Genetic Variation In Individuals Research Articles

Genetic variation in individuals from a population of the minimalist bacteriophage Merri-merri-uth nyilam marra-natj driving evolution of the virus.

Bacteriophages (phages) are viruses that prey on bacteria. This study sampled natural phage populations to test the hypothesis that untapped genetic variation within a population can be the basis for the selection of phages to diversify their host-range. Sampling of a freshwater site revealed two populations of the phage Merri-merri-uth nyilam marra-natj (phage MMNM), differing by a variant residue (Val134Ala) in the baseplate protein MMNM_26. This sequence variation modulated bacterial killing in plaques, and further evolution of the phages on a semi-permissive bacterial host led to a new generation of phages with more diverse phenotypes in killing the bacterium Klebsiella pneumoniae.

Systematic identification of genotype-dependent enhancer variants in eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a rare atopic disorder associated with esophageal dysfunction, including difficulty swallowing, food impaction, and inflammation, that develops in a small subset of people with food allergies. Genome-wide association studies (GWASs) have identified 9 independent EoE risk loci reaching genome-wide significance (p<5×10-8) and 27 additional loci of suggestive significance (5×10-8<p<1×10-5). In the current study, we perform linkage disequilibrium (LD) expansion of these loci to nominate a set of 531 variants that are potentially causal. To systematically interrogate the gene regulatory activity of these variants, we designed a massively parallel reporter assay (MPRA) containing the alleles of each variant within their genomic sequence context cloned into a GFP reporter library. Analysis of reporter gene expression in TE-7, HaCaT, and Jurkat cells revealed cell-type-specific gene regulation. We identify 32 allelic enhancer variants, representing 6 genome-wide significant EoE loci and 7 suggestive EoE loci, that regulate reporter gene expression in a genotype-dependent manner in at least one cellular context. By annotating these variants with expression quantitative trait loci (eQTL) and chromatin looping data in related tissues and cell types, we identify putative target genes affected by genetic variation in individuals with EoE. Transcription factor enrichment analyses reveal possible roles for cell-type-specific regulators, including GATA3. Our approach reduces the large set of EoE-associated variants to a set of 32 with allelic regulatory activity, providing functional insights into the effects of genetic variation in this disease.

Association of dyslipidemia with single nucleotide polymorphisms of the cholesteryl ester transfer protein gene and cardiovascular disease risk factors in a highly admixed population

Cardiovascular diseases (CVD) are major causes of mortality worldwide, leading to premature deaths, loss of quality of life, and extensive socioeconomic impacts. Alterations in normal plasma lipid concentrations comprise important risk factors associated with CVD due to mechanisms involved in the pathophysiology of atherosclerosis. Genetic markers such as single nucleotide polymorphisms (SNPs) are known to be associated with lipid metabolism, including variants in the cholesteryl ester transfer protein (CETP) gene. Thus, the study's objective was to assess the relationship among lipid profile, socioeconomic and demographic characteristics, health status, inflammatory biomarkers, and CETP genetic variants in individuals living in a highly admixed population. The study comprises an analysis of observational cross-sectional data representative at the population level from a highly admixed population, encompassing 901 individuals from three age groups (adolescents, adults, and older adults). Socioeconomic, demographic, health, and lifestyle characteristics were collected using semi-structured questionnaires. In addition, biochemical markers and lipid profiles were obtained from individuals' blood samples. After DNA extraction, genotyping, and quality control according to Affymetrix's guidelines, information on 15 SNPs in the CETP gene was available for 707 individuals. Lipid profile and CVD risk factors were evaluated by principal component analysis (PCA), and associations between lipid traits and those factors were assessed through multiple linear regression and logistic regression. There were low linear correlations between lipid profile and other individuals' characteristics. Two principal components were responsible for 80.8% of the total variance, and there were minor differences in lipid profiles among individuals in different age groups. Non-HDL-c, total cholesterol, and LDL-c had the highest loadings in the first PC, and triacylglycerols, VLDL-c and HDL-c were responsible for a major part of the loading in the second PC;, whilst HDL-c and LDL-c/HDL-c ratio were significant in the third PC. In addition, there were minor differences between groups of individuals with or without dyslipidemia regarding inflammatory biomarkers (IL-1β, IL- 6, IL-10, TNF-α, CRP, and MCP-1). Being overweight, insulin resistance, and lifestyle characteristics (calories from solid fat, added sugar, alcohol and sodium, leisure physical activity, and smoking) were strong predictors of lipid traits, especially HDL-c and dyslipidemia (p<0.05). The CETP SNPs rs7499892 and rs12691052, rs291044, and rs80180245 were significantly associated with HDL-c (p<0.05), and their inclusion in the multiple linear regression model increased its accuracy (adjusted R2 rose from 0.12 to 0.18). This study identified correlations between lipid traits and other CVD risk factors. In addition, similar lipid and inflammatory profiles across age groups in the population suggested that adolescents might already present a significant risk for developing cardiovascular diseases in the population. The risk can be primarily attributed to decreased HDL-c concentrations, which appear to be influenced by genetic factors, as evidenced by associations between SNPs in the CETP gene and HDL-c concentrations, as well as potential gene-diet interactions. Our findings underscore the significant impact of genetic and lifestyle factors on lipid profile within admixed populations in developing countries.

Benchmarking datasets for assembly-based variant calling using high-fidelity long reads

BackgroundRecent advances in long-read sequencing technologies have enabled accurate identification of all genetic variants in individuals or cells; this procedure is known as variant calling. However, benchmarking studies on variant calling using different long-read sequencing technologies are still lacking.ResultsWe used two Caenorhabditis elegans strains to measure several variant calling metrics. These two strains shared true-positive genetic variants that were introduced during strain generation. In addition, both strains contained common and distinguishable variants induced by DNA damage, possibly leading to false-positive estimation. We obtained accurate and noisy long reads from both strains using high-fidelity (HiFi) and continuous long-read (CLR) sequencing platforms, and compared the variant calling performance of the two platforms. HiFi identified a 1.65-fold higher number of true-positive variants on average, with 60% fewer false-positive variants, than CLR did. We also compared read-based and assembly-based variant calling methods in combination with subsampling of various sequencing depths and demonstrated that variant calling after genome assembly was particularly effective for detection of large insertions, even with 10 × sequencing depth of accurate long-read sequencing data.ConclusionsBy directly comparing the two long-read sequencing technologies, we demonstrated that variant calling after genome assembly with 10 × or more depth of accurate long-read sequencing data allowed reliable detection of true-positive variants. Considering the high cost of HiFi sequencing, we herein propose appropriate methodologies for performing cost-effective and high-quality variant calling: 10 × assembly-based variant calling. The results of the present study may facilitate the development of methods for identifying all genetic variants at the population level.

Machine Learning for Brain Imaging Genomics Methods: A Review

In the past decade, multimodal neuroimaging and genomic techniques have been increasingly developed. As an interdisciplinary topic, brain imaging genomics is devoted to evaluating and characterizing genetic variants in individuals that influence phenotypic measures derived from structural and functional brain imaging. This technique is capable of revealing the complex mechanisms by macroscopic intermediates from the genetic level to cognition and psychiatric disorders in humans. It is well known that machine learning is a powerful tool in the data-driven association studies, which can fully utilize priori knowledge (intercorrelated structure information among imaging and genetic data) for association modelling. In addition, the association study is able to find the association between risk genes and brain structure or function so that a better mechanistic understanding of behaviors or disordered brain functions is explored. In this paper, the related background and fundamental work in imaging genomics are first reviewed. Then, we show the univariate learning approaches for association analysis, summarize the main idea and modelling in genetic-imaging association studies based on multivariate machine learning, and present methods for joint association analysis and outcome prediction. Finally, this paper discusses some prospects for future work.

Burden of Rare Genetic Variants in Spontaneous Coronary Artery Dissection With High-risk Features

The emerging genetic basis of spontaneous coronary artery dissection (SCAD) has been defined as both partially complex and monogenic in some patients, involving variants predominantly in genes known to underlie vascular connective tissue diseases (CTDs). The effect of these genetic influences has not been defined in high-risk SCAD phenotypes, and the identification of a high-risk subgroup of individuals may help to guide clinical genetic evaluations of SCAD. To identify and quantify the burden of rare genetic variation in individuals with SCAD with high-risk clinical features. Whole-exome sequencing (WES) was performed for subsequent case-control association analyses and individual variant annotation among individuals with high-risk SCAD. Genetic variants were annotated for pathogenicity by in-silico analysis of genes previously defined by sequencing for vascular CTDs and/or SCAD, as well as genes prioritized by genome-wide association study (GWAS) and colocalization of arterial expression quantitative trait loci. Unbiased genome-wide association analysis of the WES data was performed by comparing aggregated variants in individuals with SCAD to healthy matched controls or the Genome Aggregation Database (gnomAD). This study was conducted at a tertiary care center. Individuals in the Canadian SCAD Registry genetics study with a high-risk SCAD phenotype were selected and defined as peripartum SCAD, recurrent SCAD, or SCAD in an individual with family history of arteriopathy. Burden of genetic variants defined by DNA sequencing in individuals with high-risk SCAD. This study included a total of 336 participants (mean [SD] age, 53.0 [9.5] years; 301 female participants [90%]). Variants in vascular CTD genes were identified in 17.0% of individuals (16 of 94) with high-risk SCAD and were enriched (OR, 2.6; 95% CI, 1.6-4.2; P = 7.8 × 10-4) as compared with gnomAD, with leading significant signals in COL3A1 (OR, 13.4; 95% CI, 4.9-36.2; P = 2.8 × 10-4) and Loeys-Dietz syndrome genes (OR, 7.9; 95% CI, 2.9-21.2; P = 2.0 × 10-3). Variants in GWAS-prioritized genes, observed in 6.4% of individuals (6 of 94) with high-risk SCAD, were also enriched (OR, 3.6; 95% CI, 1.6-8.2; P = 7.4 × 10-3). Variants annotated as likely pathogenic or pathogenic occurred in 4 individuals, in the COL3A1, TGFBR2, and ADAMTSL4 genes. Genome-wide aggregated variant testing identified novel associations with peripartum SCAD. In this genetic study, approximately 1 in 5 individuals with a high-risk SCAD phenotype harbored a rare genetic variant in genes currently implicated for SCAD. Genetic screening in this subgroup of individuals presenting with SCAD may be considered.

Genetic Susceptibility and Mechanisms Underlying the Pathogenesis of Anthracycline-Associated Cardiotoxicity.

Anthracyclines are chemotherapeutic agents widely used to treat a variety of cancers, and these drugs have revolutionized our management of cancer patients. The dose-dependent cardiotoxicity of anthracyclines, however, remains one of the leading causes of chemotherapy treatment-associated mortality in cancer survivors. Patient threshold doses leading to anthracycline-induced cardiotoxicity (AIC) are highly variable among affected patients. This variability is largely ascribed to genetic variants in individuals' genomes. Here, we briefly discuss the prevailing mechanisms underlying the pathogenesis of AIC, and then, we review the genetic variants, mostly identified through human genetic approaches and identified in cancer survivors. The identification of all genetic susceptibilities and elucidation of underlying mechanisms of AIC can help improve upfront risk prediction assessment for potentially severe cardiotoxicity disease and provide valuable insights into the understanding of AIC pathophysiology, which can be further leveraged to develop targeted pharmacogenetic therapies for those at high risk.

Fibrillar Collagen Variants in Spontaneous Coronary Artery Dissection

Spontaneous coronary artery dissection (SCAD) is an increasingly recognized nonatherosclerotic cause of acute myocardial infarction enriched among individuals with early-onset myocardial infarction but is of unclear etiology. To assess which genes contribute to the development of SCAD. To prioritize genes influencing risk for SCAD, whole-exome sequencing was performed among individuals with SCAD in the discovery and replication cohorts from a tertiary care hospital outpatient specialty clinic, and gene set enrichment analyses were also performed for disruptive coding variants. All patients were sequentially enrolled beginning July 2013. Aggregate prevalence of rare disruptive variants for prioritized gene sets was compared between individuals with SCAD with population-based controls comprising 46 468 UK Biobank participants with whole-exome sequencing. Complementary mice models were used for in vivo validation. Analysis took place between June 2020 and January 2021. The frequency and identity of rare genetic variants in individuals with SCAD. Of 130 patients, 109 (83.8%) were female (26 of 32 [81.2%] in the discovery cohort and 83 of 98 [84.7%] in the replication cohort) with mean (SD) age at first SCAD event of 48.41 (8.76) years in the discovery cohort and 47.74 (10.09) years in the replication cohort. Across all patients with SCAD, rare disruptive variants were found within 10 collagen genes (COL3A1, COL5A1, COL4A1, COL6A1, COL5A2, COL12A1, COL4A5, COL1A1, COL1A2, and COL27A1) were 17-fold (P = 1.5 × 10-9) enriched among individuals with SCAD compared with a background of 2506 constrained genes expressed in coronary artery. Furthermore, compared with individuals from the UK Biobank, individuals with SCAD were 1.75-fold (P = .04) more likely to carry disruptive rare variants within fibrillar collagen genes. Complementary mice models haploinsufficient for Col3a1 or Col5a1, the 2 most common collagen gene variants identified in SCAD cases, demonstrated increased risk of arterial dissection and increased size of arterial diameters especially in female mice, with resulting changes in collagen fibril organization and diameter. Unbiased gene discovery in patients with SCAD with independent human and murine validation highlights the role of the extracellular matrix dysfunction in SCAD.

Abstract 11049: Rare Genetic Variants in Individuals with Low ASCVD Risk and Hard Chd or High Coronary Artery Disease: Multi-Ethnic Study of Atherosclerosis

Introduction: Even though various risk estimators are widely used to predict atherosclerosis from subclinical levels to hard CHD, there is a remarkable proportion of low-risk individuals with inordinately high coronary artery calcification (CAC) or with hard CHD events. Rare pathogenic variants (&lt;0.1%) in the atherosclerosis gene panel with larger effect sizes may predispose low-risk individuals to develop atherosclerosis. Hypothesis: There are rare pathogenic variants in the atherosclerosis gene panel in low-ASCVD-risk individuals with high CAC scores or hard CHD events than low-risk individuals with a CAC score of zero or no events. Methods: The MESA whole-genome sequencing data (2000-02) was evaluated to capture variants in 224 atherosclerosis-related genes. Coding variants with a frequency of &lt;0.1% in each racial/ethnic group and damaging effects were assessed by the ClinVar and ACMG-AMP guidelines for pathogenicity. Participants with an ASCVD score of &lt;7.5% were defined as low risk. Two different case groups were defined based on (1) hard CHD events and (2) CAC scores higher than the 90 th percentile of age, sex, and race-adjusted reference scores. Associated control groups were age-, sex-, and race-matched participants with no CHD events or zero CAC score. Results: A total of 159 cases with high CAC and 1256 matched controls were evaluated within the low-risk group. In the case group, there were three rare, likely pathogenic variants ( LDLR c.681C&gt;G, p.D227E and c.2026G&gt;A, p.G676S; and AHI1 c.2168G&gt;A, p.R723Q ) . None of these variants were observed in the control group. A total of 86 cases had a hard CHD event, among whom two had rare, likely pathogenic variants ( KCNQ1 c.517G&gt;A, p.A173T and LDLR c.1201C&gt;G, p.L401V). None of the 1546 controls had these variants. The LDLR c.1201C&gt;G variant is currently a variant of uncertain significance that would be likely pathogenic with the assumption of genotype-phenotype specificity [pathogenicity supporting criterion 4]. Conclusions: We observed five likely pathogenic variants in atherosclerosis-related genes in low-risk individuals for ASCVD who had high CAC scores or hard CHD events. Rare variants with large effect sizes may unravel the missed risk prediction of a common trait like atherosclerosis.

16 Identification of Structural Variants Associated with Mastitis in Holstein Dairy Cows Using Whole Genome Sequencing and RNA-sequencing

Abstract For the dairy industry, animal welfare and economic viability are key factors in determining the long-term sustainability of the industry. One challenge in lactating dairy cows is mastitis, as there are significant costs associated with each mastitis case due to treatment, milk loss, and potential cow culling. Differentially expressed (DE) genes, DE mRNA isoforms and DE long non-coding RNA (lncRNA) candidates were previously identified by our group between healthy and mastitic samples from six Holstein dairy cows. In total, 7 candidate genes, 5 mRNA isoforms and 4 lncRNA were targeted as they play an important role due to their association with mastitis or the immune system. The aim of the current research is to identify new structural variants in the transcriptome of these previously identified potential candidates using RNA-Sequencing. These structural variants could occur in both coding and intergenic regions of the genome and potentially impact the amino acid that is transcribed, creating a new functional or non-functional protein. In addition, whole genome sequencing (WGS) analysis was performed using hair samples collected from ten Holstein dairy cows (first lactation). Five of these animals had no previous reports of mastitis and five animals had at least one report of mastitis in her lifespan. The WGS results will be used to identify additional structural variants, especially within introns, of the previously identified candidates that could cause a genetic variation in individuals and an association to their susceptibility to mastitis disease.

Disruption of MAP7D1 Gene Function Increases the Risk of Doxorubicin-Induced Cardiomyopathy and Heart Failure.

Doxorubicin is a cornerstone chemotherapeutic drug widely used to treat various cancers; its dose-dependent cardiomyopathy, however, is one of the leading causes of treatment-associated mortality in cancer survivors. Patients' threshold doses leading to doxorubicin-induced cardiomyopathy (DIC) and heart failure are highly variable, mostly due to genetic variations in individuals' genomes. However, genetic susceptibility to DIC remains largely unidentified. Here, we combined a genetic approach in the zebrafish (Danio rerio) animal model with a genome-wide association study (GWAS) in humans to identify genetic susceptibility to DIC and heart failure. We firstly reported the cardiac and skeletal muscle-specific expression and sarcomeric localization of the microtubule-associated protein 7 domain-containing protein 1b (Map7d1b) in zebrafish, followed by expression validation in mice. We then revealed that disruption of the map7d1b gene function exaggerated DIC effects in adult zebrafish. Mechanistically, the exacerbated DIC are likely conveyed by impaired autophagic degradation and elevated protein aggregation. Lastly, we identified 2 MAP7D1 gene variants associated with cardiac functional decline and heart failure in cancer patients who received doxorubicin therapy. Together, this study identifies MAP7D1 as a clinically relevant susceptibility gene to DIC and heart failure, providing useful information to stratify cancer patients with a high risk of incurring severe cardiomyopathy and heart failure after receiving chemotherapy.

The first insight into the genetic structure of the population of modern Serbia

The complete understanding of the genomic contribution to complex traits, diseases, and response to treatments, as well as genomic medicine application to the well-being of all humans will be achieved through the global variome that encompasses fine-scale genetic diversity. Despite significant efforts in recent years, uneven representation still characterizes genomic resources and among the underrepresented European populations are the Western Balkans including the Serbian population. Our research addresses this gap and presents the first ever targeted sequencing dataset of variants in clinically relevant genes. By measuring population differentiation and applying the Principal Component and Admixture analysis we demonstrated that the Serbian population differs little from other European populations, yet we identified several novel and more frequent variants that appear as its unique genetic determinants. We explored thoroughly the functional impact of frequent variants and its correlation with the health burden of the population of Serbia based on a sample of 144 individuals. Our variants catalogue improves the understanding of genetics of modern Serbia, contributes to research on ancestry, and aids in improvements of well-being and health equity. In addition, this resource may also be applicable in neighboring regions and valuable in worldwide functional analyses of genetic variants in individuals of European descent.

Study on the association of &lt;i&gt;SLC2A9&lt;/i&gt; rs16890979 with gout in 410 Vietnamese individuals

Gout is a common form of inflammatory arthritis caused by crystallization of acid uric in the joints. The development of gout is not only triggered by environmental factors but also by genetic variation of individuals. In this study, the association between the variation SLC2A9 rs16890979 and gout was investigated. Total DNA was extracted from 410 blood samples of 163 gout patients and 247 age-matched healthy controls. Genotypes of SLC2A9 rs16890979 were obtained using PCR-RFLP. Chi-Square test was used to test whether allele distribution of rs16890979 followed Hardy-Weinberg Equilibrium (HWE). Associations of the clinical characteristics between gout patient and control groups were assessed using Mann-Whitney U. Chi-Square test or Fisher’s exact test was used to check four models (additive, recessive, dominant, co-dominant) for association of rs16890979 with gout. The obtained results showed that the allele distribution of SLC2A9 rs16890979 was in accordance with HWE (p &gt; 0.05). Clinical characteristics such as triglyceride and creatinine were significantly different between gout patient and control groups. However, there was no association of rs16890979 with the risk of gout in Vietnamese population. Further study with a larger sample size should be implemented to confirm our results regarding the association of SLC2A9 rs16890979 with gout in the Vietnamese population. This study would help enrich the knowledge about the effects of hereditary factors on gout disease in the Vietnamese population.

A model-based cost-effectiveness analysis of pharmacogenomic panel testing in cardiovascular disease management: preemptive, reactive, or none?

PurposePharmacogenomics (PGx) studies how inherited genetic variations in individuals affect drug absorption, distribution, and metabolism. PGx panel testing can potentially help improve efficiency and accuracy in individualizing therapy. This study compared the cost-effectiveness between preemptive PGx panel testing, reactive PGx panel testing and usual care (no testing) in cardiovascular disease management.MethodsWe developed a decision analytic model from the US payer’s perspective for a hypothetical cohort of 10,000 patients ≥45 years old, using a short-term decision tree and long-term Markov model. The testing panel included the following gene–drug pairs: CYP2C19–clopidogrel, CYP2C9/VKORC1–warfarin, and SLCO1B1–statins with 30 test-return days. Costs were reported in 2019 US dollars and effectiveness was measured in quality-adjusted life years (QALYs). The primary outcome was incremental cost-effectiveness ratio (ICER = ΔCost/ΔQALY), assuming 3% discount rate for costs and QALYs. Scenario and probabilistic sensitivity analyses were performed to assess the impact of demographics, risk level, and follow-up timeframe.ResultsPreemptive testing was found to be cost-effective compared with usual care (ICER $86,227/QALY) at the willingness-to-pay threshold of $100,000/QALY while reactive testing was not (ICER $148,726/QALY). Sensitivity analyses suggested that our cost-effectiveness results were sensitive to longer follow-up, and the age group 45–64 years.ConclusionCompared with usual care, preemptive PGx panel testing was cost-effective in cardiovascular disease management.

The Influence of Chromosomal Polymorphism on Embryo Development and Embryonic Molecular Karyotype in Preimplantation Genetic Testing for Chromosomal Translocation.

Traditionally, chromosomal polymorphisms (CPMs) are normal genetic variants in individuals with no phenotypic variations. However, some studies have shown that CPM is related to reproductive diseases. We explored the influence of CPM on embryonic development and molecular karyotype in chromosomal translocation (CT) patients undergoing preimplantation genetic testing (PGT) between February 2013 and May 2019. Twenty-six cases with CPM and 56 controls with normal chromosomes were included. Furthermore, a 1:4 match pair analysis by female age included 39 cases with CTCPM and 185 controls with CT. There was no statistical difference in fertilization rate (78.48% vs. 78.33%), cleavage rate on Day 3 (90.32% vs. 89.16%), blastocyst rate (60.00% vs. 60.80%), and the high-quality blastocyst rate (36.31% vs. 35.22%) between CPM and normal chromosomes. The high-quality blastocyst rate of CTCPM was significantly lower than that for CT (26.78% vs. 38.89%). Moreover, there was no statistical difference in fertilization rate (70.65% vs. 70.37%), cleavage rate on Day 3 (88.67% vs. 89.53%), and blastocyst rate (48.48% vs. 53.17%) between CTCPM and CT. In addition, one CTCPM spouse had a lower high-quality blastocyst rate, especially of males with CTCPM. Abnormal embryo rates of CTCPM were significantly higher than those for CT (78.64% vs. 68.93%). Abnormal embryo rates were higher in both CTCPM and CPM paternal carriers with CT partners, respectively. For CT, CTCPM may have an impact on the high-quality blastocyst rate and embryonic molecular karyotype, especially in male patients. Patients with CTCPM are relatively rare, but this population would benefit from being explored using a larger sample size.

Genetic Polymorphisms and the Efficacy of Platinum-Based Chemotherapy: Review.

Previous studies have indicated that genetic variations in individuals may result in changes in gene expression and amino acids. The effect of these changes may lead to different responses to platinum-based chemotherapy. A vast response rate interval and a short survival rate indicate that the efficacy and efficiency of the selection of chemotherapy have not been optimized. This article aims to illustrate the potential relationship of various genetic polymorphisms in response to platinum-based chemotherapy for several types of cancer. This review was conducted using articles from the last three- and five-year periods (2014–2019) that use gene polymorphism and its relationship to the efficacy of platinum-based chemotherapy as their theme. A total of 26 out of 488 relevant articles were included based on specific criteria. Through various mechanisms, genes, including ERCC1, ERCC2/XPD, XPC, XPA, XRCC1, APE-1, PARP1, OGG1, ABCC2, MRP, GSTP1, GSTM1, GSTT1, MATE1, and OCT2, have been associated with patient response to platinum-based chemotherapy. We conclude that genetic polymorphism analysis is recommended for the management of cancer so that each patient can be administered therapy based on his or her genetic profile to achieve an effective and efficient outcome.

Neurological disorder-associated genetic variants in individuals with psychogenic nonepileptic seizures

Psychogenic nonepileptic seizures (PNES) are diagnosed in approximately 30% of patients referred to tertiary care epilepsy centers. Little is known about the molecular pathology of PNES, much less about possible underlying genetic factors. We generated whole-exome sequencing and whole-genome genotyping data to identify rare, pathogenic (P) or likely pathogenic (LP) variants in 102 individuals with PNES and 448 individuals with focal (FE) or generalized (GE) epilepsy. Variants were classified for all individuals based on the ACMG-AMP 2015 guidelines. For research purposes only, we considered genes associated with neurological or psychiatric disorders as candidate genes for PNES. We observe in this first genetic investigation of PNES that six (5.88%) individuals with PNES without coexistent epilepsy carry P/LP variants (deletions at 10q11.22-q11.23, 10q23.1-q23.2, distal 16p11.2, and 17p13.3, and nonsynonymous variants in NSD1 and GABRA5). Notably, the burden of P/LP variants among the individuals with PNES was similar and not significantly different to the burden observed in the individuals with FE (3.05%) or GE (1.82%) (PNES vs. FE vs. GE (3 × 2 χ2), P = 0.30; PNES vs. epilepsy (2 × 2 χ2), P = 0.14). The presence of variants in genes associated with monogenic forms of neurological and psychiatric disorders in individuals with PNES shows that genetic factors are likely to play a role in PNES or its comorbidities in a subset of individuals. Future large-scale genetic research studies are needed to further corroborate these interesting findings in PNES.

PCV10 A MODEL-Based Cost-Effectiveness Analysis of Pharmacogenomic Panel Testing in Cardiovascular Disease Management: Preemptive, Reactive or NONE?

The field of pharmacogenomics (PGx) studies how inherited genetic variations in individuals affect drug absorption, distribution and metabolism in a patient body. PGx panel testing can potentially help improve efficiency and accuracy in individualizing therapy. However, the cost-effectiveness of PGx panel testing strategies regarding the timing of the tests has not been assessed. This study aims to compare the cost-effectiveness between preemptive PGx testing, reactive PGx testing and usual care (no PGx testing) in cardiovascular disease management. We developed a decision analytic model that composed of a short-term decision tree and life-time Markov model to compare the three testing strategies. The study sample included a hypothetical cohort of 10,000 patients that represents a target US population of age 45 years or older. The testing panel assumed to include tests for the following genes and corresponding drug choices: CYP2C19 (clopidogrel vs. ticagrelor), CYP2C9/VKORC1 (warfarin vs. novel oral anticoagulants), and SLCO1B1 (statins vs. PCSK9). Scenario and probabilistic sensitivity analyses were performed to assess the impact of age, sex, race, risk level, and time frame duration. The study reported incremental cost-effectiveness ratios (ICERs) as the main outcome while costs, quality-adjusted life years (QALYs), incremental costs, and incremental QALYs were also reported for the base-case and sensitivity analyses. The results suggested that preemptive testing was cost-effective compared to usual care (ICER $71,540/QALY) at the willingness-to-pay (WTP) of $100,000/QALY while reactive testing was not (ICER $155,870/QALY). Preemptive testing gained a patient an additional 0.74 QALYs compared to usual care, while reactive testing lead to a 0.12 QALYs increase. The cost-effectiveness was not sensitive to age, sex, race and risk-level, but was sensitive to longer time frame. This study concludes that preemptive PGx panel testing for CVD diseases management was cost-effective and should be implemented in a system wide manner for the target population.

Marked mitochondrial genetic variation in individuals and populations of the carcinogenic liver fluke Clonorchis sinensis.

Clonorchiasis is a neglected tropical disease caused by the Chinese liver fluke, Clonorchis sinensis, and is often associated with a malignant form of bile duct cancer (cholangiocarcinoma). Although some aspects of the epidemiology of clonorchiasis are understood, little is known about the genetics of C. sinensis populations. Here, we conducted a comprehensive genetic exploration of C. sinensis from endemic geographic regions using complete mitochondrial protein gene sets. Genomic DNA samples from C. sinensis individuals (n = 183) collected from cats and dogs in China (provinces of Guangdong, Guangxi, Hunan, Heilongjiang and Jilin) as well as from rats infected with metacercariae from cyprinid fish from the Russian Far East (Primorsky Krai region) were deep sequenced using the BGISEQ-500 platform. Informatic analyses of mitochondrial protein gene data sets revealed marked genetic variation within C. sinensis; significant variation was identified within and among individual worms from distinct geographical locations. No clear affiliation with a particular location or host species was evident, suggesting a high rate of dispersal of the parasite across endemic regions. The present work provides a foundation for future biological, epidemiological and ecological studies using mitochondrial protein gene data sets, which could aid in elucidating associations between particular C. sinensis genotypes/haplotypes and the pathogenesis or severity of clonorchiasis and its complications (including cholangiocarcinoma) in humans.

Pathogenic and likely pathogenic variants in at least five genes account for approximately 3% of mild isolated nonsyndromic thrombocytopenia.

Thrombocytopenia has a variety of different etiologies, both acquired and hereditary. Inherited thrombocytopenia may be associated with other symptoms (syndromic forms) or may be strictly isolated. To date, only about half of all the familial forms of thrombocytopenia have been accounted for in terms of well-defined genetic abnormalities. However, data are limited on the nature and frequency of the underlying causative genetic variants in individuals with mild isolated nonsyndromic thrombocytopenia. Thirteen known or candidate genes for isolated thrombocytopenia were included in a gene panel analysis in which targeted next-generation sequencing was performed on 448 French blood donors with mild isolated nonsyndromic thrombocytopenia. A total of 68 rare variants, including missense, splice site, frameshift, nonsense, and in-frame variants (all heterozygous) were identified in 11 of the 13 genes screened. Twenty-nine percent (N = 20) of the variants detected were absent from both the French Exome Project and gnomAD exome databases. Using stringent criteria and an unbiased approach, we classified seven predicted loss-of-function variants (three in ITGA2B and four in TUBB1) and four missense variants (one in GP1BA, two in ITGB3 and one in ACTN1) as being pathogenic or likely pathogenic. Altogether, they were found in 13 members (approx. 3%) of our studied cohort. We present the results of gene panel sequencing of known and candidate thrombocytopenia genes in mild isolated nonsyndromic thrombocytopenia. Pathogenic and likely pathogenic variants in five known thrombocytopenia genes were identified, accounting for approximately 3% of individuals with the condition.