Multiple Genetic Variants Research Articles

Interplay between BMI, neutrophil, triglyceride and uric acid: a case-control study and bidirectional multivariate mendelian randomization analysis

BackgroundThis study aims to explore the interplay between body mass index (BMI), neutrophils, triglyceride levels, and uric acid (UA). Understanding the causal correlation between UA and health indicators, specifically its association with the body’s inflammatory conditions, is crucial for preventing and managing various diseases.MethodsA retrospective analysis was conducted on 4,286 cases utilizing the Spearman correlation method. BMI, neutrophil count, and triglyceride levels were determined as key exposure factors. To further investigate the causal correlation, a two-sample Mendelian randomization(MR) design was utilized, leveraging data from genome-wide association study (GWAS). Within this framework, and multivariable Mendelian randomization(MVMR) was applied to explore the linkage between multiple genetic variants and complex traits.ResultsThe study primarily focused on UA, employing genetic variation as a natural tool to assess the causal impact of various factors on UA. Spearman correlation analysis revealed significant association between UA and BMI (ρ = 0.230,p<0.01), neutrophils (ρ = 0.164,p<0.01), and triglyceride levels (ρ = 0.154,p<0.01). Additionally, two-sample MR analysis affirmed a reciprocal causal association between neutrophils and UA (OR = 1.035,95%CI:1.009–1.061,p = 0.008), as well as positive causal connection between UA and both BMI (OR = 1.083,95%CI:1.042–1.126,p<0.001) and triglyceride levels (OR = 1.090,95%CI:1.037–1.146,p<0.001). Neutrophils also demonstrated a positive causal linkage with BMI (OR = 1.034,95%CI:1.009–1.078,p = 0.012) and triglyceride levels (OR = 1.077,95%CI:1.033–1.122,p<0.001), and BMI exhibited a similar causal association with triglyceride levels (OR = 1.300,95%CI:1.212–1.385,p<0.001). These findings shed light on the causal networks connecting UA, BMI, neutrophils, and triglyceride levels. By integrating Spearman correlation analysis with various MR study designs, this study provided a robust framework for identifying key factors influencing hyperuricemia and related health issues, thereby enhancing our understanding of the interplay between inflammatory markers and these health indicators.ConclusionsOur study presents strong evidence of the complex interconnection between BMI, neutrophils, triglyceride, and UA, revealing complex causal links and highlighting potential inflammatory states as key mediators. The findings may contribute to a better understanding of these factors and potentially lead to improved clinical outcomes and patients’ health.

Epistasis between genetic variations on MdMYB109 and MdHXK1 exerts a large effect on sugar content in apple fruit.

Many quantitative traits are controlled by multiple genetic variations with minor effects, making it challenging to resolve the underlying genetic network and to apply functional markers in breeding. Affected by up to a hundred quantitative trait loci (QTLs), fruit-soluble sugar content is one of the most complex quantitative traits in apple (Malus sp.). Here, QTLs for apple fruit sucrose and fructose content were identified via QTL mapping and bulked-segregant analysis sequencing (BSA-seq) using a population derived from a 'Jonathan' × 'Golden Delicious' cross. Allelic variations and non-allelic interactions were validated in the candidate genes within these defined QTL regions. Three single-nucleotide polymorphisms (SNPs) (SNP -326 C/T, SNP -705 A/G, and SNP -706 G/T) in the MdMYB109 promoter region affected the binding ability of the repressive transcription factor MdWRKY33, leading to increased MdMYB109 expression. MdMYB109 bound directly to the promoter of the sucrose transporter gene MdSUT2.2 and activated its expression, raising fruit sucrose content. A SNP (SNP1060 A/G) in the hexokinase gene MdHXK1 affected the phosphorylation of the transcription factor MdbHLH3, and phosphorylated MdbHLH3 interacted with MdMYB109 to co-activate MdSUT2.2 expression and increase fruit sucrose content. Adding the joint effects of the genotype combinations at the SNP markers based on the SNPs in MdMYB109 and MdHXK1 increased the prediction accuracy of a genomics-assisted prediction (GAP) model for total soluble solid content from 0.3758 to 0.5531. These results uncovered functional variations in MdMYB109 and MdHXK1 regulating apple fruit sucrose content. The updated GAP model with improved predictability can be used efficiently in apple breeding.

Genetically predicted serum metabolites mediate the association between inflammatory proteins and polycystic ovary syndrome: a Mendelian randomization study.

To investigate the association between polycystic ovary syndrome (PCOS) and inflammatory proteins, and to identify and quantify the role of serum metabolites as potential mediators. Utilizing summary-level data from a genome-wide association study (GWAS), we conducted a two-sample Mendelian Randomization (MR) analysis, a genetic approach that uses genetic variants as instrumental variables to assess the causal relationships between risk factors and outcomes. This analysis involved genetically predicted PCOS (1,639 cases and 218,970 controls) and inflammatory proteins (14,824 participants of primarily European descent). Additionally, a two-step MR analysis was performed to quantify the proportion of the effect of serum metabolites-mediated inflammatory proteins on PCOS. The Inverse Variance Weighted (IVW) method, a statistical technique used within MR to combine data from multiple genetic variants, was used to estimate the causal effects. The IVW method revealed that the inflammatory proteins IFN-γ (p-value = 0.037, OR = 1.396, 95% CI = 1.020-1.910) and CCL7 (p-value = 0.033, OR = 1.294, 95% CI = 1.021-1.641) were associated with an increased risk of PCOS, while IL-6 (p-value = 0.015, OR = 0.678, 95% CI = 0.495-0.929) and MMP-10 (p-value = 0.025, OR = 0.753, 95% CI = 0.587-0.967) were associated with a decreased risk. No significant evidence suggested an effect of genetically predicted PCOS on inflammatory proteins. The serum metabolite X-11444 was found to mediate 5.44% (95% CI: 10.8-0.0383%) of the effect of MMP-10 on PCOS. This study not only introduces novel causal associations between inflammatory proteins and PCOS but also highlights the mediating role of serum metabolites in these associations. By applying MR, we were able to minimize confounding and reverse causality, offering robust insights into the biological mechanisms underlying PCOS. These findings advance the understanding of PCOS pathogenesis, particularly in relation to inflammatory pathways and serum metabolite interactions, and suggest potential therapeutic targets that could inform future clinical interventions aimed at mitigating inflammation-related PCOS risks.

Evaluation of multiple breast cancer polygenic risk score panels in women of Latin American heritage.

A substantial portion of the genetic predisposition for breast cancer is explained by multiple common genetic variants of relatively small effect. A subset of these variants, which have been identified mostly in individuals of European and Asian ancestry, have been combined to construct a polygenic risk score (PRS) to predict breast cancer risk, but the prediction accuracy of existing PRSs in Hispanic/Latinx individuals (H/L) remain relatively low. We assessed the performance of several existing PRS panels with and without addition of H/L specific variants among self-reported H/L women. PRS performance was evaluated using multivariable logistic regression and the area under the receiver operating characteristic curve (AUC). Both European and Asian PRSs performed worse in H/L samples compared to original reports. The best European PRS performed better than the best Asian PRS in pooled H/L samples. European PRSs had decreased performance with increasing Indigenous American (IA) ancestry while Asian PRSs had increased performance with increasing IA ancestry. The addition of 2 H/L SNPs increased performance for all PRSs, most notably in the samples with high IA ancestry and did not impact the performance of PRSs in individuals with lower IA ancestry. A single PRS that incorporates risk variants relevant to the multiple ancestral components of individuals from Latin America, instead of a set of ancestry specific panels, could be used in clinical practice. Results highlight the importance of population-specific discovery and suggest a straightforward approach to integrate ancestry specific variants into PRS for clinical application.

Genetics, Fitness, and Left Ventricular Remodelling: The Current State of Play.

Cardiorespiratory fitness (CRF) exists on a spectrum and is driven by a constellation of factors, including genetic and environmental differences. This results in wide interindividual variation in baseline CRF and the ability to improve CRF with regular endurance exercise training. As opposed to monogenic conditions, CRF is described as a complex genetic trait as it is believed to be influenced by multiple common genetic variants in addition to exogenous factors. Importantly, CRF is an independent predictor of morbidity and mortality, and so understanding the impact of genetic variation on CRF may provide insights into both human athletic performance and personalized risk assessment and prevention. Despite rapidly advancing technology, progress in this field has been restricted by small sample sizes and the limited number of genetic studies using the "gold standard" objective measure of peak oxygen consumption (VO2peak) for CRF assessment. In recent years, there has been increasing interest in the heritability of numerous parameters of cardiac structure and function and how this may relate to both normal cardiac physiology and disease pathology. Regular endurance training can result in exercise-induced cardiac remodelling, which manifests as balanced dilation of cardiac chambers and is associated with superior CRF. This results in a complex relationship between CRF, cardiac size, and exercise, and whether shared genetic pathways may influence this remains unknown. In this review we highlight recent and relevant studies into the genomic predictors of CRF with a unique emphasis on how this may relate to cardiac remodelling and human adaptation to endurance exercise.

Purkinje cell-specific deficiency in SEL1L-hrd1 endoplasmic reticulum-associated degradation causes progressive cerebellar ataxia in mice.

Recent studies have identified multiple genetic variants of SEL1L-HRD1 endoplasmic reticulum-associated degradation (ERAD) in humans with neurodevelopmental disorders and locomotor dysfunctions, including ataxia. However, the relevance and importance of SEL1L-HRD1 ERAD in the pathogenesis of ataxia remain unexplored. Here, we showed that SEL1L deficiency in Purkinje cells leads to early-onset progressive cerebellar ataxia with progressive loss of Purkinje cells with age. Mice with Purkinje cell-specific deletion of SEL1L (Sel1LPcp2Cre) exhibited motor dysfunction beginning around 9 weeks of age. Transmission electron microscopy analysis revealed dilated ER and fragmented nuclei in Purkinje cells of adult Sel1LPcp2Cre mice, indicative of altered ER homeostasis and cell death. Finally, loss of Purkinje cells was associated with a secondary neurodegeneration of granular cells, as well as robust activation of astrocytes and proliferation of microglia, in the cerebellums of Sel1LPcp2Cre mice. These data demonstrate the pathophysiological importance of SEL1L-HRD1 ERAD in Purkinje cells in the pathogenesis of cerebellar ataxia.

Genome-Wide Meta-Analysis Identifies Multiple Germline Genetic Variants Associated with Increased Risk of Follicular Lymphoma

Genome-Wide Meta-Analysis Identifies Multiple Germline Genetic Variants Associated with Increased Risk of Follicular Lymphoma

Predicting heart failure in cancer survivors: use of polygenic risk vs clinical score

Abstract Background The risk of heart failure (HF) is increased among cancer survivors, but predicting individual HF risk is difficult. Polygenic risk scores (PRS) for HF prediction summarize the combined effect of multiple genetic variants, specific to the individual. We sought to compare clinical HF prediction models with PRS in both cancer- and non-cancer populations. Methods Cancer and HF diagnoses were identified in the UK-Biobank from International Classification of Diseases (ICD)-10 codes. HF risk was calculated using the Atherosclerosis Risk in Communities score (ARIC-HF). PRS-HF was calculated using the Global Biobank Meta-analysis Initiative. The predictive performance of ARIC-HF and PRS-HF were compared using the area under the curve (AUC) in both cancer- and non-cancer populations. Results After excluding 2,644 participants with HF prior to consent, we identified 440,813 non-cancer participants (mean age 57 years, 53% female) and 43,720 cancer survivors (mean age 60 years, 65% female). Both ARIC-HF and PRS-HF were significant predictors for HF occurrence after adjustment for chronic kidney disease, overall health rating and total cholesterol level. The PRS-HF performed poorly in predicting HF among cancer (AUC: 0.552) and non-cancer populations (AUC: 0.571). However, the ARIC-HF predicted HF incidence in the non-cancer population (AUC: 0.806) and a reasonable performance among the cancer population (AUC: 0.748). Conclusions Prediction of HF occurrence in cancer survivors based on conventional risk factors is superior to PRS. However, both models demonstrate suboptimal discriminative capabilities in forecasting HF, emphasizing the imperative for the development of a cancer-specific HF predictive model.

Genetic inference and single cell expression analysis of potential targets in heart failure and breast cancer

BackgroundBreast cancer and heart failure are major public health issues globally, characterized by significant genetic heterogeneity and complex molecular mechanisms. This study aims to explore potential genetic targets in heart failure and breast cancer through combining genetic inference and single-cell expression analysis, and to assess the causal relationships of these targets using Mendelian randomization methods.MethodsWe first identified genetic variants associated with heart failure and breast cancer using genome-wide association study (GWAS) data. Subsequently, we analyzed the expression patterns of these genetic variants in different cell types through single-cell RNA sequencing technology. Furthermore, we utilized in vitro experiment to assess the effects of ITM2B on MCF7 using immunofluorescence.ResultsOur study identified multiple genetic variants associated with heart failure and breast cancer, showing specific expression patterns in heart and breast cells. The ITM2B gene is highly expressed in breast cancer. ITM2B shows the highest expression in T cells and the lowest expression in proliferating cells. Silencing the ITM2B gene can promote apoptosis and inhibit proliferation and migration of MCF7 breast cancer cells.ConclusionBy integrating genetic inference and single-cell expression analysis, this study revealed potential genetic targets in heart failure and breast cancer, and validated the causal effects of these targets using Mendelian randomization methods.

Rare variants and survival of patients with idiopathic pulmonary fibrosis.

The clinical course of idiopathic pulmonary fibrosis (IPF) is highly variable and unpredictable, with multiple genetic variants influencing IPF outcomes. Notably, rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in these patients. Here we assessed whether rare qualifying variants (QVs) in monogenic adult-onset pulmonary fibrosis (PF) genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in individuals carrying these QVs. We identified QVs in telomere and non-telomere genes linked to monogenic PF forms using whole-genome sequences (WGS) from 888 Pulmonary Fibrosis Foundation Patient Registry (PFFPR) individuals. We also derived a PRS for IPF (PRS-IPF) from 19 previously published common sentinel IPF variants. Using regression models, we then examined the mutual relationships of QVs and PRS-IPF and their association with survival. Validation of results was sought in WGS from an independent IPF study (PROFILE, n=472), and results from the two cohorts were meta-analyzed. Carriers of QVs in monogenic adult-onset PF genes, representing nearly 1 out of 6 IPF patients, were associated with lower PRS-IPF (Odds Ratio [OR]: 1.79; 95% Confidence Interval [CI]: 1.15-2.81; p=0.010) and shorter survival (Hazard Ratio [HR]: 1.53; 95% CI: 1.12-2.10; p=7.3×10-3). Notably, carriers of pathogenic variants at telomere genes showed the strongest association with survival (HR: 1.76; 95% CI: 1.13-2.76; p=0.013). The meta-analysis of the results showed a consistent direction of effect across both cohorts. We revealed the opposite effects of QVs and PRS-IPF on IPF survival. Thus, a distinct IPF molecular subtype might be defined by QVs in monogenic adult-onset PF genes. Assessing the carrier status for QVs and modelling PRS-IPF promises to further contribute to predicting disease progression among IPF patients.

Monitoring Calcium-Sensing Receptor (CaSR)-Induced Intracellular Calcium Flux Using an Indo-1 Flow Cytometry Assay.

The calcium-sensing receptor (CaSR) has a critical role in maintaining serum calcium concentrations within the normal physiological range, and mutations in the receptor, or components of its signaling and trafficking pathway, cause disorders of calcium homeostasis. Inactivating mutations cause neonatal severe hyperparathyroidism or familial hypocalciuric hypercalcemia (FHH), while gain-of-function mutations cause autosomal dominant hypocalcemia (ADH). Characterizing the functional impact of mutations of the CaSR, and components of the CaSR-signaling pathway, is clinically important to enable correct diagnoses of FHH and ADH, optimize management, and prevent inappropriate parathyroidectomy or vitamin D supplementation. CaSR signals predominantly by activating the G-alpha subunit-11 to mobilize calcium release from intracellular stores. Thus, measurement of CaSR-induced intracellular calcium (Ca2+i) signaling is the gold standard method to investigate the pathogenicity of CaSR genetic variants. This protocol describes a method to assess CaSR-induced Ca2+I signaling using the Indo-1 calcium indicator dye and flow cytometry. This method has been used to assess multiple genetic variants in CaSR and components of its signaling and trafficking pathway in HEK293 cells.

Leveraging large-scale datasets and single cell omics data to develop a polygenic score for cisplatin-induced ototoxicity.

Cisplatin-induced ototoxicity (CIO), characterized by irreversible and progressive bilateral hearing loss, is a prevalent adverse effect of cisplatin chemotherapy. Alongside clinical risk factors, genetic variants contribute to CIO and genome-wide association studies (GWAS) have highlighted the polygenicity of this adverse drug reaction. Polygenic scores (PGS), which integrate information from multiple genetic variants across the genome, offer a promising tool for the identification of individuals who are at higher risk for CIO. Integrating large-scale hearing loss GWAS data with single cell omics data holds potential to overcome limitations related to small sample sizes associated with CIO studies, enabling the creation of PGSs to predict CIO risk. We utilized a large-scale hearing loss GWAS and murine inner ear single nuclei RNA-sequencing (snRNA-seq) data to develop two polygenic scores: a hearing loss PGS (PGSHL) and a biologically informed PGS for CIO (PGSCIO). The PGSCIO included only variants which mapped to genes that were differentially expressed within cochlear cells that showed differential abundance in the murine snRNA-seq data post-cisplatin treatment. Evaluation of the association of these PGSs with CIO in our target CIO cohort revealed that PGSCIO demonstrated superior performance (P = 5.54 × 10- 5) relative to PGSHL (P = 2.93 × 10- 3). PGSCIO was also associated with CIO in our test cohort (P = 0.04), while the PGSHL did not show a significant association with CIO (P = 0.52). This study developed the first PGS for CIO using a large-scale hearing loss dataset and a biologically informed filter generated from cisplatin-treated murine inner ear snRNA-seq data. This innovative approach offers new avenues for developing PGSs for pharmacogenomic traits, which could contribute to the implementation of tailored therapeutic interventions. Further, our approach facilitated the identification of specific cochlear cells that may play critical roles in CIO. These novel insights will guide future research aimed at developing targeted therapeutic strategies to prevent CIO.

8481 A 32 Year Old Male With Recurrent Acute Pancreatits and Severe Hypertriglyceridemia: Importance of Considering Genetic Variants

Abstract Disclosure: M.F. Salazar Zelaya: None. J.D. Sibaja Jiménez: None. Background : Hypertriglyceridemia is a common medical scenario in daily practice, causing a variety of symptoms including recurrent episodes of acute pancreatits, which can be severe. Multiple genetic variants can lead to different spectrums of the disease. CLINICAL CASE: A 32 year old male police officer presented to our Endocrinology Outpatient Clinic with a history of long standing hypertriglyceridemia and six previous episodes of acute pancreatits, two in the last twelve months. Familiy history was negative for lipid disorders. The patient had adecuate adherence to diet and exercise as well to prescribed medications, which included Fenofibrate 250 mgs/day and Rosuvastatin 40 mgs/day. The patient denied consumption of alcoholic beverages. Recent abdominal ultrasound was reported without abnormalities. His lipid panel reported elevated triglycerides at 5831 mg/dl (n&amp;lt;150 mg/dl), Total Cholesterol normal at 147 (n&amp;lt;200 mg/dl), low HDL levels at 12 mg/dl (range 12-92 mg/dl) and direct LDL Cholesterol at 120 mg/dl. His TSH value was normal at 1.02 uUI/mL (range 0.55-4.78 uUI/mL). Creatinine level was normal at 0.81 mg/dl (range 0.7-1.3 mg/dl). Liver function tests were normal with AST level at 25 IU/L (range 13-39 IU/L) ALT levels at 22 IU/L (range 7-52 IU/L) and alcaline phosphatase at 62 IU/L (range 34-104 IU/L).His fasting glucose level were normal at 82 mg/dl (n&amp;lt;100 mg/dl). Due to a high Familial Chylomicronemia Syndrome clinical score (13 points) we proceeded with genetic analysis of this patient. Next Generation Sequencing for genes related with chylomicronemia (APOA5, APOC2, GPIHBP1,LMFI, LPL) was performed to determine gene sequence plus copy number variation.Two heterocigote variants were reported, both in the LPL gene. The first one: LPL (NM 000237.3) c.644&amp;gt;A;p.Gly215Glu heterozygous is a missense variant already reported in the literature, registered in ClinVar (ID 1522) and the Leiden Open Variation Database. This variant is classified as pathogenic according to criteria PS3, PM1, PP3, PP5 of the American College of Medical Genetics and Genomics. The second one: LPL (nm 000237.3): c.383C&amp;gt;A;p.Thr128Asn;heterozygous is also a missense variant which to the extent of our knowledge has previously been reported only once in the literature: ClinVar (ID 1520537). This variant is classified currently as of unknown clinical significance according to PM2 criteria. There is however and entry reported (PMID: 8778602) of another variant affecting the same codon (p.Thr128AIa) that is associated to chylomicronemia syndrome. Conclusion: In cases of severe hypertriglyceridemia, suspicion and determination of gene variants are of great importance nowadays as they could eventually guide treatment, given the availability in some countries (and currently pending FDA approval) of new pharmacological therapies such as apo C-III inhibitors. Presentation: 6/2/2024

8721 A Case of Congenital Hyperinsulinism Manifesting as Transient Hypoglycemia During Illness Due to Mosaic Variant of Unknown Significance in ABCC8

Abstract Disclosure: E.E. Bell-Sambataro: None. L. Mamilly: None. Background: Congenital hyperinsulinism (CHI) is characterized by inappropriate secretion of insulin during periods of low blood glucose. CHI can lead to significant complications such as seizures, developmental delays and neurologic damage. CHI can be caused by multiple genetic variants. The most common genetic etiologies are loss of function mutations in the genes ABCC8 and KCNJ11 encoding the pancreatic Beta (β)-cell ATP-sensitive potassium channel causing over secretion of insulin from the β-cells. We report a challenging pediatric case with a clinical presentation of CHI in an infant with a de novo mosaic ABCC8 gene variant of unknown significance manifesting only during times of illness. Clinical Case: A male infant born at 36 weeks gestational age was transferred to a tertiary center NICU secondary to seizure activity and hypoglycemia after the 24 hours of life with glucose levels as low as 32 mg/dL. His birth weight was normal and there was not maternal history of diabetes mellitus. The hypoglycemia persisted throughout the first week of life and required a glucose infusion rate of 11 mg/kg/min, without success in obtaining a critical sample. He had multiple seizures and MRI brain showed signs of hypoglycemic encephalopathy. Subsequently, he was weaned off IV dextrose and completed a 6 hour safety fast prior to discharge. Rapid genome testing resulted in a de novo, mosaic variant of unknown significance in ABCC8 (C.3622G&amp;gt;A resulting in amino acid substitution p.Glu1208Lys). His family reported significant but transient hypoglycemia during times of illness. At the age of 11 months, he was hospitalized for significant hypoglycemia during an episode of acute gastroenteritis and was treated with dextrose-containing fluids for 36 hours. A subsequent diagnostic fasting study resulted in hypoglycemia within 5.5 hours with capillary glucose of 49 mg/dL. At the time of hypoglycemia, beta hydroxybutyrate was inappropriately low at 0.78 mm, insulin level was suppressed &amp;lt;2 mcIU/mL. Glucagon (30 mcg/Kg) was administered after the initial sample was drawn with a significant increase in glucose from 49 mg/dL to 103 mg/dL. Based on the positive glucagon response and low serum ketone, the clinical diagnosis of CHI was made and diazoxide was initiated while awaiting other results. After the second dose of diazoxide, all glucose levels remained above 80 mg/dL. He was sent home on a continuous glucose monitor and diazoxide. Conclusion: CHI can occur due to autosomal recessive or autosomal dominant ABCC8 loss-of-function mutations of which more than half are not responsive to diazoxide. In this case report, we describe the diagnosis of hyperinsulinemic hypoglycemia in an infant with an ABCC8 variant classified with unknown significance. We describe a good initial response to diazoxide in normalizing blood glucose levels in this infant. Presentation: 6/2/2024

In search of the genetic variants of human sex ratio at birth: was Fisher wrong about sex ratio evolution?

The human sex ratio (fraction of males) at birth is close to 0.5 at the population level, an observation commonly explained by Fisher's principle. However, past human studies yielded conflicting results regarding the existence of sex ratio-influencing mutations-a prerequisite to Fisher's principle, raising the question of whether the nearly even population sex ratio is instead dictated by the random X/Y chromosome segregation in male meiosis. Here we show that, because a person's offspring sex ratio (OSR) has an enormous measurement error, a gigantic sample is required to detect OSR-influencing genetic variants. Conducting a UK Biobank-based genome-wide association study that is more powerful than previous studies, we detect an OSR-associated genetic variant, which awaits verification in independent samples. Given the abysmal precision in measuring OSR, it is unsurprising that the estimated heritability of OSR is effectively zero. We further show that OSR's estimated heritability would remain virtually zero even if OSR is as genetically variable as the highly heritable human standing height. These analyses, along with simulations of human sex ratio evolution under selection, demonstrate the compatibility of the observed genetic architecture of human OSR with Fisher's principle and render it plausible that multiple OSR-influencing genetic variants segregate among humans.

Pharmacogenetic Considerations in Beta-Blocker Therapy

Pharmacogenetic testing offers a promising approach to personalizing beta-blocker therapy which is used for a variety of diseases, such as heart failure, myocardial infarction and migraine prophylaxis. The genetic variability in the metabolism and response to beta-blockers such as metoprolol can significantly influence treatment outcomes. Understanding these genetic differences can help optimize therapy and minimize adverse effects. A brief summary of the current guideline and recommendations: Approximately 0.3-6.5% (depending on their ancestry) of patients are CYP2D6 poor metabolizers. CYP2D6 Poor Metabolizers have significantly decreased metabolism of metoprolol, leading to increased drug concentration and a higher risk of adverse effects. The highest dose of metoprolol that patients can tolerate may be lower in CYP2D6 poor metabolizers compared to those that are non-poor CYP2D6 metabolizers. Current evidence is insufficient to support routine clinical testing or therapeutic adjustments for other genes affecting beta-blocker pharmacodynamics, such as ADRB1, ADRB2, ADRA2C, and GRK5. Future research should consider the combined effects of multiple genetic variants (e.g., polygenic risk scores) rather than focusing solely on single-gene associations.

AN INTEGRATIVE NETWORK-BASED MEDIATION MODEL (NMM) TO ESTIMATE MULTIPLE GENETIC EFFECTS ON OUTCOMES MEDIATED BY FUNCTIONAL CONNECTIVITY.

Functional connectivity of the brain, characterized by interconnected neural circuits across functional networks, is a cutting-edge feature in neuroimaging. It has the potential to mediate the effect of genetic variants on behavioral outcomes or diseases. Existing mediation analysis methods can evaluate the impact of genetics and brain structurefunction on cognitive behavior or disorders, but they tend to be limited to single genetic variants or univariate mediators, without considering cumulative genetic effects and the complex matrix and group and network structures of functional connectivity. To address this gap, the paper presents an integrative network-based mediation model (NMM) that estimates the effect of multiple genetic variants on behavioral outcomes or diseases mediated by functional connectivity. The model incorporates group information of inter-regions at broad network level and imposes low-rank and sparse assumptions to reflect the complex structures of functional connectivity and selecting network mediators simultaneously. We adopt block coordinate descent algorithm to implement a fast and efficient solution to our model. Simulation results indicate the efficacy of the model in selecting active mediators and reducing bias in effect estimation. With application to the Human Connectome Project Youth Adult (HCP-YA) study of 493 young adults, two genetic variants (rs769448 and rs769449) on the APOE4 gene are identified that lead to deficits in functional connectivity within visual networks and fluid intelligence.

Use of Polygenic Risk Score for Prediction of Heart Failure in Cancer Survivors

BackgroundThe risk for heart failure (HF) is increased among cancer survivors, but predicting individual HF risk is difficult. Polygenic risk scores (PRS) for HF prediction summarize the combined effects of multiple genetic variants specific to the individual. ObjectivesThe aim of this study was to compare clinical HF prediction models with PRS in both cancer and noncancer populations. MethodsCancer and HF diagnoses were identified using International Classification of Diseases-10th Revision codes. HF risk was calculated using the ARIC (Atherosclerosis Risk in Communities) HF score (ARIC-HF). The PRS for HF (PRS-HF) was calculated according to the Global Biobank Meta-analysis Initiative. The predictive performance of the ARIC-HF and PRS-HF was compared using the area under the curve (AUC) in both cancer and noncancer populations. ResultsAfter excluding 2,644 participants with HF prior to consent, 440,813 participants without cancer (mean age 57 years, 53% women) and 43,720 cancer survivors (mean age 60 years, 65% women) were identified at baseline. Both the ARIC-HF and PRS-HF were significant predictors of incident HF after adjustment for chronic kidney disease, overall health rating, and total cholesterol. The PRS-HF performed poorly in predicting HF among cancer (AUC: 0.552; 95% CI: 0.539-0.564) and noncancer (AUC: 0.561; 95% CI: 0.556-0.566) populations. However, the ARIC-HF predicted incident HF in the noncancer population (AUC: 0.804; 95% CI: 0.800-0.808) and provided acceptable performance among cancer survivors (AUC: 0.748; 95% CI: 0.737-0.758). ConclusionsThe prediction of HF on the basis of conventional risk factors using the ARIC-HF score is superior compared to the PRS, in cancer survivors, and especially among the noncancer population.

Genetic characterization of vancomycin-resistant Enterococcus faecium isolates from neutropenic patients in Tunisia: spread of the pandemic CC17 clone associated with high genetic diversity in Tn1546-like structures.

In Tunisia, limited research has focused on characterizing clinical vancomycin-resistant Enterococcus faecium (VREfm). This study aimed to bridge this knowledge gap by molecular characterization of antimicrobial resistance, determining the genetic elements mediating vancomycin-resistance, and whole-genome sequencing of one representative VREfm isolate. Over 6 years (2011-2016), a total of eighty VREfm isolates responsible for infection or colonization were identified from hospitalized patients, with the incidence rate increasing from 2% in 2011 to 27% in 2016. All of these strains harbored the vanA gene. The screening for antimicrobial resistance genes revealed the predominance of ermB, tetM, and aac(6')-Ie-aph(2'')-Ia genes and 81.2% of strains harbored the Tn1545. Pulsed-field gel electrophoresis identified seven clusters, with two major clusters (belonging to ST117 and ST80) persisting throughout the study period. Seven Tn1546 types were detected, with type VI (truncated transposon) being the most prevalent (57.5%). Whole-genome sequencing revealed a 3 028 373bp chromosome and five plasmids. Mobile genetic elements and a type I CRISPR-cas locus were identified. Notably, the vanA gene was carried by the classic Tn1546 transposon with ISL3 insertion on a rep17pRUM plasmid. A concerning trend in the prevalence of VREfm essentially attributed to CC17 persistence and to horizontal transfer of multiple genetic variants of truncated vanA-Tn1546.

Movement disorders related to antidiabetic medications: a real-world pharmacovigilance study

BackgroundDiabetic Mellitus (DM) has progressively emerged as a worldwide health problem, leading to the widespread deployment of antidiabetic drugs as the primary therapy in the global population. The incidence of diabetes medications-related movement disorders (drMD) is noteworthy but underestimated by clinical practitioners. Research design and MethodsIn order to address the incidence of drMD in DM patients and realize the serious outcomes associated with drMD, we conducted a real-world pharmacovigilance study of 612,043 DM patients using the FDA Adverse Event Reporting System (FAERS) database from January 2004 to September 2023. Reporting Odd Ratio (ROR) was calculated to reflect the risk of drMD. A multivariable logistic regression analysis was employed to adjust crude ROR with the mixed factors including age, sex and various antidiabetic treatments. Afterward, a Mendelian Randomization (MR) study was performed to elucidate the underlying genetic correlation between the genetically proxied targets of antidiabetic drugs and motor disorders. ResultsAmong 11,729 cases of motor adverse events in DM patients, six categories of drMD were significantly associated with DM medications. Noticeably, metformin was revealed to drastically increase the incidence of parkinsonism (adjusted ROR:3.97; 95 %CI (3.03, 5.19), p = 5.68e-24), bradykinesia (adjusted ROR:1.69; 95 %CI (1.07,2.59), p = 0.02) and irregular hyperkinesia, including chorea, choreoathetosis and athetosis. Insulin/insulin analogues and GLP-1 analogues presented notably higher odds of tremor: the adjusted ROR (aROR) of insulin and GLP-1 analogue is respectively 1.24 (95 %CI (1.15,1.34), p = 2.51e-08) and 1.78 (95 %CI (1.65,1.91), p = 5.64e-54). The combined therapeutic effects of multiple genetic variants of metformin, especially AMP-activated protein kinase (AMPK) were markedly linked to a greater likelihood of developing secondary parkinsonism (OR:10.816, p = 0.049) according to MR analyses. ConclusionThe use of antidiabetic medications was significantly related to an increased incidence of movement disorders in DM patients. Moreover, MR analyses provided further genetic evidence for the pharmacovigilance study. This comprehensive investigation might help physicians recognize neurological adverse events associated with antidiabetic treatments and administer effective interventions.