Unusual BA222-like strains of Rotavirus A (Sedoreoviridae: Rotavirus: Rotavirus A): molecular and genetic analysis based on all genome segments.

INTRODUCTION: Rotavirus infection is the major cause of severe dehydrating diarrhea requiring hospitalization in young children worldwide. Due to their segmented genome, rotaviruses are capable of gene reassortment, which makes the emergence and spread of genetically novel strains possible. The purpose of this study was to search for unusual rotaviruses circulating in Nizhny Novgorod in 2021‒2023 and their molecular genetic characterization based on all genome segments. MATERIALS AND METHODS: Rotavirus-positive stool samples of children were examined by PCR genotyping and electrophoresis in PAAG. cDNA fragments of each of the 11 genes (VP1‒VP4, VP6, VP7, NSP1‒NSP5), 570 to 850 nucleotide pairs in length were sequenced for the selected strains. The phylogenetic analysis was performed in the MEGA X program. RESULTS: In the study period 2021‒2023, 11 G[P] combinations with a predominance of G3P[8] (59.5%) were identified. Six atypical Rotavirus А (RVA) strains were identified: 2 strains of the G2P[4] genotype (G2-P[4]-I2-R2-C2-M2-A3-N2-T3-E2-H3, G2-P[4]-I2-R2-C2-M2-A3-N2-T3-E3-H2) and 4 G3P[9] strains (all strains had the genotype G3-P[9]-I2-R2-C2-M2-A3-N2-T3-E3-H3). Phylogenetic analysis based on all genes showed an evolutionary relationship between rotaviruses similar to rotaviruses of cats and dogs (BA222-like) and unusual strains of the G2P[4] genotype, for which a mixed combination of genotypes was identified and characterized for the first time. DISCUSSION: The results obtained expand the understanding of the diversity of reassortant RVAs, as well as complement the data on the genotypic structure of the rotavirus population in Nizhny Novgorod. CONCLUSION: The wide genetic diversity of reassortant RVA can help rotaviruses overcome the immunological pressure provided by natural and vaccine-induced immunity. In this regard, to control the emergence of new variants and assess changes in the virulence of rotaviruses after reassortment processes, continuous molecular monitoring for circulating RVA is necessary.

Genomic Validation in the UK Biobank Cohort Suggests a Role of C8B and MFG-E8 in the Pathogenesis of Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is a severe facial pain disease of uncertain pathophysiology and unclear genetic background. Although recent research has reported a more important role of genetic factors in TN pathogenesis, few candidate genes have been proposed to date. The present study aimed to identify independent genetic variants in the protein-coding genes associated with TN. We focused on genes previously linked to TN based on the results of four proteomic studies conducted by our research team. The goal was to validate these findings on the genetic level to enhance our understanding of the role of genetics in TN. The study is based on the participants from UK Biobank cohort. Following quality control, 175 independent single nucleotide polymorphisms (SNPs) in 17 genes were selected. The study sample comprised of diagnosed TN cases (N = 555) and randomly matched controls (N = 6245) based on specific criteria. Two SNPs corresponding to C8B rs706484 [odds ratio (OR) (95% confidence interval (CI)): 1.357 (1.158-1.590); p: 0.00016] and MFG-E8 rs2015495 [OR (95% CI): 1.313 (1.134-1.521); p: 0.00028] showed significant positive association with TN, indicating a positive effect of the SNP alleles on gene expression and disease risk. Interestingly, both SNPs are Expression Quantitative Trait Loci (eQTLs), and are associated with changes in the expression activity of their corresponding gene. Our findings suggest novel genetic associations between C8B, a key component of the complement system, and MFG-E8, which plays a role in regulating neuroinflammation, in relation to TN. The identified genetic variations may help explain why some individuals develop TN while others do not, indicating a potential genetic predisposition to the condition.

PathVar: A Customisable NGS Variant Calling Algorithm Implicates Novel Candidate Genes and Pathways in Hemiplegic Migraine.

The exponential growth of next-generation sequencing (NGS) data requires innovative bioinformatics approaches to unravel the genetic underpinnings of diseases. Hemiplegic migraine (HM), a debilitating neurological disorder with a genetic basis, is one such condition that warrants further investigation. Notably, the genetic heterogeneity of HM is underscored by the fact that approximately two-thirds of patients lack pathogenic variants in the known causal ion channel genes. In this context, we have developed PathVar, a novel bioinformatics algorithm that harnesses publicly available tools and software for pathogenic variant discovery in NGS data. PathVar integrates a suite of tools, including HaplotypeCaller from the Genome Analysis Toolkit (GATK) for variant calling, Variant Effect Predictor (VEP) and ANNOVAR for variant annotation, and TAPES for assigning the American College of Medical Genetics and Genomics (ACMG) pathogenicity labels. Applying PathVar to whole exome sequencing data from 184 HM patients, we detected 648 variants that are probably pathogenic in multiple patients. Moreover, we have identified several candidate genes for HM, many of which cluster around the Rho GTPases pathway. Future research can leverage PathVar to generate high quality, candidate pathogenic variants, which may enhance our understanding of HM and other complex diseases.

Polymorphic variation of the DEFB1 gene might contribute to the development of ankylosing spondylitis: a preliminary study.

BACKGROUND: Ankylosing spondylitis (AS) is an inflammatory disease that affects the spine and can cause peripheral arthritis, enthesitis, and dactylitis, as well as extra-articular manifestations such as uveitis and inflammatory bowel disease. ß-Defensins are antimicrobial peptides involved in the activation and regulation of several immune cell types that may influence the inflammatory response in AS. The aim was to analyze the association and interaction of two functional variants of the DEFB1 gene in AS patients, and their role with inflammatory markers. METHODS AND RESULTS: The rs11362 and rs1800972 variants were genotyped using TaqMan probes in Mexican AS patients and controls. C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) were quantified. SPSS software was used for statistical analysis and multifactor dimensionality reduction (MDR) for interactions. The AA and GG genotypes were associated with AS risk in the age- and sex-adjusted model (OR = 6.89, P = 0.008 and OR = 3.43, P = 0.046, respectively); furthermore, the A-G haplotype showed a significant association with AS risk (OR = 2.94, P = 0.012). ESR and CRP were elevated in carriers of the AA genotype compared to the GA and GG genotypes of the rs11362 variant (20.89 ± 9.78 vs. 5.63 ± 4.61 and 4.10 ± 2.65 mm/h, P < 0.0001; and 10.92 ± 14.09 vs. 2.14 ± 2.02 and 2.15 ± 2.13 mg/L, P < 0.001, respectively). Using the MDR method, strong interactions of the rs11362 variant with sex were identified in the adjusted and unadjusted models. CONCLUSIONS: These results suggest that the DEFB1 gene may play a key role in AS pathogenesis.

Genomic instability in ovarian cancer: Through the lens of single nucleotide polymorphisms.

Ovarian cancer (OC) is the deadliest gynecological malignancy among all female reproductive cancers. It is characterized by high mortality rate and poor prognosis. Genomic instability caused by mutations, single nucleotide polymorphisms (SNPs), copy number variations (CNVs), microsatellite instability (MSI), and chromosomal instability (CIN) are associated with OC predisposition. SNPs, which are highly prevalent in the general population, show a greater relative risk contribution, particularly in sporadic cancers. Understanding OC etiology in terms of genetic basis can increase the use of molecular diagnostics and provide promising approaches for designing novel treatment modalities. This will help deliver personalized medicine to OC patients, which may soon be within reach. Given the pivotal impact of SNPs in cancers, the primary emphasis of this review is to shed light on their prevalence in key caretaker genes that closely monitor genomic integrity, viz., DNA damage response, repair, cell cycle checkpoints, telomerase maintenance, and apoptosis and their clinical implications in OC. We highlight the current challenges faced in different SNP-based studies. Various computational methods and bioinformatic tools employed to predict the functional impact of SNPs have also been comprehensively reviewed concerning OC research. Overall, this review identifies that variants in the DDR and HRR pathways are the most studied, implying their critical role in the disease. Conversely, variants in other pathways, such as NHEJ, MMR, cell cycle, apoptosis, telomere maintenance, and PARP genes, have been explored the least.

Causal links between blood inflammation markers and postherpetic neuralgia risk: insights from a two-sample Mendelian randomization study.

Introduction: Previous studies have suggested an association between blood inflammation-related factors and postherpetic neuralgia. However, the causal relationship between blood inflammation-related factors and postherpetic neuralgia remains unclear. Methods: We employed a bidirectional Two-sample Mendelian randomization (MR) analysis to explore the causal relationship between blood inflammation-related factors and postherpetic neuralgia. The instrumental variables were obtained from a large Genome-wide association study (GWAS) meta-analysis dataset of European descent. The instrumental variables of the blood inflammation-related factors come from the database numbers GCST004420 to GCST004460 and GCST90029070. Postherpetic neuralgia has 195,191 samples with a total of 16,380,406 single nucleotide polymorphisms (SNPs). MR analyses were performed using inverse-variance weighted, MR-Egger, and weighted median methods. Results: The MR results revealed a significant causal effect of Macrophage Inflammatory Protein 1 Beta (MIP1ß) on reducing the risk of postherpetic neuralgia (95%CI = 0.492-0.991, p = 0.044). Additionally, higher levels of interleukin (IL)-10 (95%CI = 0.973-0.998, p = 0.019) and IL-12p70 (95%CI = 0.973-0.997, p = 0.013) were associated with a lower risk of postherpetic neuralgia. Other inflammatory markers showed no significant causal relationship with this condition. Conclusion: This study identifies MIP1ß, IL-10, and IL-12p70 as potential therapeutic targets for preventing or treating postherpetic neuralgia, underscoring the need for further research in this area.

Exploration of pharmacokinetic differences between East Asians and Caucasians: insights from pharmacokinetic studies in healthy subjects.

Interethnic differences in the pharmacokinetics of drugs result from a complex interplay of environmental, genetic, and demographic factors. Identifying ethnic differences in pharmacokinetics is challenging due to the multifaceted contributions of the underlying factors. To address these challenges, this paper reviews 9 pharmacokinetic studies meeting the following criteria: (A) Conducted at Seoul National University Hospital from 2013 to 2022 as a single-center study. (B) Pharmacokinetic studies involving both East Asians (Korean, Japanese, or Chinese) and Caucasians. (C) Study drugs were administered orally. (D) Raw data was provided for reanalysis. This retrospective analysis aimed to investigate the existence of ethnic differences in drug exposure and understand the possible factors contributing to these variabilities. Pharmacokinetic, demographic, and clinical laboratory test data were analyzed to assess potential pharmacokinetic differences between East Asians and Caucasians. This assessment involved calculating the geometric mean ratio of dose-normalized area under the time-concentration curve (AUC) and dose- and weight-normalized AUC, along with their 90% confidence intervals. Additionally, pharmacological information, including metabolic pathways, was gathered from the investigational brochure or the respective country's drug label. Among 9 studies, 4 studies demonstrated approximately 1.3 to 1.8 times higher drug exposure in East Asians compared to Caucasians. These drugs were primarily eliminated through hepatic metabolism, with less than 5% excreted unchanged in the urine. Two drugs were metabolized by hepatic cytochrome P450 3A4, one by glutathione S-transferase, and specific metabolic pathways for another drug were not identified. Further research is needed to assess the causes of ethnic variability in these drugs.

Genetic variants in patients with multiple arterial aneurysms.

PURPOSE: The aim of this study was to identify causal genetic variants in patients with multiple arterial aneurysms. METHODS: From a total cohort of 3107 patients diagnosed with an arterial aneurysm from 2006 to 2016, patients with known hereditary connective tissue diseases, vasculitis, or other arterial pathologies (n = 918) were excluded. Of the remaining cohort (n = 2189), patients with at least 4 aneurysms at different arterial locations (n = 143) were included. Nine blood samples of respective patients were available and derived from the institutional vascular biomaterial bank, and analyzed by whole exome sequencing (WES). Possible candidate variants were selected based on in silico predictions: (I) Truncating variants or (II) Variants that were classified as likely pathogenic (SIFT score < 0.05 or PolyPhen score > 0.9) and with low (< 0.001) or unknown gnomAD allele frequency. The human genome databases GeneCards and MalaCards were used to correlate the variants with regard to possible associations with vascular diseases. RESULTS: A total of 24 variants in 23 different genes associated with vascular diseases were detected in the cohort. One patient with eight aneurysms was heterozygous for a variant in SMAD3, for which pathogenic variants are phenotypically associated with Loeys-Dietz syndrome 3. A heterozygous variant in TNXB was found in a patient with five aneurysms. Homozygous or compound heterozygous pathogenic variants in this gene are associated with Ehlers-Danlos syndrome (classical-like). Another patient with six aneurysms carried two heterozygous TET2 variants together with a heterozygous PPM1D variant. Pathogenic variants in these genes are associated with clonal hematopoiesis of indeterminate potential (CHIP), a known risk factor for cardiovascular disease. CONCLUSION: All nine patients in this study carried variants in genes associated with vascular diseases. Current knowledge of the specific variants is insufficient to classify them as pathogenic at the present time, underlining the need for a better understanding of the consequences of genetic variants. WES should be considered for patients with multiple arterial aneurysms to detect germline variants and to improve clinical management for the individual and family members.

Proteomic networks and related genetic variants associated with smoking and chronic obstructive pulmonary disease.

BACKGROUND: Studies have identified individual blood biomarkers associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. However, complex diseases such as COPD typically involve changes in multiple molecules with interconnections that may not be captured when considering single molecular features. METHODS: Leveraging proteomic data from 3,173 COPDGene Non-Hispanic White (NHW) and African American (AA) participants, we applied sparse multiple canonical correlation network analysis (SmCCNet) to 4,776 proteins assayed on the SomaScan v4.0 platform to derive sparse networks of proteins associated with current vs. former smoking status, airflow obstruction, and emphysema quantitated from high-resolution computed tomography scans. We then used NetSHy, a dimension reduction technique leveraging network topology, to produce summary scores of each proteomic network, referred to as NetSHy scores. We next performed a genome-wide association study (GWAS) to identify variants associated with the NetSHy scores, or network quantitative trait loci (nQTLs). Finally, we evaluated the replicability of the networks in an independent cohort, SPIROMICS. RESULTS: We identified networks of 13 to 104 proteins for each phenotype and exposure in NHW and AA, and the derived NetSHy scores significantly associated with the variable of interests. Networks included known (sRAGE, ALPP, MIP1) and novel molecules (CA10, CPB1, HIS3, PXDN) and interactions involved in COPD pathogenesis. We observed 7 nQTL loci associated with NetSHy scores, 4 of which remained after conditional analysis. Networks for smoking status and emphysema, but not airflow obstruction, demonstrated a high degree of replicability across race groups and cohorts. CONCLUSIONS: In this work, we apply state-of-the-art molecular network generation and summarization approaches to proteomic data from COPDGene participants to uncover protein networks associated with COPD phenotypes. We further identify genetic associations with networks. This work discovers protein networks containing known and novel proteins and protein interactions associated with clinically relevant COPD phenotypes across race groups and cohorts.

Causal relationship between modifiable risk factors and knee osteoarthritis: a Mendelian randomization study.

Background: While several risk factors for knee osteoarthritis (KOA) have been recognized, the pathogenesis of KOA and the causal relationship between modifiable risk factors and KOA in genetic epidemiology remain unclear. This study aimed to determine the causal relationship between KOA and its risk factors. Methods: Data were obtained from published Genome-Wide Association study (GWAS) databases. A two-sample Mendelian randomization (MR) analysis was performed with genetic variants associated with risk factors as instrumental variables and KOA as outcome. First, inverse variance weighting was used as the main MR analysis method, and then a series of sensitivity analyses were conducted to comprehensively evaluate the causal relationship between them. Results: Univariate forward MR analysis revealed that genetically predicted hypothyroidism, hyperthyroidism/thyrotoxicosis, educational level, income level, metabolic syndrome (MS), essential hypertension, height, hot drink temperature, diet (abstaining from sugar-sweetened or wheat products), and psychological and psychiatric disorders (stress, depression, and anxiety) were causally associated with KOA. Reverse MR exhibits a causal association between KOA and educational attainment. Multivariate MR analysis adjusted for the inclusion of potential mediators, such as body mass index (BMI), smoking, alcohol consumption, and sex, exhibited some variation in causal effects. However, hyperthyroidism/thyrotoxicosis had a significant causal effect on KOA, and there was good evidence that height, hypothyroidism, educational level, psychological and psychiatric disorders (stress, depression, and anxiety), and abstaining from wheat products had an independent causal relationship. The mediating effect of BMI as a mediator was also identified. Conclusion: This study used MR to validate the causal relationship between KOA and its risk factors, providing new insights for preventing and treating KOA in clinical practice and for developing public health policies.

The association between overweight and varying degrees of obesity with subjective well-being and depressive symptoms: A two sample Mendelian randomization study.

OBJECTIVE: This study utilized the Mendelian randomization (MR) method to elucidate the causal relationship between genetically predicted overweight and various degrees of obesity with depressive symptoms and subjective well-being (SWB). METHODS: Pooled genome-wide association studies (GWAS) data for overweight (BMI ≥ 25 kg/m2), class 1 obesity (BMI ≥ 30 kg/m2), and class 2 obesity (BMI ≥ 35 kg/m2) were used as exposures. Summary GWAS data for depressive symptoms and SWB were used as outcomes. Multiple MR methods, primarily inverse-variance weighted (IVW), were applied, and sensitivity analyses were conducted to assess heterogeneity and pleiotropy. RESULTS: The MR analysis provided evidence that genetically predicted overweight(IVW ß = 0.033; 95 %CI 0.008-0.057; P = 0.010) and class 1 obesity(IVW ß = -0.033; 95 %CI -0.047 - -0.020; P < 0.001) were causally associated with increased depressive symptoms. Genetically predicted class 2 obesity(IVW ß = 1.428; 95 %CI 1.193-1.710; P < 0.001) were associated with reduced SWB. There was no strong evidence of a causal association between genetically predicted overweight and class 1 obesity with SWB. Similarly, genetically predicted class 2 and class 3 obesity did not show strong evidence of a causal association with depressive symptoms. Sensitivity analysis revealed relationships of a similar magnitude. CONCLUSION: This genetically informed MR study suggests that Overweight and class 1 obesity may causally increased depressive symptoms but not decrease SWB. In contrast, class 2 obesity may causally decrease SWB but not increase depressive symptoms.

Genomic and phenotypic landscapes of X-linked hereditary hearing loss in the Chinese population.

BACKGROUND: Hearing loss (HL) is the most common sensory birth deficit worldwide, with causative variants in more than 150 genes. However, the etiological contribution and clinical manifestations of X-linked inheritance in HL remain unclear within the Chinese HL population. In this study, we focused on X-linked hereditary HL and aimed to assess its contribution to hereditary HL and identify the genotype-phenotype relationship. METHODS: We performed a molecular epidemiological investigation of X-linked hereditary HL based on next-generation sequencing and third-generation sequencing in 3646 unrelated patients with HL. We also discussed the clinical features associated with X-linked non-syndromic HL-related genes based on a review of the literature. RESULTS: We obtained a diagnostic rate of 52.72% (1922/3646) among our patients; the aggregate contribution of HL caused by genes on the X chromosome in this cohort was ~ 1.14% (22/1922), and POU3F4 variants caused ~ 59% (13/22) of these cases. We found that X-linked HL was congenital or began during childhood in all cases, with representative audiological profiles or typical cochlear malformations in certain genes. Genotypic and phenotypic analyses showed that causative variants in PRPS1 and AIFM1 were mainly of the missense type, suggesting that phenotypic variability was correlated with the different effects that the replaced residues exert on structure and function. Variations in SMPX causing truncation of the protein product were associated with DFNX4, which resulted in typical audiological profiles before and after the age of 10 years, whereas nontruncated proteins typically led to distal myopathy. No phenotypic differences were identified in patients carrying POU3F4 or COL4A6 variants. CONCLUSIONS: Our work constitutes a preliminary evaluation of the molecular contribution of X-linked genes in heritable HL (~ 1.14%). The 15 novel variants reported here expand the mutational spectrum of these genes. Analysis of the genotype-phenotype relationship is valuable for X-linked HL precise diagnostics and genetic counseling. Elucidation of the pathogenic mechanisms and audiological profiles of HL can also guide choices regarding treatment modalities.

Review of pharmacogenetics of antiseizure medications: focusing on genetic variants of mechanistic targets.

Antiseizure medications (ASMs) play a central role in seizure management, however, unpredictability in the response to treatment persists, even among patients with similar seizure manifestations and clinical backgrounds. An objective biomarker capable of reliably predicting the response to ASMs would profoundly impact epilepsy treatment. Presently, clinicians rely on a trial-and-error approach when selecting ASMs, a time-consuming process that can result in delays in receiving alternative non-pharmacological therapies such as a ketogenetic diet, epilepsy surgery, and neuromodulation therapies. Pharmacogenetic studies investigating the correlation between ASMs and genetic variants regarding their mechanistic targets offer promise in predicting the response to treatment. Sodium channel subunit genes have been extensively studied along with other ion channels and receptors as targets, however, the results have been conflicting, possibly due to methodological disparities including inconsistent definitions of drug response, variations in ASM combinations, and diversity of genetic variants/genes studied. Nonetheless, these studies underscore the potential effect of genetic variants on the mechanism of ASMs and consequently the prediction of treatment response. Recent advances in sequencing technology have led to the generation of large genetic datasets, which may be able to enhance the predictive accuracy of the response to ASMs.

Genetic variants associated with response to anti-CGRP monoclonal antibody therapy in a chronic migraine Han Chinese population.

BACKGROUND: Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have emerged as promising therapeutic options for the treatment of chronic migraine. However, treatment response varies considerably among individuals, suggesting a potential role for genetic factors. This study aimed to identify genetic variants affecting the efficacy of anti-CGRP monoclonal antibody therapy in chronic migraine among the Han Chinese population in Taiwan to enhance treatment precision and to understand the genetic architecture of migraine. METHODS: We conducted a quantitative trait locus (QTL) association study in patients with chronic migraines from a tertiary medical center in Taiwan using the Taiwan Precision Medicine Array Chip. The patients received fremanezumab or galcanezumab for at least 12 weeks. Treatment efficacy was assessed based on the improvement rate in monthly migraine days. Genetic variants were identified, and their associations with treatment efficacy were examined through quantitative trait loci analysis, linkage disequilibrium studies, and functional annotations using the Gene Ontology database. RESULTS: Six single nucleotide polymorphisms (SNPs) relative variants were significantly associated with anti-CGRP therapy response (p < 1 × 10- 7): rs116870564, rs75244870, rs56216870, rs12938101, rs74655790, and rs149540851. These variants are located in or near genes, including LRRC4C, ATAD2B, and OXR1, which are involved in neuronal development, DNA-dependent ATPase activity, and oxidation-reduction processes, respectively. The rs116870564 variant in LRRC4C showed the strongest association (ß = -0.551, p = 6.65 × 10- 9). The functional impact of these variants is attributed to their regulatory effects on gene expression, which are influenced by intron splicing regulation, transcription factors, and changes in chromatin structure. CONCLUSION: The identification of key genetic markers associated with response to anti-CGRP therapy emphasizes the importance of genetic variability in treatment efficacy. This could lead to more personalized chronic migraine management strategies and tailored therapeutic approaches based on individual genetic profiles. Further research in larger, diverse populations is warranted to validate these findings and refine our understanding of the role of CGRP in chronic migraine pathophysiology. TRIAL REGISTRATION: Not applicable.

Cancer associated variant enrichment CAVE, a gene agnostic approach to identify low burden variants in chronic lymphocytic leukemia.

Intratumoral heterogeneity is an important clinical challenge because low burden clones expressing specific genetic alterations drive therapeutic resistance mechanisms. We have developed CAVE (cancer-associated variant enrichment), a gene-agnostic computational tool to identify specific enrichment of low-burden cancer driver variants in next-generation sequencing (NGS) data. For this study, CAVE was applied to TP53 in chronic lymphocytic leukemia (CLL) as a cancer model. Indeed, as TP53 mutations are part of treatment decision-making algorithms and low-burden variants are frequent, there is a need to distinguish true variants from background noise. Recommendations have been published for reliable calling of low-VAF variants of TP53 in CLL and the assessment of the background noise for each platform is essential for the quality of the testing. CAVE is able to detect specific enrichment of low-burden variants starting at variant allele frequencies (VAFs) as low as 0.3%. In silico TP53 dependent and independent analyses confirmed the true driver nature of all these variants. Orthogonal validation using either ddPCR or NGS analyses of follow-up samples confirmed variant identification. CAVE can be easily deployed in any cancer-related NGS workflow to detect the enrichment of low-burden variants of clinical interest.

The role of lipid species in Alzheimer's disease onset: A comprehensive Mendelian randomization analysis.

BACKGROUND: Alzheimer's disease (AD) remains a significant global health challenge, with its etiology intricately linked to a variety of genetic and environmental factors. Among these, lipid metabolism has been hypothesized to play a crucial role, though the causal pathways remain inadequately elucidated. This study aims to employ Mendelian Randomization (MR) to unravel the potential causal relationships between a comprehensive array of lipid species and the risk of developing AD. METHODS: Utilizing a two-sample MR framework, we analyzed data from genome-wide association studies (GWAS) encompassing 487,511 individuals of European descent. A total of 179 lipid species across 13 lipid categories were investigated for their causal association with AD. Genetic variants serving as instrumental variables (IVs) were carefully selected based on stringent criteria to ensure validity. The statistical analyses, including inverse variance weighting (IVW), weighted median-based estimation, and sensitivity analyses, were conducted using the R software environment. RESULTS: Our findings reveal a significant causal relationship between ten specific lipid species and the risk of AD. Notably, certain lipids such as Sterol ester (27:1/15:0) and Phosphatidylcholine (16:0_22:4) exhibited a protective effect against AD, as evidenced by their inverse correlation with the disease's risk. Additionally, a reciprocal analysis suggested a negative causal impact of AD on the levels of certain Triacylglycerol species. The integrity of our results was reinforced by sensitivity analyses, including the MR Egger intercept test, indicating the absence of horizontal pleiotropy and confirming the reliability of our findings. CONCLUSIONS: This study substantiates the causal link between specific lipid species and Alzheimer's disease, highlighting the complex interplay between lipid metabolism and AD pathogenesis. The identified lipid biomarkers offer new insights into the disease's etiology and potential therapeutic targets. Furthermore, our rigorous methodological approach demonstrates the utility of MR in disentangling the causal relationships in complex diseases.

Causal association between 1400 metabolites and dilated cardiomyopathy: a bidirectional two-sample Mendelian randomization analysis.

Background: Dilated cardiomyopathy (DCM) is a cardiac disease with a poor prognosis of unclear etiology. Previous studies have shown that metabolism is associated with DCM. This study investigates the causal relationship between 1400 metabolites and DCM using a two-sample Mendelian randomization (MR) approach. Methods: The study utilized data from the OpenGWAS database, comprising 355,381 Europeans, including 1,444 DCM cases. A total of 1,400 metabolites were evaluated for their causal association with DCM. Instrumental variables (IVs) were selected based on genetic variation and used in the MR analysis. The primary analysis method was inverse variance weighting (IVW), supplemented by weighted median-based estimation and sensitivity analyses. Results: Of the 1,400 metabolites analyzed, 52 were identified as causally associated with DCM. The analysis revealed both positively and negatively correlated metabolites with DCM risk. Notable findings include the positive correlation of Tryptophan betaine and 5-methyluridine (ribothymidine) levels, and an inverse association of Myristoleate and Erythronate levels with DCM. Conclusions: The study provides significant insights into the metabolites potentially involved in the pathogenesis of DCM. These findings could pave the way for new therapeutic strategies and biomarker identification in DCM management.

The Association Between Breast Cancer Predisposing Genetic Variants and Multifocal, Multicentric Breast Cancer.

BACKGROUND: Breast-conserving surgery is often discouraged in BRCA gene carriers with early onset breast cancer. The genetic variant carrier breast cancers are more likely to be multifocal or multicentric (MFMC). PATIENTS AND METHOD: This retrospective study includes newly diagnosed patients with breast cancer undergoing genetic testing between 2010 and 2021 within the Johns Hopkins Regional Health System. After excluding patients who received neoadjuvant chemotherapy or stage IV breast cancers, patients were divided into two groups: those who tested positive for a variant recognized by the National Comprehensive Cancer Network as predisposing the patient to breast cancer (ATM, BRCA1, BRCA2, CHEK2, NF1, PALB2, RAD51C, RAD51D, and TP53) and those who tested negative. Pathologic features of the tumors were compared, focusing on evidence for MFMC disease, defined as more than one malignant foci more than 5 mm apart. RESULTS: Among the 282 eligible cases, 69 (24%) were positive for a genetic variant. The variant carriers were younger at diagnosis (p < 0.001), more likely to have invasive ductal carcinoma (p = 0.03), more likely to have undergone mastectomy (p = 0.03), and more likely to have a grade 3 cancer (p = 0.003). Variant carriers were not more likely to have MFMC disease (28% vs. 22%, p = 0.4). A positive genetic variant was not a predictor of MFMC within the entire cohort [odds ratio (OR):1.3, 95% confidence interval (CI) 0.6-2.6, p = 0.5). CONCLUSION: Genetic variant carrier cancers are not more likely to be MCMF than sporadic cancers.

Genetic and Functional Studies of Patients with Thyroid Dyshormonogenesis and Defects in the TSH Receptor (TSHR).

Genetic defects in the TSH receptor (TSHR) can cause poor thyroid differentiation (thyroid dysgenesis) and/or thyroid malfunction (thyroid dyshormonogenesis). The phenotype spectrum is wide: from severe congenital hypothyroidism to mild hyperthyrotropinemia. Over 250 TSHR variants have been published, many uncharacterized in vitro. We aimed to genetically characterize patients with thyroid dyshormonogenesis with TSHR defects and to study in vitro the effect of the genetic variants to establish the genotype-phenotype relationship. Pediatric patients with thyroid dyshormonogenesis (160 patients, Catalan CH neonatal screening program, confirmation TSH range: 18.4-100 mIU/L), were analyzed by a high-throughput gene panel. In vitro studies measuring the TSH-dependent cAMP-response-element activation were performed. Five patients with mild or severe thyroid dyshormonogenesis presented six TSHR variants, two unpublished. Each variant showed a different in vitro functional profile that was totally or partially deleterious. Depending on the genotype, some of the variants showed partial deficiency in both genotypes, whereas others presented a different effect. In conclusion, the percentage of patients with thyroid dyshormonogenesis and candidate variants in TSHR is 3.13%. Our in vitro studies contributed to the confirmation of the pathogenicity of the variants and highlighted the importance of studying the effect of the patient's genotype for a correct diagnostic confirmation.

Prevalence of Fabry Disease in Patients on Dialysis in France.

Numerous prevalence studies on Fabry disease (FD, OMIM #301500) have been conducted in dialysis populations across the world with variable and controversial results. The FABRYDIAL study aimed to estimate the prevalence of FD in patients aged 18 to 74 years on chronic dialysis in France. This cross-sectional study was conducted in patients undergoing dialysis. One hundred and twenty-four dialysis centers participated. Patients with proven causes of nephropathy unrelated to FD were excluded. Alpha-galactosidase A activity was assayed in men, and both α-galactosidase A and lyso-Gb3 were assayed in women from dried blood spots. GLA gene sequencing was performed in case of abnormal values. If a variant was identified, a diagnosis validation committee was consulted for adjudication. Among the 6032 targeted patients, 3088 were included (73.6% of the eligible patients). Biochemical results were available for 2815 (1721 men and 1094 women). A genetic variant of GLA was identified in five patients: a benign c.937G>T/p.(Asp313Tyr) variant in two individuals, a likely benign c.427G>A/(p.Ala143Thr) variant, a likely benign c.416A>G/(p.Asn139Ser) variant, and a pathogenic c.1185dupG/p.Phe396Glyfs variant. Among the screened patients, the prevalence was 0.058% [0.010;0.328] in males, 0% [0.000;0.350] in females, and 0.035% [0.006;0.201] when both genders were pooled. Among all patients aged 18-74 years undergoing dialysis without a previously known cause of nephropathy unlinked to FD, the prevalence was 0.028% [0.006;0.121]. The prevalence of FD in a cohort of French dialysis patients was low. However, considering the prognostic impact of earlier diagnosis, signs of FD should be sought in patients with nephropathies of uncertain etiology.