Role Of Genetic Variation Research Articles

Trends of genetic contributions on epigenetic clocks and related methylation sites with aging: A population-based adult twin study.

Several crucial acceleration periods exist during aging process. Epigenetic clocks, serving as indicators of aging, are influenced by genetic factors. Investigating how the genetic contributions on these clocks change with age may provide novel insights into the aging process. In this study, based on 1084 adult twins from the Chinese National Twin Registry (CNTR), we established structural equation models (SEMs) to evaluate the trends in genetic influence with aging for epigenetic clocks, which include PC-Horvath, PC-Hannum, PC-PhenoAge, PC-GrimAge, and DunedinPACE. A decline in overall heritability was observed for all five clocks from ages 31 to 70, with a relatively stable trend at first. Subsequently, apart from PC-GrimAge, the other four clocks displayed a more evident drop in heritability: DunedinPACE and PC-PhenoAge experienced a clear decline between 55 and 65 years, while PC-Horvath and PC-Hannum showed a similar decrease between 60 and 70 years. In contrast, the heritability of PC-GrimAge remained stable throughout. An analysis of methylation sites (CpGs) from these clocks identified 41, 26, 4, and 36 CpG sites potentially underlying heritability changes in DunedinPACE, PC-Horvath, PC-Hannum, and PC-PhenoAge, respectively. Data from the CNTR were collected through two surveys in 2013 and 2018. Based on 308 twins with longitudinal data, declines in genetic components were observed at follow-up compared to baseline, with significant decreases in the four PC-clocks. DunedinPACE peaked in 5-year longitudinal genetic contribution changes at age 55-60, while PC-clocks consistently peaked at age 50-55. These findings may offer novel insights into the role of genetic variations in aging.

Genotypic variation in winter wheat for fusarium foot rot and its biocontrol using Clonostachys rosea.

Biological control to manage plant diseases is an environmentally friendly alternative to using chemical pesticides. However, little is known about the role of genetic variation in plants affecting the efficacy of biological control agents (BCAs). The aim of this study was to explore the genetic variation in winter wheat for disease susceptibility to fusarium foot rot caused by Fusarium graminearum and variation in biocontrol efficacy of the fungal BCA Clonostachys rosea to control the disease. In total, 190 winter wheat genotypes were evaluated under controlled conditions in two treatments, i.e. (i) F. graminearum (Fg) and (ii) F. graminearum infection on C. rosea treated seeds (FgCr). Alongside disease severity, plant growth-related traits such as shoot length and root length were also measured. Comparison of genotypes between the two treatments enabled the dissection of genotypic variation for disease resistance and C. rosea efficacy. The study revealed significant variation among plant genotypes for fusarium foot rot susceptibility and other growth traits in treatment Fg. Moreover, significant variation in C. rosea efficacy was also observed in genotype contrasts between the two treatments for all traits. Using a 20K marker array, a genome-wide association study was also performed. We identified a total of 18 significant marker-trait associations for disease resistance and C. rosea efficacy for all the traits. Moreover, the markers associated with disease resistance and C. rosea efficacy were not co-localized, highlighting the independent inheritance of these traits, which can facilitate simultaneous selection for cultivar improvement.

Using a Polygenic Risk Score to Improve the Risk Prediction of Non-Small Cell Lung Cancer in Taiwan.

Low-dose computed tomography (LDCT) can help reducing lung cancer mortality. In Taiwan, the existing screening criteria revolve around smoking habits and family history of lung cancer. The role of genetic variation in non-small cell lung cancer (NSCLC) development is increasingly recognized. In this study, we aimed to investigate the potential benefits of polygenic risk scores (PRSs) in predicting NSCLC and enhancing the effectiveness of screening programs. We conducted a retrospective cohort study that included participants without prior diagnosis of lung cancer and later received LDCT for lung cancer screening. Genetic data for these participants were obtained from the project of Taiwan Precision Medicine Initiative. We adopted the model of genome-wide association study-derived PRS calculation using 19 susceptibility loci associated with the risk of NSCLC as reported by Dai et al. We studied a total of 2,287 participants (1,197 male, 1,090 female). More female participants developed NSCLC during the follow-up period (4.4% v 2.5%, P = .015). The only risk factor of NSCLC diagnosis among male participants was age. Among female participants, independent risk factors of NSCLC diagnosis were age (adjusted hazard ratio [aHR], 1.08 [95% CI, 1.04 to 1.11]), a family history of lung cancer (aHR, 3.21 [95% CI, 1.78 to 5.77]), and PRS fourth quartile (aHR, 2.97 [95% CI, 1.25 to 7.07]). We used the receiver operating characteristics to show an AUC value of 0.741 for the conventional model. With the further incorporation of PRS, the AUC rose to 0.778. The evaluation of PRS for NSCLC prediction holds promise for enhancing the effectiveness of lung cancer screening in Taiwan especially in women. By incorporating genetic information, screening criteria can be tailored to identify individuals at higher risks of NSCLC.

Investigating the potential impact of ELF3-associated SNPs on chondrocyte inflammation

Objective: Chondrocyte inflammation is a critical factor in degenerative joint diseases, such as osteoarthritis (OA), significantly impairing quality of life through chronic pain and limited mobility. Genetic predisposition is recognized as a critical factor in the progression of chondrocyte inflammation and OA, with particular focus on the role of genetic variants in the expression and regulation of inflammatory mediators. This study aimed to obtain information about the potential roles of a few genes containing ELF3-associated SNPs in the pathogenesis of chondrocyte inflammation. Materials and Methods: GVAT Database was used to select top candidate SNPs associated with ELF3, a cardinal transcription factor in chondrocyte inflammation. Inflammation was induced by IL-1β treatment in differentiated chondrocytes to analyze gene expression patterns. Transcriptome analysis was done by RNA sequencing. Results: The most important SNPs that could potentially affect the binding affinity of ELF3 transcription factor were analyzed. As a result of the analysis, 52% of ELF3-associated SNPs were found in protein-coding regions, 40% in gene-free intergenic regions, and 8% in non-coding RNA sequences. Some of these SNPs are located in regulatory regions (enhancers). A significant increase in expression levels in the ELF3 gene was detected after IL-1β administration, indicating that IL-1β promotes the activity of this transcription factor. mRNA expressions of TLN2, BABAM2, PEPD, and NUDT5 were also increased after IL-1β stimulation. Conclusion: The presence of ELF3-associated SNPs in the enhancer sequences of TLN2 and BABAM2 genes, in addition to the increased expression of these two genes upon IL-1β stimulation, suggested that TLN2 and BABAM2 genes may be associated with the severity of chondrocyte inflammation and OA.

Integrative Analysis of Transcriptome and Metabolome Reveals the Pivotal Role of the NAM Family Genes in Oncidium hybridum Lodd. Pseudobulb Growth.

Oncidium hybridum Lodd. is an important ornamental flower that is used as both a cut flower and a potted plant around the world; additionally, its pseudobulbs serve as essential carriers for floral organs and flower development. The NAM gene family is crucial for managing responses to various stresses as well as regulating growth in plants. However, the mechanisms by which NAM genes regulate the development of pseudobulbs remain unclear. In this study, a total of 144 NAM genes harboring complete structural domains were identified in O. hybridum. The 144 NAM genes were systematically classified into 14 distinct subfamilies via phylogenetic analysis. Delving deeper into the conserved motifs revealed that motifs 1-6 exhibited remarkable conservation, while motifs 7-10 presented in a few NAM genes only. Notably, NAM genes sharing identical specific motifs were classified into the same subfamily, indicating functional relatedness. Furthermore, the examination of occurrences of gene duplication indicated that the NAM genes display 16 pairs of tandem duplications along with five pairs of segmental duplications, suggesting their role in genetic diversity and potential adaptive evolution. By conducting a correlation analysis integrating transcriptomics and metabolomics at four stages of pseudobulb development, we found that OhNAM023, OhNAM030, OhNAM007, OhNAM019, OhNAM083, OhNAM047, OhNAM089, and OhNAM025 exhibited significant relationships with the endogenous plant hormones jasmonates (JAs), hinting at their potential involvement in hormonal signaling. Additionally, OhNAM089, OhNAM025, OhNAM119, OhNAM055, and OhNAM136 showed strong links with abscisic acid (ABA) and abscisic acid glucose ester (ABA-GE), suggesting the possible regulatory function of these NAM genes in plant growth and stress responses. The 144 NAM genes identified in this study provide a basis for subsequent research and contribute to elucidating the intricate molecular mechanisms of NAM genes in Oncidium and potentially in other species.

Novel genetic structures associated with adverse response to chemotherapy in breast cancer.

Introduction: The role of genetic variants in response to chemotherapy has been investigated in several studies. This study aimed to investigate genetic variants associated with response to chemotherapy in breast cancer (BC) patients. Methods: Significant variants (p < 5 × 10-8) associated with response to chemotherapy were obtained from GWA studies. Candidate variants were identified by haplotype analysis (r2 ≥ 0.9, D'≥0.9) using 1000Genome LD data. To determine the effects of the variants on gene expression, expression quantitative trait loci (eQTL) were evaluated. To compare the expression of the identified genes in tumor samples, expression levels were compared between TCGA tumor types and adjacent normal tissues. Results: Six rs3820706, rs147451859, rs4784750, rs17587029, rs16830728, and rs16972207 variants were significantly associated with response to chemotherapy in BC patients (p < 5 × 10-8). Seven novel haplotypic structures were identified to be associated with adverse response to chemotherapy in BC patients. These haplotypes formed two genetic structures associated with neutropenia, leukopenia, chemotherapy-induced cytotoxicity (GAG-TTAT), and chemotherapy-induced alopecia (CC-CAACTCCCGTTGCGG). These variants are located on PPCDC, NLRC5, STAM2, and TNFSF13B genes, and the expression of these genes significantly changed in BC tissues than normal tissues (P ≤ 0.05), also showing gene-gene correlation (P ≤ 0.05). Conclusions: These genetic variants and their associated novel haplotypic structures can predict adverse response to chemotherapy in BC patients and could potentially form BC-associated genetic panel for adverse response to chemotherapy.

Genetic and telomeric variability: Insights from a tropical avian hybrid zone.

Telomere lengths and telomere dynamics can correlate with lifespan, behaviour and individual quality. Such relationships have spurred interest in understanding variation in telomere lengths and their dynamics within and between populations. Many studies have identified how environmental processes can influence telomere dynamics, but the role of genetic variation is much less well characterized. To provide a novel perspective on how telomeric variation relates to genetic variability, we longitudinally sampled individuals across a narrow hybrid zone (n = 127 samples), wherein two Manacus species characterized by contrasting genome-wide heterozygosity interbreed. We measured individual (n = 66) and population (n = 3) differences in genome-wide heterozygosity and, among hybrids, amount of genetic admixture using RADseq-generated SNPs. We tested for population differences in telomere lengths and telomere dynamics. We then examined how telomere lengths and telomere dynamics covaried with genome-wide heterozygosity within populations. Hybrid individuals exhibited longer telomeres, on average, than individuals sampled in the adjacent parental populations. No population differences in telomere dynamics were observed. Within the parental population characterized by relatively low heterozygosity, higher genome-wide heterozygosity was associated with shorter telomeres and higher rates of telomere shortening-a pattern that was less apparent in the other populations. All of these relationships were independent of sex, despite the contrasting life histories of male and female manakins. Our study highlights how population comparisons can reveal interrelationships between genetic variation and telomeres, and how naturally occurring hybridization and genome-wide heterozygosity can relate to telomere lengths and telomere dynamics.

Comparison of different parts of tangerine (Citrus tangerina) for DNA extraction

The tangerine, a citrus fruit, is grown commercially worldwide in tropical, semitropical, and warm temperate countries, including the Mediterranean region. Tangerine cultivation and production are crucial for the economy of many countries, where genomic DNA plays a critical role in genetic diversity and molecular analysis of this tree. Therefore, this study was conducted in 2022 at Limpopo University to compare DNA extraction from three different parts of the tangerine tree: fresh leaves, stems, and fruit. The Chelex method was used to extract DNA from three samples of C. tangerine from South Africa. The quantity and purity of DNA were measured using a spectrophotometer. PCR amplification with 28S primers was used to confirm and evaluate the extracted DNA. The results from the spectrophotometer showed that the highest quantity of nucleic acid was extracted from the stem (98.18± 12 mg/mL), with a 260/280 ratio for DNA quality (1.85 ± 0.01). The fruit showed a high level of protein (5.8 ± 1.8 mg/mL), but the DNA concentration was lower. In conclusion the amplification of the samples indicated that the stem had high purity and concentration of DNA, which can be suitable for PCR amplification.

Clinical and cognitive outcomes in first-episode psychosis: focus on the interplay between cannabis use and genetic variability in endocannabinoid receptors.

Research data show the impact of the endocannabinoid system on psychosis through its neurotransmission homeostatic functions. However, the effect of the endocannabinoid system genetic variability on the relationship between cannabis use and psychosis has been unexplored, even less in first-episode patients. Here, through a case-only design, we investigated the effect of cannabis use and the genetic variability of endocannabinoid receptors on clinical and cognitive outcomes in first-episode psychosis (FEP) patients. The sample comprised 50 FEP patients of European ancestry (mean age (sd) = 26.14 (6.55) years, 76% males), classified as cannabis users (58%) or cannabis non-users. Two Single Nucleotide Polymorphisms (SNP) were genotyped at the cannabinoid receptor type 1 gene (CNR1 rs1049353) and cannabinoid receptor type 2 gene (CNR2 rs2501431). Clinical (PANSS, GAF) and neuropsychological (WAIS, WMS, BADS) assessments were conducted. By means of linear regression models, we tested the main effect of cannabis use and its interaction with the polymorphic variants on the clinical and cognitive outcomes. First, as regards cannabis effects, our data showed a trend towards more severe positive symptoms (PANSS, p = 0.05) and better performance in manipulative abilities (matrix test-WAIS, p = 0.041) among cannabis users compared to non-users. Second, concerning the genotypic effects, the T allele carriers of the CNR1 rs1049353 presented higher PANSS disorganization scores than CC homozygotes (p = 0.014). Third, we detected that the observed association between cannabis and manipulative abilities is modified by the CNR2 polymorphism (p = 0.022): cannabis users carrying the G allele displayed better manipulative abilities than AA genotype carriers, while the cannabis non-users presented the opposite genotype-performance pattern. Such gene-environment interaction significantly improved the overall fit of the cannabis-only model (Δ-R2 = 8.4%, p = 0.019). Despite the preliminary nature of the sample, our findings point towards the role of genetic variants at CNR1 and CNR2 genes in the severity of the disorganized symptoms of first-episode psychosis and modulating cognitive performance conditional to cannabis use. This highlights the need for further characterization of the combined role of endocannabinoid system genetic variability and cannabis use in the understanding of the pathophysiology of psychosis.

The role of genetic variants in the prediction of hearing loss due to cisplatin chemoradiotherapy.

Concomitant high-dose cisplatin with radiotherapy is commonly used for treating head and neck squamous cell carcinoma (HNSCC). Cisplatin, often used with radiotherapy, is known for causing irreversible sensorineural hearing loss, with individual variability suggesting a genetic component. This study aims to enhance the predictive ability of the clinical prediction model for cisplatin-induced hearing loss (CIHL) in HNSCC patients, as outlined in Theunissen etal., by incorporating significant genetic variants. Conducted at the Netherlands Cancer Institute, this retrospective study included 74 patients treated between 1997 and 2011. Thirty-one SNPs that were previously associated with CIHL or other cisplatin-induced toxicities were identified and incorporated into the model. The primary outcome measured was the change in decibels at posttreatment 1-2-4 kHz hearing levels per additional minor allele of these SNPs, evaluated using linear mixed-effects regression models. The model's predictive accuracy was determined by the area under the curve (AUC) using 10-fold cross-validation. The rs2289669 SNP in the SLC47A1/MATE1 gene was linked to a significant 2.67 dB increase in hearing loss per allele (95% CI 0.49-4.86, p = 0.017). Incorporating rs2289669 improved the model's AUC from 0.78 to 0.83, a borderline significant improvement (p = 0.073). This study underscores the importance of the rs2289669 SNP in CIHL and demonstrates the potential of combining genetic and clinical data for enhanced predictive models in personalized treatment strategies.

Role of genetic variations and protein expression of β-Microsemino protein in intrauterine insemination outcome of unexplained infertile men: A case-control study.

Intrauterine insemination (IUI) is often the first-line treatment for unexplained infertility. -Microsemino protein (MSMB) is an abundant protein in seminal plasma that has an inhibitory effect on spontaneous acrosome reaction. The present study aimed to evaluate MSMB gene variations and protein expression on IUI success rate in unexplained infertile men. A case-control study was performed on 100 unexplained infertile Iranian men referred to the Royan Institute, Tehran, Iran for IUI (50 men with IUI positive result [IUI+], and 50 men with IUI negative result [IUI-]). Couples with female infertility factors (such as hormonal disorders, infrequent menstrual period, abnormality in uterus, fallopian tubes, or ovaries) and men with infections of the male accessory glands, hypogonadotropic hypogonadism, clinical varicocele, retractile testis, genital trauma, drug use, or concurrent hormonal treatment Y chromosome microdeletions, and abnormal karyotype were excluded from the study. The polymerase chain reaction sequencing was performed for the promoter and the coding regions of MSMB functional domains. To study the protein expression, the total protein of sperm was extracted, and sandwich enzyme-linked immunosorbent assay was performed. 4 variations were detected (rs12770171, rs10993994, rs2075894, and rs4517463). None of them showed significant differences between the IUI+ and IUI- groups. The mean value of protein expression did not show any differences between the groups. In conclusion, there is no association between genetic variations of promoter and coding regions of MSMB functional domains as well as its expression with IUI success in unexplained infertile men.

Rare Genetic Variants in Young Adults Requiring Pacemaker Implantation

BackgroundGenetic disease has recently emerged as a cause of cardiac conduction disorders (CCDs), but the diagnostic yield of genetic testing and the contribution of the different genes to CCD is still unsettled. ObjectivesThis study sought to determine the diagnostic yield of genetic testing in young adults with CCD of unknown etiology requiring pacemaker implantation. We also studied the prevalence of rare protein-altering variants across individual genes and functional gene groups. MethodsWe performed whole exome sequencing in 150 patients with CCD of unknown etiology who had permanent pacemaker implanted at age ≤60 years at 14 Spanish hospitals. Prevalence of rare protein-altering variants in patients with CCD was compared with a reference population of 115,522 individuals from gnomAD database (control subjects). ResultsAmong 39 prioritized genes, patients with CCD had more rare protein-altering variants than control subjects (OR: 2.39; 95% CI: 1.75-3.33). Significant enrichment of rare variants in patients with CCD was observed in all functional gene groups except in the desmosomal genes group. Rare variants in the nuclear envelope genes group exhibited the strongest association with CCD (OR: 6.77; 95% CI: 3.71-13.87). Of note, rare variants in sarcomeric genes were also enriched (OR: 1.73; 95% CI: 1.05-3.10). An actionable genetic variant was detected in 21 patients (14%), with LMNA being the most frequently involved gene (4.6%). ConclusionsUnrecognized rare genetic variants increase the risk of CCD in young adults with CCD of unknown etiology. Genetic testing should be performed in patients age ≤60 years with CCD of unknown etiology. The role of genetic variants in sarcomeric genes as a cause of CCD should be further investigated.

Genetic Variation in ABCB1, ADRB1, CYP3A4, CYP3A5, NEDD4L and NR3C2 Confers Differential Susceptibility to Resistant Hypertension among South Africans.

Resistant hypertension (RHTN) prevalence ranges from 4 to 19% in Africa. There is a paucity of data on the role of genetic variation on RHTN among Africans. We set out to investigate the role of polymorphisms in ABCB1, ADRB1, CYP3A4, CYP3A5, NEDD4L, and NR3C2, on RHTN susceptibility among South Africans. Using a retrospective matched case-control study, 190 RHTN patients (cases: blood pressure (BP) ≥ 140/90 mmHg on ≥3 anti-hypertensives or BP < 140/90 mmHg on >3 anti-hypertensives) and 189 non-RHTN patients (controls: <3 anti-hypertensives, BP < 140/90 or ≥140/90 mmHg), 12 single nucleotide polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), quantitative PCR and Sanger sequencing. Genetic association analyses were conducted using the additive model and multivariable logistic regression. Homozygosity for CYP3A5 rs776746C/C genotype (p = 0.02; OR: 0.44; CI: 0.22-0.89) was associated with reduced risk for RHTN. Homozygous ADRB1 rs1801252G/G (p = 0.02; OR: 3.30; CI: 1.17-10.03) and NEDD4L rs4149601A/A genotypes (p = 0.001; OR: 3.82; CI: 1.67-9.07) were associated with increased risk for RHTN. Carriers of the of ADRB1 rs1801252-rs1801253 G-C haplotype had 2.83-fold odds of presenting with RHTN (p = 0.04; OR: 2.83; CI: 1.05-8.20). These variants that are associated with RHTN may have clinical utility in the selection of antihypertensive drugs in our population.

Trait analysis of short duration boro rice (Oryza sativa L.) varieties in northern region of Bangladesh: Insights from heatmap, correlation and PCA

The role of genetic variation is utmost importance in the selection of a desirable genotype for breeding programs. In the northern region of Bangladesh, the performance of five short duration boro rice varieties (BRRI dhan28, BRRI dhan74, BRRI dhan81, BRRI dhan88, and Bangabandhu dhan100) on yield and yield-contributing traits were evaluated in four locations. Yield attributes tiller hill-1 (TN), panicle hill-1 (PN), filled grain panicle-1 (FG), panicle length (PL), 1000-grain weight (TGW), and harvest index (HI), showed a positive correlation with grain yield (GY). Conversely, spikelet sterility (SSP) and unfilled grains panicle-1 (UFG) showed negative associations with grain yield. Principal component analysis (PCA) revealed that the first three components accounted for 89.60% of variability. The highest positive eigenvalue was observed in DF, DM, BY, HI, PN, SY, TN, PL and GY in PC1, indicating their significant influence on the overall genotype variations. PC2 was primarily driven by plant height (PH) and FG, while PC3 driven by TGW and UFG. The results suggest that grain yield is highly influenced by FG, PH, DM, DF, PN, TN, PL, TGW, SY, BY, and HI. These components highlighted the importance in distinguishing rice genotypes with higher grain yield potential. By considering these traits, BRRI dhan74 have outperformed other varieties, followed by BRRI dhan88 and Bangabandhu dhan100. BRRI dhan74 is most suitable for all four location followed by BRRI dhan88. The traits such as PN, PL, FG, TGW, PH, &amp; HI significantly influence rice yield and should be prioritized in breeding programs aimed at developing high-yielding rice varieties.

Effect of SCN1Aand SCN2A gene polymorphisms on the efficacy of valproic acid treatment in Chinese children with epilepsy.

Epilepsy patients exhibit considerable differences in their response to sodium valproate (VPA) therapy, a phenomenon that might be attributed to individual genetic variances. The role of genetic variations, specifically in sodium channels encoded by SCN1A and SCN2A genes, in influencing the effectiveness of VPA in treating epilepsy is still debated. This research focuses on examining the impact of these genetic polymorphisms on the efficacy of VPA therapy among pediatric epilepsy patients in China. Five single nucleotide polymorphisms (SNPs), including SCN1A (rs10188577, rs2298771, rs3812718) and SCN2A (rs2304016, rs17183814), were genotyped in 233 epilepsy patients undergoing VPA therapy. The associations between genotypes and the antiepileptic effects of VPA were assessed, with 128 patients categorized as VPA responders and 105 as VPA non-responders. In the context of VPA monotherapy, SCN1A rs2298771 and SCN2A rs17183814 were found to be significantly associated with VPA response (P< 0.05). Our study suggests the findings of this investigation indicate that the polymorphisms SCN1A rs2298771 and SCN2A rs17183814 could potentially act as predictive biomarkers for the responsiveness to VPA among Chinese epilepsy patients.

The ADnet Bayesian belief network for alder decline: Integrating empirical data and expert knowledge

The globalization in plant material trading has caused the emergence of invasive pests in many ecosystems, such as the alder pathogen Phytophthora ×alni in European riparian forests. Due to the ecological importance of alder to the functioning of rivers and the increasing incidence of P. ×alni-induced alder decline, effective and accessible decision tools are required to help managers and stakeholders control the disease. This study proposes a Bayesian belief network methodology to integrate diverse information on the factors affecting the survival and infection ability of P. ×alni in riparian habitats to help predict and manage disease incidence. The resulting Alder Decline Network (ADnet) management tool integrates information about alder decline from scientific literature, expert knowledge and empirical data. Expert knowledge was gathered through elicitation techniques that included 19 experts from 12 institutions and 8 countries. An original dataset was created covering 1189 European locations, from which P. ×alni occurrence was modeled based on bioclimatic variables. ADnet uncertainty was evaluated through its sensitivity to changes in states and three scenario analyses. The ADnet tool indicated that mild temperatures and high precipitation are key factors favoring pathogen survival. Flood timing, water velocity, and soil type have the strongest influence on disease incidence. ADnet can support ecosystem management decisions and knowledge transfer to address P. ×alni-induced alder decline at local or regional levels across Europe. Management actions such as avoiding the planting of potentially infected trees or removing man-made structures that increase the flooding period in disease-affected sites could decrease the incidence of alder disease in riparian forests and limit its spread. The coverage of the ADnet tool can be expanded by updating data on the pathogen's occurrence, particularly from its distributional limits. Research on the role of genetic variability in alder susceptibility and pathogen virulence may also help improve future ADnet versions.

#2436 Genetic variability in rosuvastatin metabolism explains rhabdomyolysis and consequent acute renal failure

Abstract Background and Aims Low density lipoprotein cholesterol is an independent risk factor for atherosclerotic cardiovascular disease. Rosuvastatin is one of the most frequently prescribed statins and also one of the most frequent causes of rhabdomyolysis with consequent acute renal failure (ARF). Risk factors for statin induced rhabdomyolysis, i.e. the type of statin and its dose, patient's age, kidney and liver function, gender and concurrent treatment with cytochrome P450 (CYP) inhibitors, should be considered at the time of statin prescription. Single nucleotide polymorphisms (SNPs) in genes coding the transport proteins (SLCO1B1, ABCG2) and CYP2C9, catalysing rosuvastatin oxidation, may lead to decreased protein function leading to accumulation of plasma rosuvastatin which increases the risk of rhabdomyolysis. Herewith we present a case of a female patient admitted to our department due to rhabdomyolysis and ARF with the aim of alerting against uncritical high dose rosuvastatin prescribing and of pointing out the role of genetic variability in drug metabolizing enzymes and transporters (DMET) in rosuvastatin side effects. Method a 79-years old Caucasian woman admitted to our department due to rhabdomyolysis and ARF was genotyped for polymorphisms in DMET genes coding for CYP2C9 (rs1799853, rs1057910, rs28371686, rs28371685), SLCO1B1 (rs4149056, rs2306283) and ABCG2 (rs2231142) using competitive allele specific polymerase chain reaction (KASPar). Results Presented patient suffered from an acute myocardial infarction in October 2023. She was treated with percutaneous coronary intervention, antiaggregation therapy and hypolipidemic therapy (rosuvastatin 40 mg/ezetimibe 10 mg). Her creatinine was 55 μM (eGFR 61 ml/min) at the time of statin prescription. Several months later she was admitted septic with myoglobin &amp;gt;50.000 μg/L and creatinine approximately 1600 μM. Infection was treated with piperacillin/tazobactam. Myoglobin was removed with Theranova dialyzer. The patient was dismissed home two weeks later with creatinine 230 μM. As potential patient's risk factors for rhabdomyolysis we considered high dose of rosuvastatin, patient's higher age and slower rosuvastatin disposition due to SNPs in DMET. Sepsis may have been an additional contributory factor. Genotyping revealed polymorphisms in all three genes involved in rosuvastatin metabolism and transport: CYP2C9, SLCO1B1 and ABCG2 (Table 1). Two genotypes resulted in the phenotypes with slower rosuvastatin metabolism, probably leading to gradual accumulation of plasma rosuvastatin, which may have manifested in rhabdomyolysis that contributed to ARF. Heterozygous CYP2C9*2 and *3 carriers have, in comparison to the wild type carriers, approximately 30% and 80% slower rosuvastatin metabolism, respectively. Heterozygous ABCG2 c.421C&amp;gt;A carrier state may also contribute slightly to rosuvastatin accumulation. Furthermore, the potential interaction with inflammation should not be overlooked, as inflammation may have a major effect on drug metabolism and transport through downregulation of CYP enzymes as well as drug transporters. If genotypes of the respective DMET genes were known in advance, high dose rosuvastatin could have been avoided despite relatively good kidney function at the time of rosuvastatin prescription. Conclusion Statins should be prescribed with caution and their dose adapted to the risk factors that should always be checked for at the time of statin prescription. We recommend periodical surveillance of serum creatinine, eGFR, urine protein to creatinine ratio, liver tests, creatine kinase and myoglobin in patients treated with high dose statins. Furthermore, SLCO1B1, ABCG2 and CYP2C9 genotyping before rosuvastatin prescription would enable insight into its metabolism. Genotype information could lead to more cautious statin prescribing, especially in the presence of other factors, such as infection or concomitant drug treatment that may modify the activity of DMET. In the case of chronic kidney disease drug dosing should be appropriately adjusted in accordance with drug's Summary of product characteristics and KDIGO guidelines.

Abstract 2124: Genetic Variation Associated With Progression And Severity Of Peripheral Artery Disease

Background: Peripheral Artery Disease (PAD) is a major source of cardiovascular morbidity and mortality, affecting &gt;230 million individuals worldwide. While PAD may initially cause exertional limb pain (claudication), progression leads to chronic limb threatening ischemia (CLTI; rest pain and/or tissue loss) and amputation, which are associated with high rates of hospitalization and death. Genetic variants associated with PAD susceptibility have been identified using genome-wide association studies (GWAS). However, the role of genetic variation in the progression of PAD and disease severity remains poorly understood. Methods: GWAS of progression to CLTI were performed among individuals with PAD in the VA Million Veteran Program (MVP) and Copenhagen Hospital Biobank (CHB), accounting for age, sex, and genetic principal components. GWAS were first performed among genetically inferred ancestry subpopulations (EUR: European; AFR: African; AMR: admixed American), and combined using fixed-effects meta-analysis. SlopeHunter was used to account for index-event bias using a GWAS of prevalent PAD. Genetic associations with PAD severity (claudication, CLTI, amputation) were evaluated using multinomial logistic regression. Results: Up to 21.1 million genetic variants were tested for association with CLTI (17,641 individuals) in comparison to PAD (75,133 individuals). A total of 3 genetic loci were associated with progression to CLTI (p &lt; 5x10 -8 ). The strongest association with CLTI was rs6025 (OR 1.25, 95% CI 1.18 to 1.34, p = 4.62x10 -12 ), a common missense variant (p.Arg534Gln) encoding Factor V Leiden, with consistent effects accounting for index-event bias. Compared to 489,538 individuals without PAD in MVP, rs6025 was associated with increased risk of non-specific PAD (OR 1.15, 95% CI 1.1 to 1.2, p = 5x10 -8 ), claudication (OR 1.14, 95% CI 1.1 to 1.2, p = 1x10 -4 ), CLTI (OR 1.42, 95% CI 1.3 to 1.6, p = 7x10 -23 ), and amputation (OR 1.54, 95% CI 1.4 to 1.8, p = 2x10 -10 ). Conclusion: Our results implicate F5 p.Arg534Gln as a risk factor for PAD progression and severe PAD manifestations including CLTI and amputation. This result provides genetic support for a potential role of anticoagulation as a treatment to prevent PAD progression and severe outcomes.

Associations of Dietary Cholesterol Consumption With Incident Diabetes and Cardiovascular Disease: The Role of Genetic Variability in Cholesterol Absorption and Disease Predisposition.

Whether genetic susceptibility to disease and dietary cholesterol (DC) absorption contribute to inconsistent associations of DC consumption with diabetes and cardiovascular disease (CVD) remains unclear. DC consumption was assessed by repeated 24-h dietary recalls in the UK Biobank. A polygenetic risk score (PRS) for DC absorption was constructed using genetic variants in the Niemann-Pick C1-Like 1 and ATP Binding Cassettes G5 and G8 genes. PRSs for diabetes, coronary artery disease, and stroke were also created. The associations of DC consumption with incident diabetes (n = 96,826) and CVD (n = 94,536) in the overall sample and by PRS subgroups were evaluated using adjusted Cox models. Each additional 300 mg/day of DC consumption was associated with incident diabetes (hazard ratio [HR], 1.17 [95% CI, 1.07-1.27]) and CVD (HR, 1.09 [95% CI, 1.03-1.17]), but further adjusting for BMI nullified these associations (HR for diabetes, 0.99 [95% CI, 0.90-1.09]; HR for CVD, 1.04 [95% CI, 0.98-1.12]). Genetic susceptibility to the diseases did not modify these associations (P for interaction ≥0.06). The DC-CVD association appeared to be stronger in people with greater genetic susceptibility to cholesterol absorption assessed by the non-high-density lipoprotein cholesterol-related PRS (P for interaction = 0.04), but the stratum-level association estimates were not statistically significant. DC consumption was not associated with incident diabetes and CVD, after adjusting for BMI, in the overall sample and in subgroups stratified by genetic predisposition to cholesterol absorption and the diseases. Nevertheless, whether genetic predisposition to cholesterol absorption modifies the DC-CVD association requires further investigation.

Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus.

The prevalence of metabolic-associated fatty liver disease (MAFLD) is a growing public health issue in people living with human immunodeficiency virus (PLWH). However, the pathophysiology of MAFLD is still unknown, and the role of genetic variables is only now becoming evident. To evaluate the associations of gene-polymorphism-related MAFLD in PLWH. The study employed transient elastography with a controlled attenuation parameter ≥ 248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central Thailand. Candidate single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan® MGB probe 5' nuclease assays for seven MAFLD-related genes. Statistical analyses included SNP frequency analysis, Fisher's Exact and Chi-square tests, odds ratio calculations, and multivariable logistic regression. The G-allele carriers of PNPLA3 (rs738409) exhibited a two-fold rise in MAFLD, increasing by 2.5 times in MAFLD with human immunodeficiency virus infection. The clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times (P = 0.001) more significant chance of developing aberrant triglyceride among PLWH. The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.