Contribution of de novo retroelements to birth defects and childhood cancers.

Insertion of active retroelements-L1s, Alus, and SVAs-can disrupt proper genome function and lead to various disorders including cancer. However, the role of de novo retroelements (DNRTs) in birth defects and childhood cancers has not been well characterized due to the lack of adequate data and efficient computational tools. Here, we examine whole-genome sequencing data of 3,244 trios from 12 birth defect and childhood cancer cohorts in the Gabriella Miller Kids First Pediatric Research Program. Using an improved version of our tool xTea (x-Transposable element analyzer) that incorporates a deep-learning module, we identified 162 DNRTs, as well as 2 pseudogene insertions. Several variants are likely to be causal, such as a de novo Alu insertion that led to the ablation of a whole exon in the NF1 gene in a proband with brain tumor. We observe a high de novo SVA insertion burden in both high-intolerance loss-of-function genes and exons as well as more frequent de novo Alu insertions of paternal origin. We also identify potential mosaic DNRTs from embryonic stages. Our study reveals the important roles of DNRTs in causing birth defects and predisposition to childhood cancers.

Near-gapless and haplotype-resolved apple genomes provide insights into the genetic basis of rootstock-induced dwarfing.

Dwarfing rootstocks have transformed the production of cultivated apples; however, the genetic basis of rootstock-induced dwarfing remains largely unclear. We have assembled chromosome-level, near-gapless and haplotype-resolved genomes for the popular dwarfing rootstock 'M9', the semi-vigorous rootstock 'MM106' and 'Fuji', one of the most commonly grown apple cultivars. The apple orthologue of auxin response factor 3 (MdARF3) is in the Dw1 region of 'M9', the major locus for rootstock-induced dwarfing. Comparing 'M9' and 'MM106' genomes revealed a 9,723-bp allele-specific long terminal repeat retrotransposon/gypsy insertion, DwTE, located upstream of MdARF3. DwTE is cosegregated with the dwarfing trait in two segregating populations, suggesting its prospective utility in future dwarfing rootstock breeding. In addition, our pipeline discovered mobile mRNAs that may contribute to the development of dwarfed scion architecture. Our research provides valuable genomic resources and applicable methodology, which have the potential to accelerate breeding dwarfing rootstocks for apple and other perennial woody fruit trees.

Biogas production prediction model of food waste anaerobic digestion for energy optimization using mixup data augmentation-based global attention mechanism.

Achieving rapid, efficient, and cost-effective anaerobic digestion (AD) of food waste is a key means to improve the efficiency of food waste treatment. However, in view of the shortage of historical anaerobic digestion data, the limitation of general neural networks in predicting biogas production, and its sensitivity to abnormal variation points, achieving accurate prediction of biogas production is not easy. This paper proposes a novel biogas production prediction model of food waste AD for energy optimization based on the mixup data augmentation integrating an improved global attention mechanism long short-term memory (LSTM). Taking the AD data of the actual factory as samples, the mixup data augmentation is introduced to generate virtual samples with the similar distribution as original samples. Then original samples and generated virtual samples are used as the input of the global attention mechanism LSTM to establish the food waste AD biogas production prediction model. Finally, the proposed method is applied in the biogas production prediction of actual food waste treatment plants. Compared with other industrial modeling models, the experimental results show that the proposed method has the highest prediction accuracy of 0.988, which performs well in predicting biogas production and can effectively guide and timely adjust feed configuration of AD plants.

The landscape of human SVA retrotransposons.

SINE-VNTR-Alu (SVA) retrotransposons are evolutionarily young and still-active transposable elements (TEs) in the human genome. Several pathogenic SVA insertions have been identified that directly mutate host genes to cause neurodegenerative and other types of diseases. However, due to their sequence heterogeneity and complex structures as well as limitations in sequencing techniques and analysis, SVA insertions have been less well studied compared to other mobile element insertions. Here, we identified polymorphic SVA insertions from 3646 whole-genome sequencing (WGS) samples of >150 diverse populations and constructed a polymorphic SVA insertion reference catalog. Using 20 long-read samples, we also assembled reference and polymorphic SVA sequences and characterized the internal hexamer/variable-number-tandem-repeat (VNTR) expansions as well as differing SVA activity for SVA subfamilies and human populations. In addition, we developed a module to annotate both reference and polymorphic SVA copies. By characterizing the landscape of both reference and polymorphic SVA retrotransposons, our study enables more accurate genotyping of these elements and facilitate the discovery of pathogenic SVA insertions.

ERα-associated translocations underlie oncogene amplifications in breast cancer.

Focal copy-number amplification is an oncogenic event. Although recent studies have revealed the complex structure1-3 and the evolutionary trajectories4 of oncogene amplicons, their origin remains poorly understood. Here we show that focal amplifications in breast cancer frequently derive from a mechanism-which we term translocation-bridge amplification-involving inter-chromosomal translocations that lead to dicentric chromosome bridge formation and breakage. In 780 breast cancer genomes, we observe that focal amplifications are frequently connected to each other by inter-chromosomal translocations at their boundaries. Subsequent analysis indicates the following model: the oncogene neighbourhood is translocated in G1 creating a dicentric chromosome, the dicentric chromosome is replicated, and as dicentric sister chromosomes segregate during mitosis, a chromosome bridge is formed and then broken, with fragments often being circularized in extrachromosomal DNAs. This model explains the amplifications of key oncogenes, including ERBB2 and CCND1. Recurrent amplification boundaries and rearrangement hotspots correlate with oestrogen receptor binding in breast cancer cells. Experimentally, oestrogen treatment induces DNA double-strand breaks in the oestrogen receptor target regions that are repaired by translocations, suggesting a role of oestrogen in generating the initial translocations. A pan-cancer analysis reveals tissue-specific biases in mechanisms initiating focal amplifications, with the breakage-fusion-bridge cycle prevalent in some and the translocation-bridge amplification in others, probably owing to the different timing of DNA break repair. Our results identify a common mode of oncogene amplification and propose oestrogen as its mechanistic origin in breast cancer.

Novel risk assessment model of food quality and safety considering physical-chemical and pollutant indexes based on coefficient of variance integrating entropy weight.

Food safety is important for sustainable social and economic development and people's health. The traditional single risk assessment model is one-sided to the weight distribution of food safety factors including physical-chemical and pollutant indexes, which cannot comprehensively assess food safety risks. Therefore, a novel food safety risk assessment model combining the coefficient of variation (CV) integrating the entropy weight (EWM) (CV-EWM) is proposed in this paper. The CV and the EWM are used to calculate the objective weight of each index with physical-chemical and pollutant indexes effecting food safety, respectively. Then, the weights determined by the EWM and the CV are coupled by the Lagrange multiplier method. The ratio of the square root of the product of two weights and the weighted sum of the square root of the product are regarded as the combined weight. Thus, the CV-EWM risk assessment model is constructed to comprehensively assess the food safety risk. Moreover, the Spearman rank correlation coefficient method is used to test the compatibility of the risk assessment model. Finally, the proposed risk assessment model is applied to evaluate the quality and safety risk of sterilized milk. By analyzing the attribute weight and comprehensive risk value of physical-chemical and pollutant indexes effecting the sterilized milk quality, the results show that this proposed model can scientifically obtain the weight of physical-chemical and pollutant indexes to objectively and reasonably evaluate the overall risk of food, which has certain practical value for discovering the influencing factors of risk occurrence to risk prevention and control of food quality and safety.

A Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Tacrolimus and Corticosteroids in Combination With or Without Mycophenolate Mofetil in Liver Transplantation Recipients Infected With Hepatitis B Virus.

BACKGROUND: Mycophenolate mofetil exhibits pharmacologic mechanisms different from calcineurin inhibitors. Therefore, the dose of calcineurin inhibitors can be reduced along with side effects for effective immunosuppression. We aimed to evaluate the efficacy and safety of tacrolimus and corticosteroid in combination with or without mycophenolate mofetil in living donor liver transplantation (LDLT) recipients infected with hepatitis B virus (HBV). METHODS: A randomized, open-label, comparative, multicenter, phase IV study was conducted with 119 patients from January 2014 to September 2017. In the full analysis set population, 58 and 59 patients were included in the study group (triple-drug regimen: TacroBell + My-rept + corticosteroid) and the control group (dual-drug regimen: TacroBell + corticosteroid), respectively. In the per protocol set population, 49 and 42 patients were included in the study and control groups, respectively. RESULTS: In the full analysis set population, the incidence of biopsy-proven acute cellular rejection (rejection activity index score ≥4) was 3.4% in the study group; however, this finding was not observed in the control group (P = .468). Hepatitis B virus recurrence was observed in one patient in the control group. No cases of biopsy-proven acute cellular rejection and HBV recurrence were observed in the per protocol set population. The incidences of serious adverse events were 25.9% and 18.0% in the study and control groups, respectively; however, the difference between the groups was not statistically significant (P = .376). CONCLUSION: Although the study involved a small number of patients, the triple-drug regimen can be considered safe and effective for immunosuppression after living donor liver transplantation in patients infected with HBV.

Deciphering transcriptome alterations in bone marrow hematopoiesis at single-cell resolution in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disorder, in which megakaryocyte dysfunction caused by an autoimmune reaction can lead to thrombocytopenia, although the underlying mechanisms remain unclear. Here, we performed single-cell transcriptome profiling of bone marrow CD34+ hematopoietic stem and progenitor cells (HSPCs) to determine defects in megakaryopoiesis in ITP. Gene expression, cell-cell interactions, and transcriptional regulatory networks varied in HSPCs of ITP, particularly in immune cell progenitors. Differentially expressed gene (DEG) analysis indicated that there was an impaired megakaryopoiesis of ITP. Flow cytometry confirmed that the number of CD9+ and HES1+ cells from Lin-CD34+CD45RA- HSPCs decreased in ITP. Liquid culture assays demonstrated that CD9+Lin-CD34+CD45RA- HSPCs tended to differentiate into megakaryocytes; however, this tendency was not observed in ITP patients and more erythrocytes were produced. The percentage of megakaryocytes differentiated from CD9+Lin-CD34+CD45RA- HSPCs was 3-fold higher than that of the CD9- counterparts from healthy controls (HCs), whereas, in ITP patients, the percentage decreased to only 1/4th of that in the HCs and was comparable to that from the CD9- HSPCs. Additionally, when co-cultured with pre-B cells from ITP patients, the differentiation of CD9+Lin-CD34+CD45RA- HSPCs toward the megakaryopoietic lineage was impaired. Further analysis revealed that megakaryocytic progenitors (MkP) can be divided into seven subclusters with different gene expression patterns and functions. The ITP-associated DEGs were MkP subtype-specific, with most DEGs concentrated in the subcluster possessing dual functions of immunomodulation and platelet generation. This study comprehensively dissects defective hematopoiesis and provides novel insights regarding the pathogenesis of ITP.

The global burden of disease attributable to ambient fine particulate matter in 204 countries and territories, 1990-2019: A systematic analysis of the Global Burden of Disease Study 2019.

Understanding the spatio-temporal patterns of the disease burden attributable to ambient PM2.5 across the world is essential for the prevention of related diseases, as well as ambient PM2.5 control. Following the framework and methodology of the Global Burden of Disease Study (GBD) in 2019, the global, regional, and national data on ambient PM2.5-attributable death and disability-adjusted life years (DALYs), and the age-standardized rates of mortality (ASMR) and disability-adjusted life years (ASDR) were summarized based on age, gender, year, location and specific diseases. We calculated the average annual percentage change (AAPC) to depict the secular trends of ASMR and ASDR from 1990 to 2019. In 2019, the global ambient PM2.5-related deaths and DALYs were 4,140,970 and 118.2 million, respectively, with 1,702,150 deaths and 47.5 million DALYs for females and 2,438,820 deaths and 70.7 million DALYs for male. In the 13 level-three causes, ischemic heart disease, stroke, chronic obstructive and pulmonary disease (COPD) were the leading three causes of deaths and DALYs attributable to ambient PM2.5. The number of global deaths and DALYs attributable to ambient PM2.5 has increased by 102.3% and 67.7% from 1990 to 2019, respectively. However, ASMR and ASDR showed little change. In the 13 level-three diseases, ischemic heart disease, stroke, COPD, diabetes mellitus, and lung cancer were the top five contributors to the increase of global deaths or DALYs, among which diabetes mellitus had the fastest increase of ASMR and ASDR, with AAPC of 1.5 (95% CI: 1.43, 1.58) and 2.21 (95% CI: 2.15, 2.27), respectively. The population attributable fractions (PAF) of causes in ASMR or ASDR varied significantly across regions, of which PAF of COPD, stroke and lung cancer were the top three. Regarding the GBD region, high PAF mainly occurred in North Africa and Middle East, South Asia, and East Asia. The age-specific PAFs of ischemic heart disease and stroke deaths and DALYs due to ambient PM2.5 were negatively correlated with age. ASMR and ASDR of overall PM2.5 related-burden showed an inverted "V/U" relationship with the socio-demographic index (SDI). The AAPC of ASMR and ASDR of the overall causes showed a strong negative correlation with SDI in 2019, especially at the SDI larger than 0.5. The deaths and DALYs attributable to ambient PM2.5 continued to increase under the context of population growth and aging. Decision-makers should consider controlling the PM2.5 emission when developing the economy.

Clinical Outcomes of Drug-Coated Balloon Treatment After Successful Revascularization of de novo Chronic Total Occlusions.

Background: The safety and efficacy of drug-coated balloon (DCB) treatment for de novo coronary chronic total occlusion (CTO) remain uncertain. The aim of this study was to evaluate the outcomes of DCB only treatment for de novo CTO. Methods: In this retrospective study, 101 vessels with de novo CTO lesions dilated by balloon angioplasty with thrombolysis in myocardial infarction flow grade 3 were included. Among them, 93 vessels successfully treated with DCB only treatment were analyzed. The study endpoint was major adverse cardiac events (MACE) at 2 years, a composite of cardiac death, non-fatal myocardial infarction (MI), target vessel revascularization (TVR), and target vessel thrombosis. The secondary endpoint was late lumen loss (LLL) on follow-up coronary angiography. Results: All 84 patients were followed up clinically, and 67 vessels underwent scheduled coronary angiography after 6 months. There were no procedural complications, and three vessels required bailout-stenting. The median follow-up was 720 days (interquartile range [IQR]; 406-1,268 days). MACE occurred in 8.3% of the patients after 1 year, including cardiac death (1.2%), TVR (7.1%), and no non-fatal MI and target vessel thrombosis. Two years after treatment, MACE occurred in 16.7% of the patients, including cardiac death (2.4%), non-fatal MI (3.6%), TVR (13.1%), and no target vessel thrombosis. The mean LLL was 0.03 ± 0.53 mm. Binary restenosis occurred in 14.9% of the treated vessels, and 3.0% of the vessels had late re-occlusion on follow-up coronary angiography. Conclusions: If the result of revascularization using balloon angioplasty is good, the clinical outcomes of DCB only treatment of de novo CTOs at the 2-year follow-up are encouraging, with a low rate of hard endpoints and acceptable MACE rates (Clinical Trial Registration Information; Impact of Drug-coated Balloon Treatment in de novo Coronary Lesion; NCT04619277).

Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer.

Altered RNA expression of repetitive sequences and retrotransposition are frequently seen in colorectal cancer, implicating a functional importance of repeat activity in cancer progression. We show the nucleoside reverse transcriptase inhibitor 3TC targets activities of these repeat elements in colorectal cancer preclinical models with a preferential effect in p53-mutant cell lines linked with direct binding of p53 to repeat elements. We translate these findings to a human phase II trial of single-agent 3TC treatment in metastatic colorectal cancer with demonstration of clinical benefit in 9 of 32 patients. Analysis of 3TC effects on colorectal cancer tumorspheres demonstrates accumulation of immunogenic RNA:DNA hybrids linked with induction of interferon response genes and DNA damage response. Epigenetic and DNA-damaging agents induce repeat RNAs and have enhanced cytotoxicity with 3TC. These findings identify a vulnerability in colorectal cancer by targeting the viral mimicry of repeat elements. SIGNIFICANCE: Colorectal cancers express abundant repeat elements that have a viral-like life cycle that can be therapeutically targeted with nucleoside reverse transcriptase inhibitors (NRTI) commonly used for viral diseases. NRTIs induce DNA damage and interferon response that provide a new anticancer therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1397.

Global burden of lung cancer attributable to ambient fine particulate matter pollution in 204 countries and territories, 1990-2019.

INTRODUCTION: Understanding the latest global spatio-temporal pattern of lung cancer burden attributable to ambient fine particulate matter pollution (PM2.5) is crucial to prioritize global lung cancer prevention, as well as environment improvement. METHODS: Data on lung cancer attributable to ambient PM2.5 were downloaded from the Global Burden of Disease Study (GBD) 2019. The numbers and age-standardized rates on lung cancer mortality (ASMR) and disability-adjusted life years (ASDR) were estimated by age, sex, region, and country. We used estimated annual percentage change (EAPC) to quantify the temporal trends of ASMR and ASDR from 1990 to 2019. RESULTS: In 2019, the number of global lung cancer deaths and DALYs attributable to ambient PM2.5 was approximately 0.31 million and 7.02 million respectively, among which more deaths and DALYs occurred in males. At GBD region level, the heaviest burden occurred in East Asia, accounting for over 50% worldwide, with China ranked first worldwide. The number of ambient PM2.5 attributable lung cancer deaths and DALYs has over doubled from 1990 to 2019, but high sociodemographic index (SDI) region had a rapid decrease, with EAPC -2.21 in ASMR (95% CI: -2.32, -2.09). The age-specific mortality rate or DALY rate has increased in all age groups in low to middle SDI regions from 1990 to 2019. The ASMR or ASDR showed an inverted V-shaped association with SDI. The EAPC in ASMR or ASDR was highly negatively correlated with ASMR or ASDR in 1990 and SDI in 2019, with coefficients around 0.70. CONCLUSIONS: The number of ambient PM2.5-related lung cancer deaths and DALYs has largely increased because of the increase of exposure to PM2.5, population growth, and aging. Local governments should do economic activities under the consideration of public health, especially in high-burden areas.

Coronary artery aneurysm formation after paclitaxel-coated balloon-only intervention for de novo coronary chronic total occlusion.

Background: Although coronary artery aneurysm (CAA) is an uncommon complication of drug-coated balloon (DCB) treatment, the incidence and mechanisms CAA formation after DCB intervention for chronic total occlusion (CTO) remains to be clarified. The aim of this study was to investigate the incidence of CAA after DCB intervention for the treatment of CTO of coronary arteries. Materials and methods: This was a retrospective analysis of 82 patients, contributing 88 vessels, who underwent successful DCB-only treatment for de novo CTO lesions. Follow-up angiography was performed in all cases, at a mean 208.5 (interquartile range [IQR]: 174.8 to 337.5) days after the index procedure. Results: CAA was identified in seven vessels, in seven patients, at the site of previous successful DCB-only treatment. Of these, six were fusiform in shape and one saccular, with a mean diameter of 4.2 ± 1.0 mm and length of 6.7 ± 2.6 mm. Six CAAs developed at the CTO inlet site, and all CAAs occurred at the lesions following dissection immediately after DCB treatment. CAAs were not associated with an increased risk of major clinical events over the median follow-up of 676.5 (IQR: 393.8 to 1,304.8) days. Conclusion: The incidence of CAA after DCB-only treatment for CTO lesions was 8.0% in this study. Further research is warranted, using intravascular imaging, to clarify the mechanism of DCB-related CAA formation and prognosis.

Whole-genome analysis reveals the contribution of non-coding de novo transposon insertions to autism spectrum disorder.

BACKGROUND: Retrotransposons have been implicated as causes of Mendelian disease, but their role in autism spectrum disorder (ASD) has not been systematically defined, because they are only called with adequate sensitivity from whole genome sequencing (WGS) data and a large enough cohort for this analysis has only recently become available. RESULTS: We analyzed WGS data from a cohort of 2288 ASD families from the Simons Simplex Collection by establishing a scalable computational pipeline for retrotransposon insertion detection. We report 86,154 polymorphic retrotransposon insertions-including > 60% not previously reported-and 158 de novo retrotransposition events. The overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 117, and 206 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 21 births total. However, ASD cases showed more de novo L1 insertions than expected in ASD genes. Additionally, we observed exonic insertions in loss-of-function intolerant genes, including a likely pathogenic exonic insertion in CSDE1, only in ASD individuals. CONCLUSIONS: These findings suggest a modest, but important, impact of intronic and exonic retrotransposon insertions in ASD, show the importance of WGS for their analysis, and highlight the utility of specific bioinformatic tools for high-throughput detection of retrotransposon insertions.

Induced Quantized Spin Current in Vacuum.

We uncover a fundamental effect of the QED vacuum in an external electromagnetic (EM) field. We show that the quantized vacuum of electrons is spin polarized by the EM field and manifests as a vacuum spin current. An experiment is proposed to measure the spin torque exerted by the spin current by measuring the twisted angle of the director axis of a nematic liquid crystal.

Comprehensive identification of transposable element insertions using multiple sequencing technologies.

Transposable elements (TEs) help shape the structure and function of the human genome. When inserted into some locations, TEs may disrupt gene regulation and cause diseases. Here, we present xTea (x-Transposable element analyzer), a tool for identifying TE insertions in whole-genome sequencing data. Whereas existing methods are mostly designed for short-read data, xTea can be applied to both short-read and long-read data. Our analysis shows that xTea outperforms other short read-based methods for both germline and somatic TE insertion discovery. With long-read data, we created a catalogue of polymorphic insertions with full assembly and annotation of insertional sequences for various types of retroelements, including pseudogenes and endogenous retroviruses. Notably, we find that individual genomes have an average of nine groups of full-length L1s in centromeres, suggesting that centromeres and other highly repetitive regions such as telomeres are a significant yet unexplored source of active L1s. xTea is available at https://github.com/parklab/xTea .

BamSnap: a lightweight viewer for sequencing reads in BAM files.

SUMMARY: Despite the improvement in variant detection algorithms, visual inspection of the read-level data remains an essential step for accurate identification of variants in genome analysis. We developed BamSnap, an efficient BAM file viewer utilizing a graphics library and BAM indexing. In contrast to existing viewers, BamSnap can generate high-quality snapshots rapidly, with customized tracks and layout. As an example, we produced read-level images at 1000 genomic loci for >2500 whole-genomes. AVAILABILITY AND IMPLEMENTATION: BamSnap is freely available at https://github.com/parklab/bamsnap. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

HiTea: a computational pipeline to identify non-reference transposable element insertions in Hi-C data.

Hi-C is a common technique for assessing 3D chromatin conformation. Recent studies have shown that long-range interaction information in Hi-C data can be used to generate chromosome-length genome assemblies and identify large-scale structural variations. Here, we demonstrate the use of Hi-C data in detecting mobile transposable element (TE) insertions genome-wide. Our pipeline Hi-C-based TE analyzer (HiTea) capitalizes on clipped Hi-C reads and is aided by a high proportion of discordant read pairs in Hi-C data to detect insertions of three major families of active human TEs. Despite the uneven genome coverage in Hi-C data, HiTea is competitive with the existing callers based on whole-genome sequencing (WGS) data and can supplement the WGS-based characterization of the TE-insertion landscape. We employ the pipeline to identify TE-insertions from human cell-line Hi-C samples. AVAILABILITY AND IMPLEMENTATION: HiTea is available at https://github.com/parklab/HiTea and as a Docker image. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The design and construction of reference pangenome graphs with minigraph.

The recent advances in sequencing technologies enable the assembly of individual genomes to the quality of the reference genome. How to integrate multiple genomes from the same species and make the integrated representation accessible to biologists remains an open challenge. Here, we propose a graph-based data model and associated formats to represent multiple genomes while preserving the coordinate of the linear reference genome. We implement our ideas in the minigraph toolkit and demonstrate that we can efficiently construct a pangenome graph and compactly encode tens of thousands of structural variants missing from the current reference genome.

Effect of CYP3A5 on the Once-Daily Tacrolimus Conversion in Stable Liver Transplant Patients.

Cytochrome P450 (CYP) 3A5 polymorphism influences tacrolimus metabolism, but its effect on the drug pharmacokinetics in liver transplant recipients switched to once-daily extended-release formulation remains unknown. The aim of this study is to analyze the effect of CYP3A5 polymorphism on liver function after once-daily tacrolimus conversion in liver transplant patients. A prospective open-label study included 60 stable liver transplant recipients who underwent 1:1 conversion from twice-daily tacrolimus to once-daily tacrolimus. All participants were genotyped for CYP3A5 polymorphism. The study was registered at ClinicalTrials.gov (NCT02882113). Twenty-eight patients were enrolled in the CYP3A5 expressor group and 32 in the non-expressor group. Although there was no statistical difference, incidence of liver dysfunction was higher in the expressor group than in the non-expressor group when converted to once-daily extended-release tacrolimus (p = 0.088). No biopsy-proven acute rejection, graft failure, and mortality were observed in either group. The decrease in dose-adjusted trough level (-42.9% vs. -26.1%) and dose/kg-adjusted trough level of tacrolimus (-40.0% vs. -23.7%) was significantly greater in the expressor group than in the non-expressors after the conversion. A pharmacokinetic analysis was performed in 10 patients and tacrolimus absorption in the non-expressor group was slower than in the expressor group. In line with this observation, the area under the curve for once-daily tacrolimus correlated with trough level (Cmin) in the non-expressors and peak concentration (Cmax) in the expressors. CYP3A5 genotyping in liver transplant recipients leads to prediction of pharmacokinetics after switching from a twice-daily regimen to a once-daily dosage form, which makes it possible to establish an appropriate dose of tacrolimus.