism with postpartum depression, and its effect on the circulating markers of vitamin B12 and folate deficiency. Women were screened at 6 weeks postpartum for the probability of depression by EPDS score, and a score of >10 was taken as a cut-off ( n = 434; 217 in each group). Plasma was used for the estimation of homocysteine, methylmalonic acid (MMA), 5-methyl tetrahydrofolate, and holotranscobalamin by commercially available ELISA kits, and whole blood was used for extraction of DNA, which was further genotyped by real-time PCR using Taqman probes. No difference was observed between the distribution of genotypes and alleles of TCN-2 C776G and RFC-1 G80A between women with and without probable depression. On comparing the effect of various genotypes on circulating levels of metabolites, we observed TCN2 C776G CG genotype to be associated with lower 5-methyl THF levels whereas RFC-1 G80A GA genotype was associated with lower vitamin B12 levels. These results suggest the metabolic effect of transporter genotype in folate-supplemented postpartum women.

The IL-22 gene rs2227478 polymorphism significantly decreases the risk of colorectal cancer in a Han Chinese population

To examine the role of IL-22 gene in colorectal cancer (CRC) susceptibility, we identified causative genetic polymorphisms in promoter region of IL-22 gene and explored the mechanism underlying their contribution to CRC development in a Chinese population of Hubei province. 13 target single nucleotide polymorphisms (SNPs) in IL-22 gene promoter were genotyped in 787 CRC patients (426 colon cancer and 361 rectal cancer) and 800 normal controls. The results demonstrated that the rs2227478 T > C polymorphism was significantly associated with the risk of colon cancer, rectal cancer and CRC, and the C allele was associated with a decreased cancer risk than the T allele. In CRC tissue samples, the subjects with CT+CC genotypes of rs2227478 had lower levels of IL-22 mRNA than the subjects with TT genotypes. Further functional analysis revealed that the transcription repressor Sp1 possessed a higher binding affinity to the C allele than the T allele. Collectively, the rs2227478 T > C is a functional genetic polymorphism that significantly reduces the CRC risk in a Han Chinese population.