Some Single Nucleotide Polymorphisms Research Articles

Rheumatoid arthritis and the risk of chronic kidney diseases: a Mendelian randomization study

BackgroundThe extra-articular lesions of rheumatoid arthritis (RA) are reported to involve multiple organs and systems throughout the body, including the heart, kidneys, liver, and lungs. This study assessed the potential causal relationship between RA and the risk of chronic kidney diseases (CKDs) using the Mendelian randomization (MR) analysis.MethodIndependent genetic instruments related to RA and CKD or CKD subtypes at the genome-wide significant level were chosen from the publicly shared summary-level data of genome-wide association studies (GWAS). Then, we obtained some single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs), which are associated with RA in individuals of European origin, and had genome-wide statistical significance (p5 × 10−8). The inverse-variance weighted (IVW) method was the main analysis method in MR analysis. The other methods, such as weighted median, MR–Egger, simple mode, and weighted mode were used as supplementary sensitivity analyses. Furthermore, the levels of pleiotropy and heterogeneity were assessed using Cochran’s Q test and leave-one-out analysis. Furthermore, the relevant datasets were obtained from the Open GWAS database.ResultsUsing the IVW method, the main method in MR analysis, the results showed that genetically determined RA was associated with higher risks of CKD [odds ratio (OR): 1.22, 95% confidence interval (CI) 1.13–1.31; p < 0.001], glomerulonephritis (OR: 1.23, 95% CI 1.15–1.31; p < 0.000), amyloidosis (OR = 1.43, 95% CI 1.10–1.88, p < 0.001), and renal failure (OR = 1.18, 95% CI 1.00–1.38, p < 0.001). Then, using multiple MR methods, it was confirmed that the associations persisted in sensitivity analyses, and no pleiotropy was detected.ConclusionThe findings revealed a causal relationship between RA and CKD, including glomerulonephritis, amyloidosis, and renal failure. Therefore, RA patients should pay more attention to monitoring their kidney function, thus providing the opportunity for earlier intervention and lower the risk of progression to CKDs.

Treatment outcome and germline predictive factors of ropeginterferon alpha-2b in myeloproliferative neoplasm patients.

Studies have shown that some single nucleotide polymorphisms (SNPs) could serve as excellent markers in foretelling the treatment outcome of interferon (IFN) in myeloproliferative neoplasms (MPN). However, most work originated from western countries, and data from different ethnic populations have been lacking. To gain insights, targeted sequencing was performed to detect myeloid-associated mutations and SNPs in eight loci across three genes (IFNL4, IFN-γ, and inosine triphosphate pyrophosphatase [ITPA]) to explore their predictive roles in our cohort of 21 ropeginterferon alpha-2b (ROPEG)-treated MPN patients, among whom real-time quantitative PCR was also performed periodically to monitor the JAK2V617F allele burden in 19 JAK2V617F-mutated cases. ELN response criteria were adopted to designate patients as good responders if they achieved complete hematological responses (CHR) within 1 year (CHR1) or attained major molecular responses (MMR), which occurred in 70% and 45% of the patients, respectively. IFNL4 and IFN-γ gene SNPs were infrequent in our population and were thus excluded from further analysis. Two ITPA SNPs rs6051702 A>C and rs1127354 C>A were associated with an inferior CHR1 rate and MMR rate, respectively. The former seemed to be linked to grade 2 or worse hepatotoxicity as well, although the comparison was of borderline significance only (50%, vs. 6.7% in those with common haplotype, p = 0.053). Twelve patients harbored 19 additional somatic mutations in 12 genes, but the trajectory of these mutations varied considerably and was not predictive of any response. Overall, this study provided valuable information on the ethnics- and genetics-based algorithm in the treatment of MPN.

Recent advances in different interactions between toll-like receptors and hepatitis B infection: a review.

Hepatitis B virus (HBV) B infections remain a primary global health concern. The immunopathology of the infection, specifically the interactions between HBV and the host immune system, remains somewhat unknown. It has been discovered that innate immune reactions are vital in eliminating HBV. Toll-like receptors (TLRs) are an essential category of proteins that detect pathogen-associated molecular patterns (PAMPs). They begin pathways of intracellular signals to stimulate pro-inflammatory and anti-inflammatory cytokines, thus forming adaptive immune reactions. HBV TLRs include TLR2, TLR3, TLR4, TLR7 and TLR9. Each TLR has its particular molecule to recognize; various TLRs impact HBV and play distinct roles in the pathogenesis of the disease. TLR gene polymorphisms may have an advantageous or disadvantageous efficacy on HBV infection, and some single nucleotide polymorphisms (SNPs) can influence the progression or prognosis of infection. Additionally, it has been discovered that similar SNPs in TLR genes might have varied effects on distinct populations due to stress, diet, and external physical variables. In addition, activation of TLR-interceded signaling pathways could suppress HBV replication and increase HBV-particular T-cell and B-cell reactions. By identifying these associated polymorphisms, we can efficiently advance the immune efficacy of vaccines. Additionally, this will enhance our capability to forecast the danger of HBV infection or the threat of dependent liver disease development via several TLR SNPs, thus playing a role in the inhibition, monitoring, and even treatment guidance for HBV infection. This review will show TLR polymorphisms, their influence on TLR signaling, and their associations with HBV diseases.

Transcriptomic profile of the most successful Mycobacterium tuberculosis strain in Aragon, the MtZ strain, during exponential and stationary growth phases.

The Mycobacterium tuberculosis Zaragoza (MtZ) strain has produced the largest outbreak in Aragon Community, Spain, as it started in the 90s and continues today, contributing with more than 240 cases of tuberculosis, around 10% of the TB cases. Previous studies were carried out to identify the reasons for its successful spread capacity among the population. Some single nucleotide polymorphisms (SNPs) in genes considered as virulence factors were found, as well as an oversecretion of PE_PGRS factors. Different copies of IS6110 have been localized, and a transcriptomic study was carried out to study how the different IS6110 copies could affect the adjacent gene expression. In this work, we analyzed the transcriptomic profile of the MtZ, strain trying to delve into the mechanisms behind its success. We found that ESX-1 system is upregulated during both exponential and stationary growth phases in vitro, as well as the virulence pathways of cholesterol degradation and peptidoglycan biosynthesis. In addition, MtZ has the iron uptake genes downregulated in exponential growth phase (mycobactin biosynthesis and IrtAB transporters), while the iron storage could be upregulated. The desA3 gene transcription was interrupted by the insertion of an IS6110 copy. This gene codes for a stearoyl-coenzyme A (CoA) Δ9 desaturase involved in the production of oleic acid, which is necessary for the metabolism of the bacteria. In spite of this, although MtZ strain has an initial long lag phase growing in liquid media, it is capable of achieving normal growth, suggesting the existence of an alternative route for obtaining oleic acid. IMPORTANCE Aragon Community suffered, during the first years of the beginning of this century, a large outbreak caused by the MtZ strain, producing more than 240 cases to date. MtZ strain and the outbreak have been previously studied from an epidemiological and molecular point of view. In this work, we analyzed the transcriptomic profile of the strain for better understanding of its success among our population. We have discovered that MtZ has some upregulated virulence pathways, such as the ESX-1 system, the cholesterol degradation pathway or the peptidoglycan biosynthesis. Interestingly, MtZ has downregulated the uptake of iron. Another special feature of MtZ strain is the interruption of desA3 gene, essential for producing oleic acid. Although the strain takes a long time to grow in the initial culture media, eventually it is able to reach normal optical densities, suggestive of the presence of another route for obtaining oleic acid in Mycobacterium tuberculosis.

Remote modulation of WWOX by an intronic variant associated with survival of Chinese gastric cancer patients.

The protein WWOX was reported to be involved in cancer progression via interaction with mTOR and DNA repair pathway. We previously reported noteworthy association of some single nucleotide polymorphisms (SNPs) in mTOR and DNA repair pathways with gastric cancer (GCa) patients' survival. We hypothesized that genetic variants in WWOX gene could predict the survival of GCa patients. By extracting WWOX genetic variants from our ongoing genome-wide association study including 796 GCa patients from an Eastern Chinese population, we identified 51 out of 1913 SNPs to be significantly associated with survival of GCa patients, which passed the false positive probability tests. In particular, the intronic variant rs9922483, a G>T change, was associated with 21% increased death risk for GCa patients (HR = 1.21, 95% CI = 1.04-1.42, P = .015). This locus was predicted to be involved in potential enhancer by bioinformatics analysis. Genotype-phenotype correlation analysis revealed decreased expression of WWOX by rs9922483 G>T change. Mechanistically, rs9922483 locus may exhibits long-range interaction with WWOX promoter, and the G>T change inhibited the transcriptional activity driven by WWOX promoter in luciferase reporter system. Especially, the G>T change had an allele-specific negative effect on NR3C1 binding, and NR3C1 promoted the expression of WWOX in GCa cells. Further functional analysis indicated an increase in proliferation, migration and invasion of GCa cells by knockdown of WWOX. In conclusion, WWOX genetic variants may modulate survival of Chinese GCa patients by exerting remote regulatory effect on WWOX expression. Our results highlight the cis-regulatory effect of genetic variants on genes and survival modulation for GCa patients.

Association of Polymorphism of the Enzyme Catechol-O-Methyltransferase with Fibromialgic Syndrome and its Clinical Repercussions

Objective: Fibromyalgia syndrome (FMS) is a clinical condition that mostly affects women, with chronic diffuse pain, physical disability, mood swings, anxiety, fatigue and insomnia. There are genetic contributions to its pathophysiology. Some single nucleotide polymorphisms (SNPs) can change the function of proteins that participate in pain modulation. Catechol-O-methyltransferase (COMT) is an enzyme responsible for the inactivation of catecholamines in the central nervous system, participating in descending nociceptive inhibitory pathways. This study verified the association of SNPs rs4680, rs6269, rs4633 and rs4818 of the COMT gene with clinical aspects in patients with FMS in Brazil. Methods: Forty-seven volunteers whith FMS were selected, in which the Fibromyalgia Impact Questionnaire, the Beck’s Depression and Anxiety Inventories, the Insomnia Severity Index and the Mini-Mental State Examination were applied. The DNA was extracted by salting out and the SPNs were evaluated by real time reverse transcription polymerase chain (RT-PCR). The association between clinic and SPNs was tested by the Fisher’s exact test. A 95% CI and p value < 0.05 were adopted. Results: The results showed that there was no association between such SNPs and the participants’ clinic regarding the tests used. Conclusions: This study showed that, although the disease has an important impact on patients’ daily lives, increasing the chances of depression, anxiety, insomnia and cognitive losses, it is not associated with the SNPs researched. Further investigations, with larger samples, are needed to assess these and other associations between genetics factors and FMS.

Associations between high-altitude adaptation and risk of cardiovascular diseases: a bidirectional Mendelian randomization study.

High-altitude adaptation (HAA) was reported to be significantly associated with reduced risks for multiple cardiovascular diseases (CVDs). However, the causality and direction of the associations are largely uncharacterized. We aimed to examine the potential causal relationships between HAA and six types of CVD, including coronary artery disease (CAD), cerebral aneurysm, ischemic stroke, peripheral artery disease, arrhythmia and atrial fibrillation. We obtained the summary data from largest available genome-wide association study of HAA and six types of CVD. Two-sample bidirectional Mendelian randomization (MR) analyses were performed to infer the causality between them. In the sensitivity analyses, MR-Egger regression analyses and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global analyses were used to assess the pleiotropic effects; Cochran's Q tests were used to test the heterogeneity by inverse variance-weighted (IVW) and MR-Egger methods; and the leave-one-out analyses were used to examine whether some single nucleotide polymorphisms (SNPs) could influence the results independently. The MR main analyses showed that the genetically instrumented HAA was significantly causally associated with the reduced risks of CAD (odds ratio [OR] = 0.029; 95% confidence interval [CI] = 0.004-0.234; P = 8.64 × 10-4). In contrast, there was no statistically significant relationship between CVDs and HAA. Our findings provide evidence for the causal effects of HAA on the reduced risks of CAD. However, there is no causality of CVDs on HAA. These findings might be helpful in developing the prevention and intervention strategies for CAD.

Association of Polymorphisms in FSHR, INHA, ESR1, and BMP15 with Recurrent Implantation Failure.

Recurrent implantation failure (RIF) refers to two or more unsuccessful in vitro fertilization embryo transfers in the same individual. Embryonic characteristics, immunological factors, and coagulation factors are known to be the causes of RIF. Genetic factors have also been reported to be involved in the occurrence of RIF, and some single nucleotide polymorphisms (SNPs) may contribute to RIF. We examined SNPs in FSHR, INHA, ESR1, and BMP15, which have been associated with primary ovarian failure. A cohort of 133 RIF patients and 317 healthy controls consisting of all Korean women was included. Genotyping was performed by Taq-Man genotyping assays to determine the frequency of the following polymorphisms: FSHR rs6165, INHA rs11893842 and rs35118453, ESR1 rs9340799 and rs2234693, and BMP15 rs17003221 and rs3810682. The differences in these SNPs were compared between the patient and control groups. Our results demonstrate a decreased prevalence of RIF in subjects with the FSHR rs6165 A>G polymorphism [AA vs. AG adjusted odds ratio (AOR) = 0.432; confidence interval (CI) = 0.206-0.908; p = 0.027, AA+AG vs. GG AOR = 0.434; CI = 0.213-0.885; p = 0.022]. Based on a genotype combination analysis, the GG/AA (FSHR rs6165/ESR1 rs9340799: OR = 0.250; CI = 0.072-0.874; p = 0.030) and GG-CC (FSHR rs6165/BMP15 rs3810682: OR = 0.466; CI = 0.220-0.987; p = 0.046) alleles were also associated with a decreased RIF risk. Additionally, the FSHR rs6165GG and BMP15 rs17003221TT+TC genotype combination was associated with a decreased RIF risk (OR = 0.430; CI = 0.210-0.877; p = 0.020) and increased FSH levels, as assessed by an analysis of variance. The FSHR rs6165 polymorphism and genotype combinations are significantly associated with RIF development in Korean women.

TYK2 single-nucleotide variants associated with the severity of COVID-19 disease

Coronavirus disease 2019 (COVID-19) is a lethal disease caused by the coronavirus SARS-CoV-2, which can result in a broad clinical spectrum of respiratory symptoms. While many clinical risk factors such as concomitant chronic diseases play roles in the pathophysiology of COVID-19, genetic predisposition factors have not been widely studied. The aim of this study was, therefore, to evaluate the relationship between some singlenucleotide polymorphisms (SNPs) of the human genes TYK2 and ACE2 and the severity of SARS-CoV-2 infection. Genomic DNA was isolated from 200 SARS-CoV-2-infected individuals with severe (n = 100) or mild (n = 100) disease. Owing to the importance of ACE2 and TYK2 genes in regulating the immune response to SARS-CoV-2 infection, TYK2 gene SNPs, i.e. rs2304255, rs2304256, rs12720270, and rs12720354 and ACE2 rs382746 variants, were genotyped in the samples. To confirm the results, the expression of different TYK2 genotypes was investigated using real-time PCR. The presence of the nucleotide T at the locus rs2304255 was shown to be a risk factor linked to disease severity (OR [95% CI] = 3.2485 [2.1554-4.8961]). Similarly, the presence of A at the locus rs12720354 increased the risk of severity (OR [95% CI]) = 3.9721 [2.6075-6.0509]). In contrast, the presence of A at the loci rs2304256 and rs12720270 was observed to reduce the severity risk (OR [95% CI] = 0.2495 [0.1642-0.3793] and 0.1668 [0.1083-0.2569], respectively). Real-time PCR results also demonstrated that the expression level of TYK2 in samples with the TT genotype of rs2304255 and the AA genotype of rs12720354 and in samples with the GG genotype of rs12720207 was significantly lower than in those with other genotypes. The results of this study suggest that TYK2 SNPs might be utilized to identify individuals who are at risk for severe COVID-19, in order to better manage their health care. It is predicted that the presence of some alleles (T in rs2304255, A in rs12720354, and G in rs12720207) of TYK2 can affect COVID-19 severity by reducing TYK2 expression and thereby affecting the regulatory role of TYK2 in the immune response.

Gene amplification acts as a molecular foothold to facilitate cross-species adaptation and evasion of multiple antiviral pathways.

Cross-species spillover events are responsible for many of the pandemics in human history including COVID-19; however, the evolutionary mechanisms that enable these events are poorly understood. We have previously modeled this process using a chimeric vaccinia virus expressing the rhesus cytomegalovirus-derived protein kinase R (PKR) antagonist RhTRS1 in place of its native PKR antagonists: E3L and K3L (VACVΔEΔK + RhTRS1). Using this virus, we demonstrated that gene amplification of rhtrs1 occurred early during experimental evolution and was sufficient to fully rescue virus replication in partially resistant African green monkey (AGM) fibroblasts. Notably, this rapid gene amplification also allowed limited virus replication in otherwise completely non-permissive human fibroblasts, suggesting that gene amplification may act as a 'molecular foothold' to facilitate viral adaptation to multiple species. In this study, we demonstrate that there are multiple barriers to VACVΔEΔK + RhTRS1 replication in human cells, mediated by both PKR and ribonuclease L (RNase L). We experimentally evolved three AGM-adapted virus populations in human fibroblasts. Each population adapted to human cells bimodally, via an initial 10-fold increase in replication after only two passages followed by a second 10-fold increase in replication by passage 9. Using our Illumina-based pipeline, we found that some single nucleotide polymorphisms (SNPs) which had evolved during the prior AGM adaptation were rapidly lost, while thirteen single-base substitutions and short indels increased over time, including two SNPs unique to human foreskin fibroblast (HFF)-adapted populations. Many of these changes were associated with components of the viral RNA polymerase, although no variant was shared between all three populations. Taken together, our results demonstrate that rhtrs1 amplification was sufficient to increase viral tropism after passage in an 'intermediate species' and subsequently enabled the virus to adopt different, species-specific adaptive mechanisms to overcome distinct barriers to viral replication in AGM and human cells.

SNP rs2920280 in PSCA Is Associated with Susceptibility to Gastric Mucosal Atrophy and Is a Promising Biomarker in Japanese Individuals with Helicobacter pylori Infection.

Helicobacter pylori infection results in gastric cancer (GC) with gastric mucosal atrophy (GMA). Some single-nucleotide polymorphisms (SNPs) in the prostate stem cell antigen gene (PSCA) are associated with GC and duodenal ulcers. However, the relationship of other identified SNPs in PSCA with these diseases remains unclear. Herein, the association between PSCA SNPs and GMA among 195 Japanese individuals with H. pylori infection was evaluated. The definition of GMA or non-GMA was based on serum pepsinogen levels or endoscopic findings. Five tag PSCA SNPs were analyzed using PCR high-resolution melting curve analysis with nonlabelled probes. The frequencies of alleles and the genotypes of each tag SNP were compared between the GMA and non-GMA groups. Subsequently, a genetic test was performed using associated SNPs as biomarkers to detect patients developing GMA. Two tag PSCA SNPs (rs2920280 and rs2294008) were related to GMA susceptibility. Individuals with the rs2920280 G/G genotype or the rs2294008 T/T genotype in PSCA had 3.5- and 2.1-fold susceptibility to GMA, respectively. In conclusion, SNP rs2920280 is a possible biomarker for detecting individuals developing GMA. PSCA polymorphisms may be useful biomarkers for predicting GMA linked to GC risk and a screening endoscopy strategy to detect GC related to early stage H. pylori associated GMA.

Meta-analysis of association between c.963A>G single-nucleotide polymorphism on BMP15 gene and litter size in goats.

Litter size is an important economic trait in the goat industry. Previous studies on the bone morphogenetic protein15 (BMP15) gene detected some single-nucleotide polymorphisms (SNPs) such as c.963A G that were associated with an increase in ovulation rate and litter size. The aim of this study was to conduct a meta-analysis on the effect of this polymorphism on litter size. We gathered and pooled data from five eligible published studies. To investigate the effect of c.963A G on litter size, we utilized four different genetic models assuming dominant (GG GA vs. AA), recessive (GG vs. GA AA), additive (GG vs. AA) and co-dominant (GG AA vs. GA) model of inheritance. Data were analyzed under random-effects models based on the value. Furthermore, sensitivity analysis was carried out to validate the stability of results. The results showed that the c.963A G polymorphism is associated with litter size when applying a dominant model (standardized mean difference (SMD) is 0.815, 95 % CI[0.170, 1.461], value 0.013) and also with an additive model (SMD 0.755, 95 % CI[0.111, 1.400], value 0.022). However, the effect of c.963A G polymorphism was not significant under recessive (SMD 0.186, 95 % CI[ 0.195, 4.259], value 0.339) and co-dominant (SMD 0.119, 95 % CI[ 0.525, 0.288], value 0.568) models. Sensitivity analysis demonstrated that dropping studies with wide confidence intervals affects overall results under the assumption of an additive model. The meta-analysis results revealed that the AA genotype could be positively connected with litter size in goats.

Pharmacogenomics of Monoclonal Antibodies for the Treatment of Rheumatoid Arthritis.

Precision medicine refers to a highly individualized and personalized approach to patient care. Pharmacogenomics is the study of how an individual’s genomic profile affects their drug response, enabling stable and effective drug selection, minimizing side effects, and maximizing therapeutic efficacy. Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation in the joints. It mainly starts in peripheral joints, such as the hands and feet, and progresses to large joints, which causes joint deformation and bone damage due to inflammation of the synovial membrane. Here, we review various pharmacogenetic studies investigating the association between clinical response to monoclonal antibody therapy and their target genetic polymorphisms. Numerous papers have reported that some single nucleotide polymorphisms (SNPs) are related to the therapeutic response of several monoclonal antibody drugs including adalimumab, infliximab, rituximab, and tocilizumab, which target tumor necrosis factor (TNF), CD20 of B-cells, and interleukin (IL)-6. Additionally, there are some pharmacogenomic studies reporting on the association between the clinical response of monoclonal antibodies having various mechanisms, such as IL-1, IL-17, IL-23, granulocyte-macrophage colony-stimulating factor (GM-CSF) and the receptor activator of nuclear factor-kappa B (RANK) inhibition. Biological therapies are currently prescribed on a “trial and error” basis for RA patients. If appropriate drug treatment is not started early, joints may deform, and long-term treatment outcomes may worsen. Pharmacogenomic approaches that predict therapeutic responses for RA patients have the potential to significantly improve patient quality of life and reduce treatment costs.

Genetic variants associated with metabolic dysfunction-associated fatty liver disease in western China.

IntroductionWe aimed to confirm the association between some single nucleotide polymorphisms (SNPs) and metabolic dysfunction‐associated fatty liver disease (MAFLD) in western China.MethodsA total of 286 cases and 250 healthy controls were enrolled in our study. All samples were genotyped for patatin‐like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, membrane‐bound O‐acyltransferase domain containing 7 (MBOAT7) rs641738, glucokinase regulator (GCKR) rs1260326 and rs780094, and GATA zinc finger domain containing 2A (GATAD2A) rs4808199. Using logistic regression analysis, we evaluated the association between MAFLD and each SNP under different models. Multiple linear regression was used to find the association between SNPs and laboratory characteristics. Multifactor dimensionality reduction was applied to test SNP–SNP interactions.ResultsThe recessive model and additive model of PNPLA3 rs738409 variant were related to MAFLD (odds ratio [OR] = 1.791 and 1.377, respectively, p = 0.038 and 0.027, respectively). However, after Benjamini‐Hochberg adjustment for multiple tests, all associations were no longer statistically significant. PNPLA3 rs738409 correlated with AST levels. GCKR rs780094 and rs1260326 negatively correlated with serum glucose but positively correlated with triglycerides in MAFLD. Based on MDR analysis, the best single‐locus and multilocus models for MAFLD risk were rs738409 and six‐locus models, respectively.ConclusionsIn the Han population in western China, no association was found between these SNPs and the risk of MAFLD. PNPLA3 rs738409 was associated with aspartate aminotransferase levels in MAFLD patients. GCKR variants were associated with increased triglyceride levels and reduced serum fasting glucose in patients with MAFLD.

Genetic variations of estrogen receptor (ESR) associated with hepatitis C virus-induced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and a major public health concern in Egypt. HCC is a tough condition to cure, and genetic diversity has been linked to the disease's progression. HCC is a complicated condition in which 95% of patients have chronic liver disorders, the majority of which are caused by viruses. One of the causes of HCC is the hepatitis C virus (HCV). Sex hormones, such as estrogen, have an effect on the liver. Although estrogen (ER) is known to play a function in a range of biological processes, its role in the development of HCC is controversial, with evidence pointing to both a carcinogenic and a preventative effect on the liver. Estrogen receptor (ESR) was shown to be strongly expressed in HCV-infected people. This study reveals that ESR and its variants play a role in hepatocarcinogenesis development. Some single nucleotide polymorphisms (SNPs) may have a functional influence on the end product of a gene, which may be assessed, and may play a role in pathogenic alterations.

HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus.

Diabetes, a disease characterized by hyperglycemia, has a serious impact on the lives and families of patients as well as on society. Diabetes is a group of highly heterogeneous metabolic diseases that can be classified as type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM), or other according to the etiology. The clinical manifestations are more or less similar among the different types of diabetes, and each type is highly heterogeneous due to different pathogenic factors. Therefore, distinguishing between various types of diabetes and defining their subtypes are major challenges hindering the precise treatment of the disease. T2D is the main type of diabetes in humans as well as the most heterogeneous. Fortunately, some studies have shown that variants of certain genes involved in monogenic diabetes also increase the risk of T2D. We hope this finding will enable breakthroughs regarding the pathogenesis of T2D and facilitate personalized treatment of the disease by exploring the function of the signal genes involved. Hepatocyte nuclear factor 1 homeobox A (HNF1α) is widely expressed in pancreatic β cells, the liver, the intestines, and other organs. HNF1α is highly polymorphic, but lacks a mutation hot spot. Mutations can be found at any site of the gene. Some single nucleotide polymorphisms (SNPs) cause maturity-onset diabetes of the young type 3 (MODY3) while some others do not cause MODY3 but increase the susceptibility to T2D or GDM. The phenotypes of MODY3 caused by different SNPs also differ. MODY3 is among the most common types of MODY, which is a form of monogenic diabetes mellitus caused by a single gene mutation. Both T2D and GDM are multifactorial diseases caused by both genetic and environmental factors. Different types of diabetes mellitus have different clinical phenotypes and treatments. This review focuses on HNF1α gene polymorphisms, HNF1A-MODY3, HNF1A-associated T2D and GDM, and the related pathogenesis and treatment methods. We hope this review will provide a valuable reference for the precise and individualized treatment of diabetes caused by abnormal HNF1α by summarizing the clinical heterogeneity of blood glucose abnormalities caused by HNF1α mutation.

Beta-adrenergic receptors gene polymorphisms are associated with cardiac contractility and blood pressure variability.

Beta-adrenergic receptors (beta-ARs) play a pivotal role in the cardiovascular regulation. In the human heart beta1- and beta2-ARs dominate in atria as well as in ventricle influencing heart rate and myocardial contractility. Some single nucleotide polymorphisms (SNPs) of beta-ARs might influence cardiovascular function. However, the influence of beta-AR genes SNPs on hemodynamic parameters at rest and their reactivity under stress is still not well known. We aimed to explore the associations between four selected beta-ARs gene polymorphisms and selected cardiovascular measures in eighty-seven young healthy subjects. While in beta1-AR polymorphism rs1801252 no significant association was observed, second beta1-AR polymorphism rs1801253 was associated with decreased cardiac output and cardiac index during all phases and with decreased flow time corrected and ejection time index at rest and during mental arithmetics. Polymorphism rs1042713 in beta2-AR was associated with alterations in blood pressure variability at rest and during head-up-tilt, while rs1042714 was associated predominantly with decreased parameters of cardiac contractility at rest and during mental arithmetics. We conclude that complex analysis of various cardiovascular characteristics related to the strength of cardiac contraction and blood pressure variability can reveal subtle differences in cardiovascular sympathetic nervous control associated with beta-ARs polymorphisms.

The alleles of AGT and HIF1A gene affect the risk of hypertension in plateau residents.

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.

Association of Two Variable Number of Tandem Repeats in the Monoamine Oxidase A Gene Promoter with Schizophrenia.

BackgroundMonoamine oxidase-A (MAO-A) decomposes dopamine and serotonin, and decreased MAO-A expression increases monoamine levels and is related to the pathophysiology of schizophrenia. Previous studies have reported that variable number of tandem repeats (VNTR), namely, upstream (u)VNTR, and some single nucleotide polymorphisms (SNPs) in the MAOA gene are associated with schizophrenia.MethodsWe investigated the two VNTRs and their related SNPs (rs6323 and rs1137070) in the MAOA gene promoter in 859 patients with schizophrenia and 826 healthy controls. Distal (d)VNTR and uVNTR were genotyped with fluorescence-based fragment polymerase chain reaction assays, and rs6323 and rs1137070 with TaqMan SNP genotyping assays.ResultsNeither the genotype nor allelic frequency of the VNTRs or SNPs showed significant differences between the schizophrenia and control groups. On the other hand, analysis of the dVNTR-uVNTR-rs6323-rs1137070 haplotype showed significant association for nine repeats (9R)-3R-T-C in female patients (corrected p = 0.0006, odds ratio [confidence interval] = 2.17 [1.446–3.257]).ConclusionOur findings provide novel evidence that MAOA gene polymorphisms are associated with an increased risk of developing schizophrenia in females.

MC1R Is a Prognostic Marker and Its Expression Is Correlated with MSI in Colorectal Cancer.

Melanocortin 1 receptor (MC1R) is thought to be a marker of poor prognosis and a potential target for the treatment of melanoma. Studies have found that MC1R promotes several tumor behaviors, including cell proliferation and differentiation, pigment formation, and genome damage repair. Some single-nucleotide polymorphisms (SNPs) of MC1R are involved in the occurrence and development of melanoma. A few studies have reported a relationship between MC1R and colorectal cancer (CRC). In this research, our objective was to examine MC1R expression and MC1R SNPs and investigate their correlation with the clinicopathological features of human CRC tissues. We evaluated MC1R mRNA expression by performing bioinformatic analyses on human CRC expression datasets. We used Western blotting and RT-qPCR to compare MC1R expression in CRC tissues with that in normal tissues, and MC1R SNPs in CRC tissues were detected by PCR-direct sequencing (DS). The expression of MC1R was significantly decreased in CRC tissues compared with normal tissue, and its expression was negatively associated with P53 expression, MLH1 expression, and PMS2 expression, and high MC1R expression was significantly associated with microsatellite instability (MSI). MC1R SNPs were also associated with the clinicopathological characteristics of CRC; for example, the rs2228479 locus genotype was correlated with Ki67 status, and the rs885479 locus genotype was correlated with age and T stage. In conclusion, MC1R plays a crucial role in the progression of CRC and may be a marker of poor prognosis in CRC.