Relevant Single Nucleotide Polymorphisms Research Articles

Prevalence of Diamine Oxidase Enzyme (DAO) Deficiency in Subjects with Insomnia-Related Symptoms.

Background: To assess the prevalence of diamine oxidase (DAO) enzyme deficiency caused by single nucleotide polymorphisms (SNPs) of the AOC1 gene in a sample of patients with symptoms of insomnia. Methods: A total of 167 adult patients (>18 years of age) with symptoms of insomnia attended a specialized institute for healthy sleep, in Barcelona (Spain), between May and November 2023, and underwent genotyping analysis of the four most relevant SNP variants, including c.691G>7 (rs2052129), c.47C>T (rs10156191), c.995C>T (rs1049742), and c.1990C>G (rs1049793). Results: Genetic DAO deficiency was present in 138 patients, with a prevalence rate of 82.6% (95% CI 76-88.1%). Difficulties in staying asleep were the most common complaints in 88% of patients followed by trouble falling asleep in 60.5%. More than half of patients suffered from insomnia symptoms every day. Also, 99.4% reported daytime consequences of insomnia, with fatigue (79.6%), mood changes (72.5%), and impaired concentration in 70.1%. When patients were grouped by DAO-score, which reflected the number of heterozygous and homozygous SNPs variants, the group with a DAO-score ≥ 4 vs. 1 showed higher percentages of insomnia-related symptoms, in particular, trouble staying asleep and early morning awakening. These two symptoms were also more common in the presence of the c.1990C>G (rs1049793) variant. Conclusions: This preliminary real-world study presents novel evidence of a potential link between a DAO enzyme deficiency of a genetic origin and clinical symptoms of insomnia, which may suggest the potential benefit of DAO supplementation to improve the quality of sleep in these subjects. The study was registered at ClinicalTrials.gov (NCT06488027).

ADRB2 and ADCY9 Sequence Variations in Brazilian Asthmatic Patients.

Asthma is a chronic inflammatory respiratory condition, characterized by variable airflow limitation, leading to clinical symptoms such as dyspnea and chest tightness. These symptoms result from an underlying inflammatory process. The β2 agonists are bronchodilators prescribed for the relief of the disease. Nevertheless, their efficacy exhibits substantial interindividual variability. Currently, there is widespread recognition of the association between specific genetic variants, predominantly located within the ADRB2 and ADCY9 genes and their efficacy. This association, usually represented by the presence of non-synonymous single nucleotide polymorphisms (SNPs) have a strong impact in the protein functionality. The prevalence of these mutations varies based on the ethnic composition of the population and thus understanding the profiles of variability in different populations would contribute significantly to standardizing the use of these medications. In this study, we conducted a sequence-based genotyping of the relevant SNPs within the ADRB2 and ADCY9 genes in patients undergoing treatment with bronchodilators and/or corticosteroids at two healthcare facilities in the state of Rio de Janeiro, Brazil. We investigated the presence of c.46A>G, c.79C>G, c.252G>A, and c.491C>T SNPs within the ADRB2, and c.1320018 A>G within the ADCY9. Our results were in line with existing literature data with both for individuals in Brazil and Latin American.

Causal association between 25-hydroxyvitamin D status and cataract development: A two-sample Mendelian randomization study.

Vitamin deficiencies are linked to various eye diseases, and the influence of vitamin D on cataract formation has been noted in prior research. However, detailed investigations into the causal relationship between 25-(OH)D status and cataract development remain scarce. To explore a possible causal link between cataracts and vitamin D. In this study, we explored the causal link between 25-(OH)D levels and cataract development using Mendelian randomization. Our analytical approach included inverse-variance weighting (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. The primary analyses utilized IVW with random effects, supplemented by sensitivity and heterogeneity tests using both IVW and MR-Egger. MR-Egger was also applied for pleiotropy testing. Additionally, a leave-one-out analysis helped identify potentially impactful single-nucleotide polymorphisms. The analysis revealed a positive association between 25-(OH)D levels and the risk of developing cataracts (OR = 1.11, 95%CI: 1.00-1.22; P = 0.032). The heterogeneity test revealed that our IVW analysis exhibited minimal heterogeneity (P > 0.05), and the pleiotropy test findings confirmed the absence of pleiotropy within our IVW analysis (P > 0.05). Furthermore, a search of the human genotype-phenotype association database failed to identify any potentially relevant risk-factor single nucleotide polymorphisms. There is a potential causal link between 25-(OH)D levels and the development of cataracts, suggesting that greater 25-(OH)D levels may be a contributing risk factor for cataract formation. Further experimental research is required to confirm these findings.

Ulcerative colitis and nephrotic syndrome: a two-sample Mendelian randomization study.

To investigate the potential causal relationship between ulcerative colitis and nephrotic syndrome. We obtained the whole-genome association study data of ulcerative colitis in the European population from the GWAS database. Relevant single nucleotide polymorphisms (SNPs) were selected for analysis. We employed the inverse variance-weighted meta-analysis of multiplicative random effects models to obtain SNP-specific Wald ratio estimates, which assume horizontal pleiotropy. In addition, we performed sensitivity analyses using MR-Egger, weighted median, and IVW. Our findings suggest a strong association between ulcerative colitis and nephrotic syndrome (P < 0.05). After conducting sensitivity analyses, we found no evidence of horizontal pleiotropy or heterogeneity (P > 0.05). This study provides evidence for an association between ulcerative colitis and nephrotic syndrome, which may help us better understand the conditions of ulcerative colitis and nephropathy.

The potential up-regulation risk of 3′ UTR SNP (rs10787760 G > A) for the VAX1 gene is associated with NSCLP in the northwest Chinese population

AimsTo investigate the association between single nucleotide polymorphisms (SNPs) in 3′UTR region of VAX1, SYT14 and PAX7 genes and the risk of non-syndromic cleft palate (NSCLP) in a northwest Chinese population. Main methodsA case-control study was conducted in 406 normal controls and 399 NSCLP patients. Using iMLDRTM genotyping technology, eight SNPs of three genes ((rs10787760, rs7086344 at VAX1), (rs1010113, rs851114, and rs485874 at PAX7), and (rs61820397, rs4609425, rs12133399 at SYT14)) were genotyped to investigate the differences in alleles and genotype distribution frequencies between NSCLP patients and healthy controls. RNA Folding Form software was used to predict RNA secondary structure and expression vectors were constructed to explore the function of the relevant SNP. The effect of SNP polymorphism of gene transcription and translation was assessed using qPCR and Western blot analysis.Key findings.Among the eight SNPs of three genes, rs10787760 of VAX1 gene was found to be associated with an increased risk of NSCLP (OR = 1.341, CI = 1.004–1.790) and the GA genotype of rs10787760 increased the risk of cleft lip and/or palate (CL/P) about 1.42 times (p < 0.05), and carrying the A allele might increase the risk of NSCL/P in male (OR = 1.356, 95 % CI = 1.010–1.823). But there was no association observed with cleft palate only (CPO). Cell function experiments revealed that the G to A mutation in rs10787760 up-regulated GFP-VAX1 transcriptional level by 2.39 and 3.13 times in two cell lines respectively, and enhance the protein expression of the VAX1 gene further. RNA secondary structure study showed that the rs10787760 (G > A) had two different secondary structures in 3′UTR region. SignificanceThe rs10787760 variant in the 3′UTR region of VAX1 gene is associated with CL/P in northwest Chinese population. We hypothesize that the machanism of it might be caused by the RNA differenct fold in the 3′UTR region caused by the polymorphism of the gene. Level of evidenceOriginal Reports.

FishSNP: a high quality cross-species SNP database of fishes

The progress of aquaculture heavily depends on the efficient utilization of diverse genetic resources to enhance production efficiency and maximize profitability. Single nucleotide polymorphisms (SNPs) have been widely used in the study of aquaculture genomics, genetics, and breeding research since they are the most prevalent molecular markers on the genome. Currently, a large number of SNP markers from cultured fish species are scattered in individual studies, making querying complicated and data reuse problematic. We compiled relevant SNP data from literature and public databases to create a fish SNP database, FishSNP (http://bioinfo.ihb.ac.cn/fishsnp), and also used a unified analysis pipeline to process raw data that the author of the literature did not perform SNP calling on to obtain SNPs with high reliability. This database presently contains 45,690,243 (45 million) nonredundant SNP data for 13 fish species, with 30,288,958 (30 million) of those being high-quality SNPs. The main function of FishSNP is to search, browse, annotate and download SNPs, which provide researchers various and comprehensive associated information.

Effects and considerations of multiplexing ForenSeq Kintelligence libraries with a negative control.

The negative template control or negative amplification control has been an essential component of the forensic DNA analysis workflow that helps monitor contamination. As such, the inclusion of a negative control in forensic DNA analysis has been a requirement for all laboratories audited under the FBI's Quality Assurance Standards. As massively parallel sequencing (MPS) becomes more conventional in forensic laboratories, considerations for the inclusion of a negative control in every sequencing run can be evaluated. Although the inclusion of a negative control in library preparation and the first sequencing run has a practical function, there is less utility for its inclusion in all subsequent sequencing runs for that library preparation. Although this is universal to all MPS assays, it is most relevant for an assay that has a low sample multiplexing capacity, such as the ForenSeq Kintelligence Kit (Qiagen/Verogen, Inc.). The ForenSeq Kintelligence Kit is an investigative genetic genealogy (IGG) sequencing-based assay that targets 10,230 forensically relevant single-nucleotide polymorphisms. The manufacturer recommends multiplexing 3 libraries per sequencing run, which includes controls. The purpose of this study was to investigate the effect of the inclusion of a negative control in every Kintelligence sequencing run. We observed that the library generated from a negative amplification control will take 7%-14% of the run output. The loss of sequencing space taken by a negative control decreased the available output for DNA-containing samples, leading in some cases to allele or locus dropout and accompanying higher numbers of sixth to seventh order unknown associations in GEDmatch PRO.

Education and cardiovascular diseases: a Mendelian randomization study.

Observational studies have indicated a potential association between education and cardiovascular diseases (CVDs). However, uncertainties regarding the causal relationship persist. Therefore, this study aimed to investigate whether higher levels of education causally reduce the risks of CVDs. Employing a two-sample Mendelian randomization (MR) design, our study examined the relationship between education and ten different CVDs. Utilizing data from the IEU Open GWAS database, relevant single nucleotide polymorphisms (SNPs) were identified through stringent screening criteria. Causality was assessed using the inverse-variance weighted (IVW), ME-Egger regression, and weighted median methods. Sensitivity analyses, including heterogeneity and pleiotropy tests, were conducted to ensure the robustness of our findings. Our study identified a genetic predisposition associated with an additional 3.6 years of education, which significantly reduced the risk of various CVDs. Specifically, this genetic factor was found to lower the risk of type 2 diabetes by 46.5%, coronary heart disease by 37.5%, ischemic stroke by 35.4%, cardiac-related mortality by 28.6%, heart failure by 28.2%, transient ischemic attack by 24%, atrial fibrillation by 15.2%, peripheral artery disease by 0.3%, and hypertension by 0.3%. However, no significant evidence revealed a causal relationship between education and pulmonary embolism. Our study provides robust evidence supporting the role of higher educational attainment in reducing the incidence of various cardiovascular diseases, including type 2 diabetes, coronary heart disease, ischemic stroke, cardiac-related mortality, heart failure, transient ischemic attack, atrial fibrillation, peripheral artery disease, and hypertension. However, the impact of education on pulmonary embolism remains inconclusive.

TOMM40 Correlates with Cholesterol and is Predictive of a Favorable Prognosis in Endometrial Carcinoma.

A link between cholesterol and endometrial cancer has been established, but current studies have been limited in their findings. We aimed to elucidate the causal relationship between cholesterol and endometrial cancer and to find prognostic genes for endometrial cancer. We first explored the causal relationship between total cholesterol and endometrial cancer using two-sample Mendelian randomization and then obtained differential genes to screen for prognosis-related genes in endometrial cancer. Then, we utilized pan-cancer analysis based on RNA sequencing data to evaluate the expression pattern and immunological role of the Translocase of Outer Mitochondrial Membrane 40 (TOMM40). Through multiple transcriptome datasets and multi-omics in-depth analysis, we comprehensively explore the relationship of TOMM40 expression with clinicopathologic characteristics, clinical outcomes and mutations in endometrial cancer. Lastly, we systematically associated the TOMM40 with different cancers from immunological properties from numerous perspectives, such as immune cell infiltration, immune checkpoint inhibitors, immunotherapy, gene mutation load and microsatellite instability. We found a negative association between cholesterol and endometrial cancer. A total of 78 genes were enriched by relevant single nucleotide polymorphisms (SNPs), of which 12 upregulated genes and 5 downregulated genes in endometrial cancer. TOMM40 was found to be a prognostic gene associated with endometrial cancer by prognostic analysis. TOMM40 was found to be positively correlated with the infiltration of most immune cells and immunization checkpoints in a subsequent study. Meanwhile, TOMM40 also was an oncogene in many cancer types. High TOMM40 was associated with lower genome stability. The findings of our study indicate that the maintenance of normal total cholesterol metabolism is associated with a decreased risk of developing endometrial cancer. Moreover, TOMM40 may have potential as a prognostic indicator for endometrial cancer.

Controversial causal association between IGF family members and osteoporosis: a Mendelian randomization study between UK and FinnGen biobanks.

Osteoporosis, a prevalent skeletal disorder characterized by reduced bone strength, is closely linked to the IGF system, crucial for skeletal metabolism. However, the precise nature of this relationship remains elusive. In this study, we employed Mendelian randomization (MR) to unravel the associations between genetically predicted serum IGF system member levels and osteoporosis. A two-sample MR approach was employed to investigate these causal associations based on two individual datasets. Predictions of 14 serum levels of IGF system members were made using 11,036,163 relevant Single Nucleotide Polymorphisms (SNPs) within a cohort of 4,301 individuals of European descent. Genetic association estimates for osteoporosis were derived from two publicly available GWAS consortia: the Finnish consortium from the FinnGen biobank, comprising 212,778 individuals of Finnish descent (3,203 cases and 209,575 controls), and the UK consortium from the UK Biobank, including 337,159 individuals of European descent (5,266 cases and 331,893 controls). According to the UK dataset, IGF-1 levels were associated with a reduced risk of osteoporosis, as indicated by the weighted median method (Odds Ratio [OR] = 0.998, 95% CI = 0.997-1.000, P = 0.032). Additionally, higher levels of IGFBP-3 were linked to a decreased risk of osteoporosis using the Inverse-Variance Weighted (IVW) method (OR = 0.999, 95% CI = 0.998-1.000, P = 0.019), and CTGF levels exhibited a negative association with osteoporosis, as determined by the weighted median method (OR = 0.998, 95% CI = 0.996-0.999, P = 0.004). In the FinnGen dataset, IGF-1 and IGFBP-3 were not identified to be associated with osteoporosis. While, IGF-LR1 levels displayed a negative association with osteoporosis, according to the MR-Egger method (OR = 0.886, 95% CI = 0.795-0.987, P = 0.036), while CYR61 was linked to an increased risk of osteoporosis based on both the weighted median and IVW methods (OR = 1.154, 95% CI = 1.009-1.319, P = 0.037, and OR = 1.115, 95% CI = 1.022-1.215, P = 0.014, respectively). This study provides compelling evidence that certain IGF family members play a role in the pathogenesis of osteoporosis between different datasets, indicating population specific causal effects between IGF family and osteoporosis. Although the results from both datasets demonstrated that IGF family involved in the pathogenesis of osteoporosis, but the responding key molecules might be various among different population. Subsequent research is warranted to evaluate the potential of these biomarkers as targets for osteoporosis prevention and treatment in specific population.

Repurposing antihypertensive drugs for pain disorders: a drug-target mendelian randomization study.

Addressing the rising prevalence of pain disorders and limitations of current analgesics, our study explores repurposing antihypertensive drugs for pain management, inspired by the link between hypertension and pain. We leverage a drug-target Mendelian Randomization (MR) approach to explore their dual benefits and establish causal connections. A comprehensive compilation of antihypertensive drug classes was undertaken through British National Formulary, with their target genes identified using the DrugBank database. Relevant single nucleotide polymorphisms (SNPs) associated with these targets were selected from published genomic studies on systolic blood pressure (SBP) as genetic instruments. These SNPs were validated through MR against acute coronary artery disease (CAD) to ensure genes not linked to CAD were excluded from acting as proxies for antihypertensive drugs. An MR analysis of 29 pain-related outcomes was conducted using the FinnGen R10 database employing the selected and validated genetic instruments. We utilized the Inverse Variance Weighted (IVW) method for primary analysis, applying Bonferroni correction to control type I error. IVW's multiplicative random effects (MRE) addressed heterogeneity, and MR-PRESSO managed pleiotropy, ensuring accurate causal inference. Our analysis differentiates strong and suggestive evidence in linking antihypertensive drugs to pain disorder risks. Strong evidence was found for adrenergic neuron blockers increasing migraine without aura risk, loop diuretics reducing panniculitis, and vasodilator antihypertensives lowering limb pain risk. Suggestive evidence suggests alpha-adrenoceptor blockers might increase migraine risk, while beta-adrenoceptor blockers could lower radiculopathy risk. Adrenergic neuron blockers also show a potential protective effect against coxarthrosis (hip osteoarthritis) and increased femgenpain risk (pain and other conditions related to female genital organs and menstrual cycle). Additionally, suggestive links were found between vasodilator antihypertensives and reduced radiculopathy risk, and both alpha-adrenoceptor blockers and renin inhibitors possibly decreasing dorsalgianas risk (unspecified dorsalgia). These findings highlight the intricate effects of antihypertensive drugs on pain disorders, underlining the need for further research. The findings indicate that antihypertensive medications may exert varied effects on pain management, suggesting a repurposing potential for treating specific pain disorders. The results advocate for further research to confirm these associations and to explore underlying mechanisms, to optimize pain management practices.

Genetic evidence reveals a causal relationship between rheumatoid arthritis and interstitial lung disease.

Background/purpose: Previous epidemiological studies have associated interstitial lung disease (ILD) with rheumatoid arthritis (RA), yet the causality of this relationship remains uncertain. This study aimed to investigate the genetic causal link between ILD and RA. Methods: Genome-wide association study (GWAS) statistics for ILD and RA were collected from public datasets. Relevant single-nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. A two-sample bidirectional Mendelian randomization (MR) analysis was performed to assess the causal relationship between the two conditions. The MR analysis primarily used the inverse variance weighting (IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses, including MR-Egger, leave-one-out, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), were conducted to evaluate the heterogeneity and pleiotropy. Replication analyses using Asian datasets were also conducted to enhance the robustness of our findings. Results: In the European population, RA was found to increase the risk of ILD by 9.6% (OR: 1.096, 95% CI: 1.023-1.174, p = 0.009). Conversely, ILD was associated with a 12.8% increased risk of RA (OR: 1.128, 95% CI: 1.013-1.256, p = 0.029). Replication analyses from Asian GWAS further supported these findings, particularly the increased risk of ILD attributable to RA (OR: 1.33, 95% CI: 1.18-1.49, p-value <0.001). Conclusion: Our findings underscore the clinical importance of screening for ILD in RA patients and suggest that effective management of RA could significantly benefit ILD patients. The potential applicability of novel RA treatments to ILD warrants further exploration. Additionally, racial disparities in the manifestation of these diseases should not be overlooked, as they may offer new perspectives for targeted therapies in diverse populations.

A genome-wide and candidate gene association study of preterm birth in Korean pregnant women.

Preterm birth (PTB) refers to delivery before 37 weeks of gestation. Premature neonates exhibit higher neonatal morbidity and mortality rates than term neonates; therefore, it is crucial to predict and prevent PTB. Advancements enable the prediction and prevention of PTB using genetic approaches, especially by investigating its correlation with single nucleotide polymorphisms (SNPs). We aimed to identify impactive and relevant SNPs for the prediction of PTB via whole-genome sequencing analyses of the blood of 31 pregnant women with PTB (n = 13) and term birth (n = 18) who visited the Ewha Womans University Mokdong Hospital from November 1, 2018 to February 29, 2020. A genome-wide association study was performed using PLINK 1.9 software and 256 SNPs were selected and traced through protein-protein interactions. Moreover, a validation study by genotyping was performed on 60 other participants (preterm birth, n = 30; term birth, n = 30) for 25 SNPs related to ion channel binding and receptor complex pathways. Odds ratios were calculated using additive, dominant, and recessive genetic models. The risk of PTB in women with the AG allele of rs2485579 (gene name: RYR2) was significantly 4.82-fold increase, and the risk of PTB in women with the AG allele of rs7903957 (gene name: TBX5) was significantly 0.25-fold reduce. Our results suggest that rs2485579 (in RYR2) can be a genetic marker of PTB, which is considered through the association with abnormal cytoplasmic Ca2+ concentration and dysfunctional uterine contraction due to differences of RYR2 in the sarcoplasmic reticulum.

Association of GNB3, ACE polymorphisms with POAG and NTG

ABSTRACT Purpose Primary open-angle glaucoma (POAG) represents the most prevalent form of glaucoma and stands as a foremost contributor to irreversible vision impairment on a global scale. Despite notable strides made in comprehending the genetic underpinnings of POAG, investigations within the context of Russia remain constrained. Methods The study cohort comprised a total of 235 individuals, with 135 of them exhibiting various forms of glaucoma encompassing both POAG and (NTG, while the remaining 100 individuals served as control subjects. Each participant underwent a comprehensive ocular examination to ascertain their ocular health status. Genotyping of the relevant single nucleotide polymorphisms (SNPs) was carried out using the Taq Man genotyping assay. Specifically, the two SNPs under scrutiny were GNB3 rs5443 gene and ACE rs4646994. Statistical analysis was performed to evaluate the association of these SNPs with glaucoma risk. Results The presence of the T allele of rs5443 was found to be associated with NTG (p = .004). However, no statistically significant correlation was identified between this SNP and POAG (p = .88). Conclusion This study provides evidence of an association between the T allele of rs5443 and a reduced susceptibility NTG within the Russian population. These observations augment the comprehension of the genetic underpinnings of glaucoma and hold potential implications for the prospective development of targeted therapeutic interventions.

A transformer-based genomic prediction method fused with knowledge-guided module.

Genomic prediction (GP) uses single nucleotide polymorphisms (SNPs) to establish associations between markers and phenotypes. Selection of early individuals by genomic estimated breeding value shortens the generation interval and speeds up the breeding process. Recently, methods based on deep learning (DL) have gained great attention in the field of GP. In this study, we explore the application of Transformer-based structures to GP and develop a novel deep-learning model named GPformer. GPformer obtains a global view by gleaning beneficial information from all relevant SNPs regardless of the physical distance between SNPs. Comprehensive experimental results on five different crop datasets show that GPformer outperforms ridge regression-based linear unbiased prediction (RR-BLUP), support vector regression (SVR), light gradient boosting machine (LightGBM) and deep neural network genomic prediction (DNNGP) in terms of mean absolute error, Pearson's correlation coefficient and the proposed metric consistent index. Furthermore, we introduce a knowledge-guided module (KGM) to extract genome-wide association studies-based information, which is fused into GPformer as prior knowledge. KGM is very flexible and can be plugged into any DL network. Ablation studies of KGM on three datasets illustrate the efficiency of KGM adequately. Moreover, GPformer is robust and stable to hyperparameters and can generalize to each phenotype of every dataset, which is suitable for practical application scenarios.

Pharmacogenetic Factors of Clozapine-Induced Metabolic Syndrome

(1) Introduction: Despite modern therapies, approximately 20-30% of patients with schizophrenia remain resistant to psychopharmacotherapy. Clozapine is the only antipsychotic with proven efficacy for treatment resistance in schizophrenia (TRS). The most common adverse drug reaction (ADR) during clozapine administration are metabolic disturbances, particularly metabolic syndrome (MS). Because MS leads to a twofold increase in mortality from cardiovascular disease and a 1.5-fold increase in mortality from all causes, and clozapine is often the only treatment option for TRS, it is critical to monitor and management metabolic abnormalities. The high interindividual differences in the development of clozapine-induced MS suggest that genetic factors may play an important role. (2) Purpose: The aim of this study was to identify relevant single nucleotide polymorphisms (SNPs) of candidate genes for clozapine-induced MS, because based on these data, a genetic risk panel can be constructed to assess the likelihood of developing clozapine-induced MS in patients with schizophrenia. (3) Materials and Methods: We searched for full-text publications in PubMed, Web of Science, Springer, Google Scholar, and electronic libraries in English and Russian, available from inception to 30 October 2023. Keywords were the following: metabolic disturbances, clozapine, metabolic syndrome, schizophrenia, genes, adverse drug reactions, antipsychotics, pharmacogenetics, genetic biomarker, single nucleotide variant, polymorphism, association, variation, and metabolic syndrome genes. (4) Results: we included 6 naturalistic cross-sectional open-label trials, included patients with schizophrenia, schizoaffective, schizophreniform disorder or psychotic disorder, who were treated with first and second generations antipsychotics, among which there was also clozapine and 1 meta-analysis which reviewed association between HTR2C gene polymorphisms and anti-psychotic-induced MS in schizophrenia patients. According to the results of our scoping review the carriage of SNPs in the studied candidate genes associated with clozapine-induced MS are the following: 1) CYP1A2 gene: genotype AA of rs762551 (NG_008431.2:g.32035C&gt;A); 2) CYP2C19 gene: CYP2C19*2 polymorphism; 3) HTR2C gene: genotype CC of rs518147 (NM_000868.2:c.-697G&gt;C), minor allele C of rs1414334 (NG_012082.3:g.324497C&gt;G), genotype CC of rs518147 (NM_000868.2:c.-697G&gt;C), genotype GG of rs12836771 (NG_012082.3:g.71829A&gt;G); 4) LEP gene: genotypes AG and GG of rs7799039 (NG_044977.1:g.475G&gt;A); 5) LEPR gene: genotypes AG and GG of rs1137101 (NG_015831.2:g.177266A&gt;G). (4) Conclusions: Uncovering the genetic biomarkers of clozapine-induced MS may provide a key to developing a strategy for the personalized prevention and treatment of this ADRs of clozapine in patients with schizophrenia spectrum disorders in real clinical practice.

Genetic association between interleukin-17 and susceptibility to rheumatoid arthritis

BackgroundThe pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been found to have increased expression in the joints of patients with RA compared to healthy individuals. However, the causal relationship between the expression level of IL-17 or IL-17 receptor (IL-17R) and RA remained unknown. In this study, two-sample Mendelian randomization (MR) was used to investigate the causal relationship between IL-17 and RA.MethodsSummary statistics for RA (14,361 RA cases and 43,923 healthy controls) and IL-17 (3,301 samples) were obtained from an available meta-analysis of published genome-wide association studies (GWAS). Relevant single nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. Then we used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality. MR and MVMR analyses progressed mainly using inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods, which were applied to the genetic instrumental variables (IVs) of IL-17A/IL-17 RA, IL-17C/IL-17 RC, and IL-17D/IL-17RD and RA. For assessing the robustness of the results, we also carried out a sensitivity analysis to assess heterogeneity and pleiotropy, such as MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO).ResultsTwo-sample MR Analysis showed the causal relationship between IL-17A/IL-17RA and RA. The presence of genetically high IL-17A/IL-17RA may increase the risk of RA (IL-17A(OR = 1.095; 95% C.I., 0.990-1.210, p.adj = 0.013), IL-17RA(OR = 1.113, 95%CI = 1.006-1.231, p.adj = 0.006)). However, the results indicated that IL-17C/IL-17RC, and IL-17D/IL-17RD demonstrated no causal impact on RA (IL-17C(OR = 1.007, 95%CI = 0.890-1.139, p.adj = 0.152), IL-17RC(OR = 1.006, 95%CI = 0.904-1.119, p.adj = 0.152), IL-17D(OR = 0.979, 95%CI = 0.843-1.137, p.adj = 0.130), IL-17RD(OR = 0.983, 95%CI = 0.876-1.104, p.adj = 0.129)). Furthermore, MVMR analysis shown that IL-17RA(OR = 1.049, 95% CI: 0.997-1.102, p.adj = 0.014) was associated with increased risk of RA. Sensitivity analysis showed no heterogeneity and pleiotropy, suggesting that the above results were robust and reliable.ConclusionThe MR analysis provides evidence that IL-17A/IL-17RA are risk factors for RA. This emphasizes the importance of intervention on IL-17A/IL-17RA in patients with RA. Developing drugs that limit IL-17A may reduce the risk of RA.

Genetic polymorphisms in interleukin-1β (rs1143634) and interleukin-8 (rs4073) are associated with survival after resection of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a rare, understudied primary hepatic malignancy with dismal outcomes. Aiming to identify prognostically relevant single-nucleotide polymorphisms, we analyzed 11 genetic variants with a role in tumor-promoting inflammation (VEGF, EGF, EGFR, IL-1B, IL-6, CXCL8 (IL-8), IL-10, CXCR1, HIF1A and PTGS2 (COX-2) genes) and their association with disease-free (DFS) and overall survival (OS) in patients undergoing curative-intent surgery for iCCA. Genomic DNA was isolated from 112 patients (64 female, 48 male) with iCCA. Germline polymorphisms were analyzed with polymerase chain reaction-restriction fragment length polymorphism protocols. The IL-1B +3954 C/C (73/112, hazard ratio (HR) = 1.735, p = 0.012) and the IL-8 -251 T/A or A/A (53/112 and 16/112, HR = 2.001 and 1.1777, p = 0.026) genotypes were associated with shorter OS in univariable and multivariable analysis. The IL-1B +3954 polymorphism was also associated with shorter DFS (HR = 1.983, p = 0.012), but this effect was not sustained in the multivariable model. A genetic risk model of 0, 1 and 2 unfavorable alleles was established and confirmed in multivariable analysis. This study supports the prognostic role of the IL-1B C+3954T and the IL-8 T-251A variant as outcome markers in iCCA patients, identifying patient subgroups at higher risk for dismal clinical outcomes.

Major depressive disorder plays a vital role in the pathway from gastroesophageal reflux disease to chronic obstructive pulmonary disease: a Mendelian randomization study.

Background: Observational studies have shown a bidirectional association between chronic obstructive pulmonary disease (COPD) and gastroesophageal reflux disease (GERD), but it is not clear whether this association is causal. In our previous study, we found that depression was a hot topic of research in the association between COPD and GERD. Is major depressive disorder (MDD) a mediator of the association between COPD and GERD? Here, we evaluated the causal association between COPD, MDD, and GERD using Mendelian randomization (MR) study. Methods: Based on the FinnGen, United Kingdom Biobank, and Psychiatric Genomics Consortium (PGC) databases, we obtained genome-wide association study (GWAS) summary statistics for the three phenotypes from 315,123 European participants (22,867 GERD cases and 292,256 controls), 462,933 European participants (1,605 COPD cases and 461,328 controls), and 173,005 European participants (59,851 MDD cases and 113,154 controls), respectively. To obtain more instrumental variables to reduce bias, we extracted relevant single-nucleotide polymorphisms (SNPs) for the three phenotypes from published meta-analysis studies. Bidirectional MR and expression quantitative trait loci (eQTL)-MR were performed using the inverse variance weighting method to assess the causal association between GERD, MDD, and COPD. Results: There was no evidence of a causal effect between GERD and COPD in the bidirectional MR analysis [forward MR for GERD on COPD: odds ratios (OR) = 1.001, p = 0.270; reverse MR for COPD on GERD: OR = 1.021, p = 0.303]. The causal effect between GERD and MDD appeared to be bidirectional (forward MR for GERD on MDD: OR = 1.309, p = 0.006; reverse MR for MDD on GERD: OR = 1.530, p < 0.001), while the causal effect between MDD and COPD was unidirectional (forward MR for MDD on COPD: OR = 1.004, p < 0.001; reverse MR for COPD on MDD: OR = 1.002, p = 0.925). MDD mediated the effect of GERD on COPD in a unidirectional manner (OR = 1.001). The results of the eQTL-MR were consistent with those of the bidirectional MR. Conclusion: MDD appears to play a vital role in the effect of GERD on COPD. However, we have no evidence of a direct causal association between GERD and COPD. There is a bidirectional causal association between MDD and GERD, which may accelerate the progression from GERD to COPD.

New genotyping rescues old phenotypes: beneficial traits in Heterorhabditis bacteriophora wild type material and association to single nucleotide polymorphisms

Summary The entomopathogenic nematode (EPN), Heterorhabditis bacteriophora, is a biocontrol agent with almost world-wide distribution, thus providing a huge source of biodiversity available for exploitation in breeding programmes to improve beneficial traits. For management of economically important insect pests, the nematode is mass-produced in liquid culture, formulated with inert carriers, and transported under controlled temperature conditions to maintain its quality. The biocontrol potential of nematode materials is defined by their genetic background. Previous reports have assessed the phenotypic plasticity of H. bacteriophora. Major beneficial traits are field efficacy influenced by their virulence, longevity and field persistence and tolerance to abiotic stresses like oxidative stress, desiccation and extreme low and high temperatures. For several of these traits high heritability values (h2) have been reported, providing a platform for trait improvement by selection. Modern breeding uses molecular markers to track beneficial traits. Recent studies reported hundreds of single nucleotide polymorphisms (SNPs) in H. bacteriophora. This investigation revived a large set of cryopreserved wild types, hybrids and phenotyped materials of H. bacteriophora. Additional phenotypic data on the virulence (LC50) of H. bacteriophora strains against mealworm (Tenebrio molitor) were produced ranging from 1.4 ± 0.3 to 8.0 ± 3.6 nematodes per insect. Markers linked to beneficial traits were used for a comprehensive genotype analysis transferring reported SNP sequence information into the multiplex platform SeqSNP. Specific alleles associated to beneficial traits were identified and 65 materials were classified for the presence of relevant SNPs associated to beneficial traits. This information provides a valuable platform for exploitation of the nematode’s biodiversity for future breeding and selection approaches.