Selected Single Nucleotide Polymorphisms Research Articles

Clinical impact of single nucleotide polymorphisms (SNPs) in PDCD1 in patients with non-small cell lung cancer (NSCLC) receiving anti-PD1 immunotherapy.

e20625 Background: Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Over the past few years, immunotherapy has emerged as a key treatment option for NSCLC, particularly targeting the PD-1/PD-L1 pathway. Although current biomarkers have significantly improved the treatment of NSCLC, the need for additional biomarkers remains critical. The identification of genetic variations, such as single nucleotide polymorphisms (SNPs) in PDCD1 gene, has gained attention due to their potential prognostic and predictive value. These SNPs may provide valuable information regarding treatment response, side effects, and overall survival in patients undergoing anti-PD1 therapy. In the current study we investigated the clinical significance of specific SNPs in PDCD1 gene and their impact on treatment outcomes in NSCLC patients receiving anti-PD1 immunotherapy. Methods: For this purpose, we studied the polymorphisms rs2227981 (PD1.5) and rs7421861 (PD1.7).The selection of the specific SNPs was based mostly on literature. Blood samples from 90 patients with stage III and IV NSCLC treated with anti-PD1 immunotherapy in the University Hospital of Patras were used. DNA was extracted and utilized for genotyping using Real-Time PCR with appropriate primers and labeled probes. Sanger sequencing was subsequently performed for specific samples for additional confirmation of the results. The genotypes frequencies were correlated with the clinicopathological characteristics and clinical outcomes of the patients. Finally, data analysis was carried out using the statistical software SPSS 28.0. Results: Interestingly, the rs7421861 polymorphism and especially the allele A, was associated with fewer irAEs (Immune-Related Adverse Events) ( p =0.021). In addition, A allele of rs7421861 was also associated with longer time to disease progression (TPP) and longer overall survival (OS, p =0.041 and p =0.003, respectively). On the other hand, no association was found between rs2227981 with the clinical outcome of the patients, however, this polymorphism was associated with the disease stage, specifically the AG genotype with stage III (p=0.016). Conclusions: Our study suggests that the single nucleotide polymorphism rs2227981 may, in the future, be used as prognostic and predictive biomarkers for patients with NSCLC receiving anti-PD1 immunotherapy, however more studies are needed to further validate its clinical significance.

Does the ABO gene have prognostic value for immunotherapy efficacy?

e14656 Background: The potential linkage of ABO blood group with the immune system and cancer risk has been widely studied. However, the value of ABO single nucleotide polymorphisms (SNPs) on the prognosis of immune checkpoint inhibitors (ICIs) treatment remains unclear. Methods: 1. Study population: We included consecutive patients admitted for malignancy to the Second Xiangya Hospital, Central South University in Changsha, China, from May 2016 to April 2022. We collected the blood samples from patients receiving ICIs therapies regardless of treatment lines. 2. Data collection and follow-up method: From the electronic medical record information system, patients’ elements were abstracted and entered into a clinical data sheet.The primary outcome of this study was the efficacy of the ICI treatment. According to RECIST 1.1 criteria, the progression-free survival (PFS) and the overall survival (OS) were used to assess the treatment efficacy. The second outcomes were irAEs, which were assessed and graded using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE4.0). 3. Candidate SNPs selection: We downloaded the ABO gene sequence in the three prime untranslated regions (3’UTR) of Chinese South population from the 1000 Genomes Project (http://www.1000genomes.org/) and obtained 11 tag SNPs following the above criteria with Haploview 4.2 software. 4. SNP genotyping: Blood samples were collected after enrollment at hospital admission. Genotyping was performed using the SNP Sequenom MassARRAY platform. 5. Statistical analysis: The statistical analysis was applied using SPSS 19.0 (IBM Corp., Armonk, New York, USA) and Plink v1.07 (URL: http://pngu.mgh.harvard.edu/purcell/plink/). Results: Three SNPs, rs9411476, rs61527302, and rs10901251, were strongly associated with progression-free survival (PFS). Cox regression analysis revealed that rs9411476 AA+GA carriers experienced significantly extended PFS ( P -value = 0.006, adjusted HR = 0.62, 95%CI = 0.44-0.87) compared with GG carriers. The rs61527302 GA+AA carriers and rs10901251 AC+CC carriers experienced significantly prolonged PFS compared with rs61527302 GG carriers ( P -value = 0.016, adjusted HR = 0.66, 95%CI = 0.47-0.93) and rs10901251 AA carriers ( P -value = 0.023, adjusted HR = 0.69, 95%CI = 0.50-0.95), respectively. The ABO haplotype analysis revealed that the multiple mutations carriers exhibited significantly prolonged PFS ( P -value = 0.005, adjusted HR = 0.61, 95%CI = 0.44-0.86) than other patients.The ABO multiple mutations haplotype was not associated with the occurrence of overall immune-related adverse events (irAEs) and toxicity in most specific organs. Besides, multiple ABO mutations carriers were less likely to experience diarrhea ( P -value = 0.023). Conclusions: our findings showed that the multiple ABO mutations carriers did not suffer more irAEs while exhibiting better immunotherapy efficacy.

Schizophrenia, bipolar disorder and major depressive disorder are probably not risk factors for cardiovascular disease: A Mendelian randomized study.

Schizophrenia, bipolar disorder and major depressive disorder are probably not risk factors for cardiovascular disease: A Mendelian randomized study.

Causal link between mental disorders and gastrointestinal diseases: a Mendelian randomization study.

Observational research suggests that mental diseases may increase the risk of gastrointestinal diseases. However, the causal link between these conditions remains unclear. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal associations between common mental diseases and the risk of gastrointestinal diseases. First, a series of parameters were set to select single-nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS). Second, A two-sample Mendelian randomization analysis was conducted to investigate the causal link between mental diseases (Alzheimer's disease, depression, major depressive disorder, Parkinson's disease, schizophrenia) and gastrointestinal diseases (gastritis and duodenitis, gastric cancer) while removing outliers using MR-PRESSO. Finally, eight methods of MR analysis were used to generate forest plots, including inverse variance weighted (IVW), inverse variance weighted (fixed effects) (IVW fixed effects), maximum likelihood (ML), MR-Egger, weighted median, penalized weighted median, simple mode, and weighted mode, with IVW considered the primary method. The result demonstrated that most MDs have no evidence of a causal link between gastrointestinal diseases except Parkinson's disease and gastric cancer based on the IVW method (OR = 0.929 [95% CI = 0.869-0.992], p = 0.029). Subsequently, we performed a robustness analysis to ensure consistency. Our method provided evidence supporting a causal link between Parkinson's disease and the risk of gastric cancer. However, no evidence was found for other mental diseases influencing the risk of gastrointestinal diseases. Further research is warranted to explore how mental diseases affect the development of gastrointestinal diseases.

Instrumenting Carotid Sonography Biomarkers and Polygenic Risk Score As a Novel Screening Approach for Retinal Detachment.

Retinal detachment (RD) is a vision-threatening condition that manifests silently before abrupt disease onset; thus, most of the RD at-risk individuals are left unchecked until the first RD attack. To establish an RD risk-informing system for a broader population, we utilized carotid ultrasonography (CUS) biometrics, RD polygenic risk score (PRSRD), and clinical covariates (COVs) to assess RD risk predisposition factors. First, a backpropagation logistic regression model identified RD-associated CUS biomarkers and further incorporated them as a multivariable RD-risk nomogram. Next, a PRSRD model was established with the selected single-nucleotide polymorphisms (SNPs) curated as high functional expression candidates in the retina single-cell RNA datasets. Finally, a three-component RD prediction model (CUS, PRSRD, and COVs) was assembled by logistic cumulative analysis. Demographic analysis reported hypertension (HTN) status was associated with RD (odds ratio [OR] = 1.601). The CUS regression model revealed that the minimum flow of the right internal carotid artery (ICA-Qmin; OR = 1.04) and the time-averaged maximum velocity of the right common carotid artery (CCA-TAMAX; OR = 1.03) were associated with increased RD risk. Notably, genome-wide association studies (GWAS) identified three significant SNPs (IGFBPL1 rs117248428, OR = 1.63; CELF2 rs56168975, OR = 1.72; and PAX6 rs11825821, OR = 1.61; P < 5.00 × 10-6) that are highly expressed at the RD border of the retinal pigment epithelium and choroid. Finally, the three-component model demonstrated state-of-the-art RD prediction (AUCHTN+ = 0.95, AUCHTN- = 0.93). Based on instrumenting CUS images and genetic PRSRD, we are proposing a screening method for RD at-risk patients. Results from this study demonstrated the combination of CUS and GWAS as a cost-effective, population-wide screening framework for identifying RD at-risk individuals.

Causal relationship analysis of MRI measurements of major human internal organs and liver disease

BackgroundThis study aimed to explore the causal association between imaging measurement indicators of major internal organs and liver lesions using a two-sample Mendelian randomization (MR) method.MethodsData from the UK Biobank and GWAS Catalog platform were used to select single nucleotide polymorphisms (SNPs) associated with MRI or derived measurement results of various organ indicators as genetic instrumental variables. Data from the FinnGen project’s R9 version were used to select liver lesion outcomes, such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic cirrhosis, and primary hepatocellular carcinoma (HCC). UVMR analysis were utilized variable-by-variable, and MVMR was used to adjust for confounding on significant variables. Steiger directional test, heterogeneity, pleiotropy, and sensitivity tests were conducted to enhance reliability.ResultsUnivariate Mendelian randomization analysis (UVMR) indicated that liver volume (LV), liver fat (LF), and subcutaneous adipose tissue measurement (SATM) are risk factors for NAFLD. The multivariable MR (MVMR) results for NAFLD showed that LV and LF remained significant, while SATM did not. For cirrhosis (NAC), UVMR suggested that LV, LF, and SATM are risk factors, but MVMR results showed that only LV and LF remained significant. Additionally, pancreatic volume (PV) was found to be a protective factor, while splenic volume (SV) was a pathogenic factor for NAC. For HCC, both UVMR and MVMR analyses suggested that LF and liver iron (LI) are risk factors, while SATM did not remain significant in the MVMR analysis.ConclusionsLV, LF, and SATM are associated with NAFLD. In the NAC stage, additional pathogenic effects of PV and SV were observed. The related results for LF and LI support the pathogenic effect of liver iron factors in the HCC stage.

Genetic variants in glycosylation pathways are associated with colorectal cancer risk.

The glycosylation pathway serves as a vital regulatory mechanism in colorectal cancer. However, how genetic variants in these pathways may affect the risk of colorectal cancer is still unknown. To examine the relationships between the risk of colorectal cancer and the presence of selected single-nucleotide polymorphisms (SNPs), 1,150 patients and 1,342 controls were included in this case‒control study. We found that GALNT2 rs76000797 and rs11576324, GALNT6 rs67726586, FUT8 rs117497405, FUT2 rs111311275 and B4GALT5 rs6125695 were strongly correlated with the risk of colorectal cancer. Moreover, rs111311275 exhibited an expression quantitative trait locus effect on FUT2 in colorectal cancer tissues, which could increase the risk of colorectal cancer by influencing FUT2 expression. GEPIA research and microarray data revealed that FUT2 expression was higher in colorectal cancer tissues than in normal tissues and that individuals with colon cancer with high expression of FUT2 had longer overall survival times. Our study highlights the significant impact of genetic variants on glycosylation pathways and offers novel insights into potential biomarkers for colorectal cancer risk.

Exploring the association between 91 circulating inflammatory proteins and the risk of carcinoid syndrome: a Mendelian randomization analysis

This study aims to explore the potential correlation between circulating inflammatory proteins and carcinoid syndrome (CS). Using summary data from genome-wide association studies (GWAS), we conducted a Mendelian randomization (MR) analysis with two samples, treating 91 circulating inflammatory proteins as exposure factors and CS as the outcome. Based on genetic loci closely associated with circulating inflammatory proteins selected as instrumental variables, we primarily employed the inverse-variance weighted (IVW) method for analysis, combined with the weighted median method (WM), simple median method (SM), weighted mode estimation (WME), and MR-Egger regression for comprehensive analysis. Initial IVW results revealed significant causal effects of six circulating inflammatory proteins on CS. Specifically, Interleukin-17C levels were negatively correlated with CS risk, indicating a protective effect; whereas beta-nerve growth factor, C-C motif chemokine 20, Natural killer cell receptor 2B4, C-X-C motif chemokine 5, and Leukemia inhibitory factor levels were positively correlated with CS risk, suggesting detrimental effects. In heterogeneity tests, the selected single-nucleotide polymorphisms (SNPs) did not show heterogeneity, and analysis using Egger intercept and MR-PRESSO test did not detect pleiotropy of SNPs, thus validating the reliability of the study. Furthermore, sensitivity analysis using the leave-one-out method further confirmed the robustness of the results. In summary, this study identified significant causal relationships between six inflammatory proteins—Interleukin-17C, beta-nerve growth factor, C-C motif chemokine 20, Natural killer cell receptor 2B4, C-X-C motif chemokine 5, and Leukemia inhibitory factor—and CS risk through MR analysis. This finding not only emphasizes the important role of inflammation in the pathogenesis of CS but also suggests the potential value of inflammatory proteins as targets for early diagnosis and therapeutic interventions.

Mendelian randomization reveals probucol’s preventive role in Behçet’s disease via circulating metabolites

Behçet’s disease (BD) is a chronic, recurrent condition for which effective preventive medications are currently lacking. This disease often disrupts lipid metabolism, adversely affecting vascular endothelial function. Exploring preventive strategies, such as lipid-lowering medications, is crucial. Probucol, known for its lipid-lowering properties, emerges as a promising candidate. By inhibiting the ATP-binding cassette transporter A1 (ABCA1), probucol is hypothesized to regulate circulating metabolites, potentially reducing the risk of BD. This study employs Mendelian randomization (MR) to evaluate probucol’s impact on BD and investigate its preventive potential through the modulation of circulating metabolites. For this MR study, we selected single nucleotide polymorphisms (SNPs) associated with probucol as instrumental variables and conducted a positive control analysis with SNPs linked to high-density lipoprotein (HDL) to validate our instrument selection. The study was structured in two steps: first, using probucol’s eQTLs to estimate its causal effect on circulating metabolites; second, using SNPs linked to these metabolites to assess their causal impact on Behcet’s disease risk. To ensure the robustness and validity of our findings, we employed several MR methods, including the Inverse Variance Weighted (IVW) approach, heterogeneity tests, and pleiotropy analysis. This study identified a total of 30 SNPs associated with BD, 7502 SNPs linked to circulating metabolites, and 1,049 SNPs associated with BD from circulating metabolites, all derived from ABCA1 expression quantitative trait loci (eQTL) data. Utilizing Mendelian randomization (MR) analysis, it was confirmed that probucol leads to a reduction in concentrations of cholesterol esters in HDL, consistent with findings from randomized drug trials (odds ratio [OR] = 0.932, 95% confidence interval [CI] 0.907–0.958, P < 0.001). Furthermore, the study demonstrated that probucol significantly decreased the risk of BD with an OR of 0.496 (95% CI 0.283–0.868, P = 0.014). Among 123 assessed circulating metabolites, thirty-six were found to be associated with probucol. Notably, probucol demonstrated a notable reduction in very large HDL particle concentrations (OR = 0.917, 95% CI 0.889–0.947, P < 0.001), contributing to approximately 10.407% of its overall impact on decreasing BD risk. This study establishes that probucol significantly lowers the risk of BD by reducing very large HDL particle concentrations. It provides a genetic basis for considering probucol as a potential therapeutic option for BD high risk individuals.

Unraveling the Molecular Nexus between Ankylosing Spondylitis and IgA Nephropathy: Insights from Mendelian Randomization and Bioinformatics Analysis

Introduction: Renal complications are frequently observed in patients with ankylosing spondylitis (AS), with IgA nephropathy (IgAN) being a particularly significant concern. Although anecdotal evidence suggests a potential association between AS and IgAN, robust epidemiological data remain limited. Previous studies have reported varying prevalence rates of IgAN among AS patients, but these studies are often constrained by small sample sizes and inconsistent methodologies. Establishing a causal relationship between AS and IgAN through conventional observational studies has proven challenging due to confounding factors and reverse causality. Mendelian randomization (MR) offers a promising alternative, utilizing genetic variants to explore causal relationships. This study employs MR combined with bioinformatics analysis to investigate the molecular link between AS and IgAN, aiming to identify potential therapeutic targets. Methods: Two publicly available datasets were utilized: a genome-wide association study (GWAS) of AS (dataset ID: ebi-a-GCST005529) with 9,069 AS cases and 13,578 controls, and IgAN data from the FinnGen project, which included 653 cases and 411,528 controls. Instrumental variables were selected based on stringent criteria. MR analysis was conducted using the inverse variance weighted, weighted median, and MR-Egger methods to assess the causal relationship between AS and IgAN. Reverse MR analysis and sensitivity analysis were conducted to validate the findings. Bioinformatics analysis involved acquiring gene expression data from the GEO database and identifying differentially expressed genes (DEGs) using the limma package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, protein-protein interaction (PPI) network construction, and hub gene identification were performed to elucidate the biological functions involved. Results: A total of 24 independent single-nucleotide polymorphisms (SNPs) associated with AS were identified through stringent SNP selection. MR analysis revealed a protective causal relationship between AS and IgAN (odds ratio = 0.552, 95% confidence interval, 0.339–0.900; p = 0.017). Analysis of DEGs identified 332 DEGs for IgAN and 5,521 DEGs for AS, with 59 common DEGs shared between the two diseases. Functional enrichment analysis highlighted significant changes in biological processes, cellular components, molecular functions, and KEGG pathways. PPI network analysis identified eight hub genes, including CX3CR1, which links AS and IgAN. External validation confirmed CX3CR1 as a crucial gene associated with both diseases. Conclusion: This study provides evidence of a protective causal relationship between AS and IgAN using MR analysis. Furthermore, bioinformatics analysis identifies CX3CR1 as a key gene, suggesting its role in mediating the protective link between AS and IgAN. These findings provide valuable insights into the molecular mechanisms underlying the connection between the two diseases and propose CX3CR1 as a potential therapeutic target for IgAN.

Variants of the Progesterone Receptor Gene as Modulators of Risk for Idiopathic Spontaneous Premature Birth.

Premature birth (PTB) is the most common cause of perinatal mortality and morbidity. We performed a case-control study to determine whether two selected single-nucleotide polymorphisms (SNPs) of the progesterone receptor gene (PGR) (rs4754732 and rs653752) play a role in the modulation of the risk for spontaneous PTB. This study included 400 mothers (199 with premature delivery and 201 with term delivery) and 400 newborns (201 term-born and 199 premature-born) of European descent. Genotyping was performed with an ABI PRISM 7500 SDS using TaqMan SNP genotyping assays. We found no statistically significant difference in the distribution of genotypes and allele frequencies between prematurely born newborns and newborns at term for either investigated SNP. There was no statistically significant difference in the distribution of genotypes and allele frequencies between groups of mothers with extremely early and early PTB compared to the group of mothers with term births. Potential association of the mothers' C allele of rs653752 with lower odds of PTB (p = 0.03; odds ratio 1.36; 95% confidence interval 1.02-1.81; Chi-square test), and association of the mothers' CC genotype of rs653752 in the recessive inheritance model with lower odds of PTB in general (p = 0.02; odds ratio 0.54; 95% confidence interval 0.32-0.91; Chi-square test) and with a late PTB (p = 0.005, odds ratio 0.45, 95% confidence interval 0.23-0.79; Chi-square test), were found. It was also found that the mothers who were carriers of the haplotype T-G combination of rs4754732 and rs653752 were 1.5 times more likely to have PTB, even after correcting the p-value for multiple comparisons (p = 0.008; odds ratio 1.59; 95% confidence interval 1.13-2.24, Chi-square test). Further research on a larger number of subjects of these and other PGR SNPs will be needed in order to confirm the presented results.

Relationship of depression and asthma: a observational and Mendelian randomization study

Background Both depression and asthma have a significant impact on the quality of life for individuals. Studies have shown that patients with depression often experience comorbid asthma; however, the precise relationship between these two conditions remains unclear. The objective of this study is to investigate the causal relationship between depression and asthma. Methods In a cross-sectional study, we utilized data from the National Health and Nutrition Examination Survey (NHANES) 2009-2014 and employed logistic regression to assess the correlation between depression and asthma. In the subsequent Mendelian randomization (MR) analysis, we selected single nucleotide polymorphisms (SNPs) closely linked to both depression and asthma as instrumental variables, based on summary data from genome-wide association studies (GWAS). The inverse variance weighted method (IVW) was then applied to ascertain the causal relationship between depression and asthma. Results Based on the results of the cross-sectional study, it was found that the status of depression was significantly associated with a higher risk of asthma (OR = 2.15, 95%CI = 1.79 ∼ 2.59, p < 0.001). Furthermore, in the MR analysis, a causal relationship was further identified between depression, severe depression, and the increased incidence of asthma (OR = 1.11, 95%CI = 1.05 ∼ 1.18, p < 0.001), (OR = 1.01, 95%CI = 1.01 ∼ 1.02, p < 0.001); the results of the reverse MR analysis indicated no causal relationship between asthma and the increased incidence of depression and severe depression (OR = 1.01, 95%CI0.99 ∼ 1.03, p = 0.50), (OR = 1.07, 95%CI: 0.82 ∼ 1.40, p = 0.64). Conclusion This study has revealed a causal relationship between depression and an increased risk of developing asthma, offering new insights for the clinical intervention of both asthma and depression.

Genetic Dissection of Anthocyanin Accumulation in Tomato Using GWAS and Hybridization Probe Melting (HPM) for Marker-Assisted Breeding

Tomato fruit color is primarily influenced by the accumulation of pigments such as carotenoids and anthocyanins, which are regulated by a complex network of genes and environmental factors. The presence of anthocyanins, in particular, contributes to the purple phenotype in tomatoes, which has been associated with improved nutritional quality and disease resistance. Previous studies have identified key regulatory genes, including SlMYBATV and SlANT1, that control anthocyanin biosynthesis in tomatoes. A total of 48 tomato accessions were selected, including both anthocyanin-producing and non-producing cultivars, to assess genetic variation in relation to fruit color. GWAS analysis identified significant associations between single-nucleotide polymorphisms (SNPs) on chromosomes 7 and 10 and the purple fruit phenotype. These genomic regions contained key anthocyanin regulatory genes, SlMYBATV on chromosome 7 and SlANT1 on chromosome 10, confirming their roles in anthocyanin biosynthesis. Linkage disequilibrium (LD) analysis further revealed strong correlations between SNPs within these regions, facilitating the selection of representative SNPs for genotyping. The genotyping of SNPs Ch07_60981501 and Ch10_64354129 using HPM demonstrated clear differentiation between purple and non-purple cultivars based on melting temperature differences, validating the functional significance of the identified loci. The results confirmed that the nonfunctional SlMYBATV allele at the atv locus allows for enhanced anthocyanin accumulation by relieving repression of anthocyanin activators like SlANT1. This interaction between the Aft and atv loci drives light-dependent anthocyanin biosynthesis in purple tomatoes. HPM genotyping offers a cost-effective tool for allele identification, supporting breeding programs for anthocyanin-rich tomatoes. SNP markers enable marker-assisted selection (MAS) for improved nutritional and aesthetic traits. This study highlights SlMYBATV and SlANT1 in anthocyanin biosynthesis, advancing efforts to develop enriched tomato varieties and supporting agricultural productivity and health.

Causality between insulin use and malignant tumors of the digestive system: a two-sample mendelian randomized study

BackgroundExisting cohort studies show no association between insulin use and cancers of the digestive system, while numerous meta-analyses suggest that insulin use increases the risk of digestive system tumours. This study uses two-sample Mendelian randomization (MR) to further investigate the causal relationship between the two.MethodsWe selected single nucleotide polymorphisms (SNPs) strongly associated with insulin use as instrumental variables and used aggregated statistics on digestive system neoplasms as the outcome event. The primary method of analysis was inverse variance weighting (IVW), supplemented by weighted median, MR-Egger regression, weighted mode and simple mode methods. The reliability of the study was assessed by heterogeneity testing, pleiotropy analysis and sensitivity analysis.ResultA total of 8 SNPs associated with insulin use were included as instrumental variables. Random-effects IVW analysis showed an association between insulin use and increased risk of colorectal cancer (OR = 1.1037, 95%CI = 1.0183–1.1962, P = 0.016). No statistically significant association was found between insulin use and the development of other digestive system tumours. The results were unaffected by pleiotropy and heterogeneity, and the reliability of the findings was confirmed by sensitivity analysis.ConclusionOur Mendelian randomization study suggests an association between insulin use and an increased risk of CRC, with no clear association observed for other digestive system tumours. However, further MR studies with larger sample sizes from genome-wide association study (GWAS) data are needed to verify this association.

Idiopathic Pulmonary Fibrosis Is Associated With Type 1 Diabetes: A Two-Sample Mendelian Randomization Study.

The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear; previous studies revealed the underlying connection between IPF and diabetes, but there is no consensual opinion. This study is aimed at examining the association between Type 1 diabetes (T1D) and IPF using Mendelian randomization (MR). In our two-sample MR study, we selected single nucleotide polymorphisms (SNPs) that are strongly associated with T1D in a genome-wide association study (GWAS) from IEU (dataset: ebi-a-GCST005536) and obtained their corresponding effect estimates on T1D risk in an IPF GWAS from IEU (dataset: finn-b-IPF). We conducted a multivariable Mendelian randomization (MVMR) analysis to eliminate the interference of aging. In the outcome of inverse-variance weighted (IVW) method, T1D showed a promoting effect on IPF (odds ratio (OR): 1.132, p = 0.005). The statistics passed the MR-PRESSO test, and no outliers were observed (global test p = 0.238). MVMR study was performed, and the aging-adjusted result remains almost the same (OR = 1.132, OR_95% CI: 1.034-1.239, p = 0.007). Our study shows a causal relation between T1D and IPF; further investigation should be conducted.

Profiling antimalarial drug-resistant haplotypes in Pfcrt, Pfmdr1, Pfdhps and Pfdhfr genes in Plasmodium falciparum causing malaria in the Central Region of Ghana: a multicentre cross-sectional study.

The proliferation of Plasmodium parasites resistant to antimalarial drugs poses a serious threat to human life and remains an obstacle to managing and eradicating Plasmodium falciparum. The surveillance of molecular markers has become necessary to monitor the spread of resistant haplotypes and discover emerging mutations. This molecular epidemiological study aimed to evaluate the prevalence of known mutations in the drug resistance genes Pfcrt, Pfmdr1, Pfdhfr and Pfdhps in the Central Region of Ghana. A multi-centre cross-sectional study. This prospective study utilised dried blood spots from individuals with P. falciparum-infection from five districts in the Central Region of Ghana. Selective Whole Genome Amplification (sWGA) and Single Nucleotide Polymorphisms (SNPs) in P. falciparum chloroquine transporter genes (Pfcrt), P. falciparum multidrug resistance 1 (Pfmdr1), P. falciparum dihydropteroate synthase (Pfdhps) and P. falciparum dihydrofolate reductase (Pfdhfr) were analysed. Whole genome sequencing was carried out on 522 samples. Of these, 409 (78%) samples were successfully sequenced. Six (6) of the sequenced samples were of co-infection of other parasite species with P. falciparum and excluded from the analysis. Analysis of the Pfcrt gene revealed 0.5% were CVIET (C72, V73, M74I, N75E, K76T) while the Pfcrt CVMNK (C72, V73, M74, N75, K76) wild-type haplotypes were 97% with (2.5%) (CV[M/I][N/E][K/T]) being mixed haplotypes. In the Pfmdr1 gene, monoclonal haplotypes; NFD (N86, Y184F, D1246) and YFN (N86Y, Y184F, D1246N) occurred at 44% and 9.8%, respectively, whereas mixed- haplotypes (N[Y/F]D and [N/Y][Y/F]D) were 23.5% and 0.3%, respectively. Combined Pfdhfr/Pfdhps genes yielded about 88% Pfdhfr IRNI (N51I, C59R, S108N, I164) + Pfdhps A437G haplotypes (conferring partial resistance to Sulphadoxine-Pyrimethamine (SP)) while 9% of the parasites had Pfhdfr IRNI + Pfdhps A437G + K540E haplotypes (conferring full resistance to SP). The wild-type haplotype, Pfdhfr (N51, C59, S108, I164) and Pfdhps (S436, A437, K540, A581, A613) was not observed. The findings show a low prevalence of CVIET and relatively higher rates for Pfmdr1 NFD and parasites with Pfdhfr IRNI (N51I, C59R, S108N, I164) + Pfdhps A437G haplotypes. These observations advocate for enhanced surveillance which is inimical to malaria management in an endemic area.

Causal relationship between branched-chain amino acids and leukemia risk: insights from a two-sample Mendelian randomization study

ABSTRACT Background Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids involved in protein synthesis, energy metabolism, and immune regulation. While BCAAs are known to influence cancer biology, their role in leukemia remains unclear. This study employs Mendelian randomization (MR) analysis to explore the causal relationship between BCAA levels and four leukemia subtypes: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). Methods Data from genome-wide association studies (GWAS) were used to select single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for BCAA levels. The inverse-variance weighted (IVW) method served as the primary analytical approach, with heterogeneity assessed via Cochran’s Q test and pleiotropy through MR-Egger intercept. Sensitivity analysis was performed using leave-one-out analysis. Results A significant inverse association was observed between total BCAA levels, leucine, valine, and ALL risk. Total BCAA levels showed an odds ratio (OR) of 0.16 (95% CI: 0.05–0.54, p=0.003), leucine 0.17 (95% CI: 0.04–0.61, p=0.007), and valine 0.21 (95% CI: 0.07–0.61, p=0.004). No significant associations were found for AML, CLL, or CML. Conclusion This study suggests that BCAAs, particularly leucine and valine, may protect against ALL, offering insights into leukemia metabolic regulation and potential targets for prevention and therapy.

Genetic Association Study of Acetylcholinesterase (ACHE) and Butyrylcholinesterase (BCHE) Variants in Sudden Infant Death Syndrome (SIDS).

Sudden infant death syndrome (SIDS) is the leading cause of death among infants aged between one month and one year. Altered enzyme activities or expression of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) have been observed in SIDS patients that might lead to disturbed autonomic function and, together with other risk factors, might trigger SIDS. To explore the contribution of AChE and BChE from a genomic viewpoint, we sought to investigate the association between SIDS and selected single nucleotide polymorphisms (SNPs) in the ACHE and BCHE genes. In this case-control study, 13 potentially regulatory SNPs were selected from ACHE and BCHE and were genotyped in 201 SIDS cases and 338 controls. The association of SIDS with the 11 successfully genotyped candidate variants was examined using statistical analyses of overall or stratified cases and haplotype analyses. No significant overall associations were observed between SIDS and ACHE and BCHE variants in allele, genotype, and haplotype analyses. In subgroup analyses, eight variants were found to be nominally associated with SIDS, though these associations did not remain statistically significant after correction for multiple comparisons. One haplotype (T-C-G-C-C in rs3495-rs1803274-rs1355538-rs2048493-rs1126680) of BCHE was associated with the female SIDS subgroup (57.3% in controls vs. 46.3% in female SIDS cases, p = 0.010). The selected variants in ACHE and BCHE were not overall associated with SIDS in this study, and thus cannot generally explain the previously reported dysregulation of enzyme activities in SIDS. However, some evidence of association in subgroups and a possible contribution of variants other than those tested here would need to be explored in larger studies.

Evaluating Genomic Selection in beef cattle: Insights from computer simulations using real SNP data

Genomic Selection (GS) is a method that employs genomic data to estimate breeding values and rank candidates for selection. Despite its numerous advantages, its application in cattle breeding programs remains in the early stages in many livestock systems developed in tropical and subtropical environments, such as those in Paraguay. Computational simulations are powerful tools that enhance our understanding of GS applications in different scenarios and are invaluable as an initial step before implementing this technique in "real" genetic improvement programs. In this study, real data from single nucleotide polymorphisms (SNPs) of the Indicus and Taurus breeds were employed to simulate three crossing schemes: F1 crosses, grading up, and rotational crosses. Phenotypes were selected for traits related to shear force, growth, and tolerance. The predictive accuracy of three 50k SNP chips, differing in their SNP selection methodologies, was compared: random selection, selection based on minimum allele frequency differences between breeds, and selection based on minimum allele frequency differences between breeds with a threshold of 0.09 in Taurus. The findings indicate that rotational crossing demonstrates optimal predictive accuracy (0.38), while marker selection based on allele frequency differences between breeds (0.18 and 0.17, respectively) does not benefit predictions significantly.

Incidence of PAX6 single nucleotide polymorphisms in congenital iridofundal coloboma and other congenital ocular abnormalities: a tertiary care hospital experience from central India

Purpose of this study is to identify selected single nucleotide polymorphisms (SNP) of the PAX6 gene and to assess their correlation with congenital iridofundal colobomas and other congenital ocular anomalies.Material and methods. It was a case-control study done on 45 patients aged from 75 days to 58 years (mean age 29.36 ± 14.4 years) with irido-fundal coloboma and 45 healthy controls aged 35.23 ± 13.92 years. Ocular examination was done by using slit-lamp microscopy inspection, fundoscopy and intraocular pressure measurement. Genotyping was done by using the polymerase chain reaction — restriction fragment length polymorphism (PCR-RFLP) method.Results. Two irido — fundal coloboma patients showed CT (+/-) heterozygous genotype of rs667773 SNP and the rest were wild-type CC (-/-) homozygous genotype. All controls showed CC-/- wild-type homozygous genotype. PAX6 SNP rs3026354 showed CC (-/-) wild-type homozygous genotype condition in all patients. Neither CG (+/-) heterozygous nor homozygous GG (+/+) genotype was reported in patients and controls. SNP rs662702, genotype pattern was CC-/- wild type homozygous in all patients and controls. CC genotype frequency was 95.56 and CT genotype was 4.4% while C allele frequency was 97.78 and T allele frequency was 2.22 % in rs667773 C&gt;T SNP. rs3026354C&gt;G SNP had 100 % CC genotype and C allele frequency in both case and control populations. SNP rs 662702C&gt;T showed 100 % CC genotype and C allele frequency in the case and control respectively.Conclusion. The elevated frequency of the CC genotype with C allele was more common in irido fundal patients. Two heterozygous CT genotype of rs667773C&gt;T SNP were reported in two irido-fundal coloboma patients.