Identification of the Beta Subunit Fas1p of Fatty Acid Synthetase as an Interacting Partner of Yeast Calcium/Calmodulin-Dependent Protein Kinase Cmk2p Through Mass Spectrometry Analysis.

The calcium/calmodulin-dependent protein kinase II (CaMKII) is a mediator of calcium signals and regulates fatty acid metabolism in mammalian cells. Cmk2p is a yeast homolog of CaMKII and functions as a negative regulator of calcium signaling. However, its substrates remain to be identified. Combination of immunoprecipitation (IP) and mass spectrometry has been proven to be very useful for identification of interacting partner proteins and interactome. In this study, through these approaches, we have identified 65 and 110 potential Cmk2p-interacting proteins in yeast cells in the absence or presence of calcium stress, respectively. In yeast cells expressing both CMK2-HA and FAS1-GFP fusion proteins, in the absence or presence of calcium stress, less amounts of FAS1-GFP proteins are present in cell lysates after IP with anti-HA antibody than cell lysates before IP, while FAS1-GFP proteins are detected on both types of IP beads. However, as an internal control, similar amounts of Pgk1p proteins were detected in both after-IP and before-IP cell lysates but not on the IP beads. Therefore, our biochemical analysis demonstrates that the ß subunit Fas1p of fatty acid synthetase interacts with Cmk2p in yeast cells independent of calcium stress. It is also interesting to note that, in addition to the expected 52-kDa CMK2-HA band, a faster-moving 48-kDa CMK2-HA band is present in the calcium-stressed cell lysate but not in the cell lysate without calcium stress. Our data would provide important clues for understanding the functions of CaMKII in the regulation of fatty acid metabolism as well as related diseases such as cancers, diabetes, and obesity.

Amino acid metabolism and MAP kinase signaling pathway play opposite roles in the regulation of ethanol production during fermentation of sugarcane molasses in budding yeast.

Sugarcane molasses is one of the main raw materials for bioethanol production, and Saccharomyces cerevisiae is the major biofuel-producing organism. In this study, a batch fermentation model has been used to examine ethanol titers of deletion mutants for all yeast nonessential genes in this yeast genome. A total of 42 genes are identified to be involved in ethanol production during fermentation of sugarcane molasses. Deletion mutants of seventeen genes show increased ethanol titers, while deletion mutants for twenty-five genes exhibit reduced ethanol titers. Two MAP kinases Hog1 and Kss1 controlling the high osmolarity and glycerol (HOG) signaling and the filamentous growth, respectively, are negatively involved in the regulation of ethanol production. In addition, twelve genes involved in amino acid metabolism are crucial for ethanol production during fermentation. Our findings provide novel targets and strategies for genetically engineering industrial yeast strains to improve ethanol titer during fermentation of sugarcane molasses.

Transcriptional expression of PHR2 is positively controlled by the calcium signaling transcription factor Crz1 through its binding motif in the promoter.

IMPORTANCE: The fungal cell wall consists of glucans, mannoproteins, and chitin and is essential for cell viability, morphogenesis, and pathogenesis. The enzymes of the GH72 family are responsible for ß-(1,3)-glucan elongation and branching, which is crucial for the formation of the glucan-chitin polymer at the bud neck of yeast cells. In the human fungal pathogen Candida albicans, there are five GH72 enzyme-encoding genes: PHR1, PHR2, PHR3, PGA4, and PGA5. It is known that expression of PHR1 and PHR2 is controlled by the pH-responsive Rim101 pathway through the transcription factor Rim101. In this study, we have demonstrated that the transcription expression of PHR2 is also controlled by the transcription factor Crz1 through its binding motif in the promoter. Therefore, we have uncovered a dual-control mechanism by which PHR2 expression is negatively regulated via CaRim101 through the pH-responsive pathway and positively modulated by CaCrz1 through the calcium/calcineurin signaling pathway.

Lymphovascular invasion is a significant risk factor for non-sentinel nodal metastasis in breast cancer patients with sentinel lymph node (SLN)-positive breast cancer: a cross-sectional study.

BACKGROUND: A connection between lymphovascular invasion and axillary lymph node metastases in breast cancer has been observed, but the findings are inconsistent and primarily based on research in Western populations. We investigated the association between lymphovascular invasion and non-sentinel lymph node (non-SLN) metastasis in breast cancer patients with sentinel lymph node (SLN) metastasis in western China. METHODS: This study comprised 280 breast cancer patients who tested positive for SLN through biopsy and subsequently underwent axillary lymph node dissection (ALND) at The People's Hospital of Guangxi Zhuang Autonomous Region between March 2013 and July 2022. We used multivariate logistic regression analyses to assess the association between clinicopathological characteristics and non-SLN metastasis. Additionally, we conducted further stratified analysis. RESULTS: Among the 280 patients with positive SLN, only 126 (45%) exhibited non-SLN metastasis. Multivariate logistic regression demonstrated that lymphovascular invasion was an independent risk factor for non-SLN in breast cancer patients with SLN metastasis (OR = 6.11; 95% CI, 3.62-10.32, p < 0.05). The stratified analysis yielded similar results. CONCLUSIONS: In individuals with invasive breast cancer and 1-2 positive sentinel lymph nodes, lymphovascular invasion is the sole risk factor for non-SLN metastases. This finding aids surgeons and oncologists in devising a plan for local axillary treatment, preventing both over- and undertreatment.

High-efficiency all-fluorescent white organic light-emitting diode based on TADF material as a sensitizer.

The use of TADF materials as both sensitizers and emitters is a promising route to achieve high-efficiency all-fluorescent white organic light-emitting diodes (WOLEDs). In this study, the thermally-activated delayed-fluorescent (TADF) material DMAC-TRZ (9,9-dimethyl-9,10-dihydroacridine-2,4,6-triphenyl-1,3,5-triazine) was selected as a sensitizer for the conventional fluorescent emitter DCJTB (4-(dicyanomethylene)-2-t-butyl-6-(1,1,7,7-tetramethyljulolidyl-9-enyl)-4H-pyran), which was co-doped in a wide bandgap host of DPEPO (bis[2-(diphenylphosphino)phenyl]ether oxide) to fabricate WOLEDs. For the emitting layer of DPEPO:DMAC-TRZ:DCJTB, the DPEPO host can dilute the exciton concentration formed on the DMAC-TRZ sensitizer, which benefits the suppression of exciton quenching. The effect of the doping concentration of DCJTB on the carrier recombination and energy transfer process was investigated. With an optimized doping concentration of DCJTB as 0.8%, highly efficient WOLED was achieved with a maximum external quantum efficiency (EQE), power efficiency (PE), and current efficiency (CE) of 11.05%, 20.83 lm W-1, and 28.83 cd A-1, respectively, corresponding to the Commission Internationale de I' Eclairage (CIE) coordinates of (0.45, 0.46). These superior performances can be ascribed to the fact that the hole-trapping effect of the emitter and Dexter energy transfer (DET) from sensitizer to emitter can be suppressed simultaneously by the extremely low doping concentration.

Age has a U-shaped relationship with breast cancer outcomes in women: a cohort study.

Background and Objectives: Age is a significant determinant of susceptibility to breast cancer. Currently, the available evidence regarding the non-linear correlation between the age of diagnosis and the prognosis of breast cancer patients is contradictory. Insufficient data currently exist regarding the influence of age at diagnosis on the prognosis of breast cancer. The objective of our investigation was to examine the relationship between age at diagnosis and overall survival (OS), breast cancer-specific survival (BCSS), and disease-free survival (DFS). Methods: This retrospective cohort study included 1054 patients diagnosed with breast cancer between March 7, 2013 and December 31, 2019. The hazard ratios (HRs) and 95% confidence interval (CI) for OS, BCSS, DFS were assessed using Cox proportional hazard ratio models and restricted cubic splines (RCS). Results: The study included 1054 breast cancer patients who met the criteria. With a median follow-up of 4.86 years, 71 patients (6.74%) died and 144 patients (13.66%) relapsed. After multivariable adjustment, age showed a U-shaped association with OS, BCSS, and DFS, with significantly higher risk at two ends, with age inflection points of 44, 44, and 41 years for OS, BCSS, and DFS, respectively. For OS, Quartile 1 (HR, 2.09; 95% CI: 0.90-4.84), Quartile 3 (HR, 2.44; 95% CI: 1.05-5.65) and Quartile 4 (HR, 3.38; 95% CI: 1.51-7.54) had poorer OS compared with Quartile 2. Similar results were found for BCSS and DFS. Conclusions: This study confirmed a U-shaped association between age at diagnosis and breast cancer outcome.

Effect of preoperative peripheral blood platelet volume index on prognosis in patients with invasive breast cancer.

Aim: This study was designed to investigate the prognostic value of the platelet volume index in patients with invasive breast cancer (IBC). Methods: A total of 524 patients with IBC were enrolled in this study, with a median follow-up time of 6.76 years. The relationship between platelet volume indices and breast cancer prognosis was analyzed. Results: There is a strong correlation between a higher platelet distribution width-to-platelet count ratio (PDW/P) and poorer disease-free survival (DFS) in patients with IBC. The DFS rate was significantly lower among individuals with elevated PDW/P ratios compared with those with lower ratios. Conclusion: The PDW/P ratio is an independent risk factor for predicting DFS in patients with IBC.

Smart hydrothermally responsive microneedle for topical tumor treatment.

Locoregional therapy has attracted increasing attention for subcutaneous tumors owing to its merits of minimally invasive operation and negligible systematic toxicity. However, to accelerate clinical translation, further promotions in deep-seated penetration, temporal-spatial controllability, personalized adaptability, as well as easy operation are still urgently needed. This work proposed a self-heating-cooking-package-inspired hydrothermally responsive multi-round acturable microneedle (HRMAM) system, which loaded docetaxel (DTX) in the polycaprolactone (PCL), to serve as deeply penetrable, hydrothermal-chemotherapy synergetic, on-demand and self-service anti-tumor treatment. The optimized hydrothermally responsive formulation served as base components for water-based self-heating responsive drug release with synergistic anti-tumor thermal therapy, and simultaneously in combination with well-designed grooved-structure needle tips for directional deep delivery and enhanced transfer efficiency. To satisfy spatial precision and flexible controllability, this engineering-based detachable HRMAM system was divided into three relatively independent segments, which were fitted perfectly with an original-designed applicator for ensuring easy operation in a smart self-service manner. Impressively, the HRMAM system achieved encouraging tumor growth inhibition of 75.11% and 72.29% in animal model of melanomas and breast carcinoma, respectively, much higher than those of other groups receiving traditional treatment, without obvious side effects. It was anticipated that the HRMAM system would manifest great promise to combat unreachable and deep-seated subcutaneous tumors, bellowing clinical values upon locoregional therapy products with high efficiency, low toxicity, flexible controllability, temporal-spatial precision, easy operation, as well as patient's painless, comfort and compliance.

The relationship between metabolic dysfunction-associated fatty liver disease and the incidence rate of extrahepatic cancer.

Background: The associations between metabolic dysfunction-associated fatty liver disease (MAFLD) and cancer development, especially extrahepatic cancers, are unknown. The aims of the current study were to investigate the cancer incidence rates of MAFLD and analyze the associations between MAFLD and the development of cancers. Methods: This historical cohort study included participants who underwent ultrasonographic detection of hepatic steatosis at a tertiary hospital in China from January 2013 to October 2021. MAFLD was diagnosed in accordance with The International Expert Consensus Statement. Cox proportional hazards regression modeling was used to assess the associations between MAFLD and the development of cancers. Results: Of the 47,801 participants, 16,093 (33.7%) had MAFLD. During the total follow-up of 175,137 person-years (median 3.3 years), the cancer incidence rate in the MAFLD group was higher than that in the non-MAFLD group [473.5 vs. 255.1 per 100,000 person-years; incidence rate ratio 1.86; 95% confidence interval (CI) 1.57-2.19]. After adjustment for age, gender, smoking status, and alcohol status, MAFLD was moderately associated with cancers of the female reproductive system/organs (labium, uterus, cervix, and ovary) [hazard ratio (HR) 2.24; 95% CI 1.09-4.60], thyroid (HR 3.64; 95% CI 1.82-7.30), and bladder (HR 4.19; 95% CI 1.15-15.27) in the total study cohort. Conclusion: MAFLD was associated with the development of cancers of the female reproductive system/organs (labium, uterus, cervix, and ovary), thyroid, and bladder in the total study cohort.

Agronomic and metabolomics analysis of rice-Tartary buckwheat (Fagopyrum tataricum Gaertn) bred by hybridization.

Tartary buckwheat (TB) is an edible pseudocereal with good health benefits, but its adhering thick shell and bitter taste inhibit its consumption. In this study, the first hybrid rice-Tartary buckwheat (RTB) variety Mikuqiao18 (M18), bred by the pedigree selection of crossbreeding 'Miqiao' (MQ) with 'Jingqiaomai2' (JQ2), was selected for an agronomic and metabolomics analysis. Compared with JQ2, M18 demonstrated a significantly lower yield per plant owing to the decreased grain weight and similar full-filling grain number per plant. However, M18 had a similar kernel weight per plant because of the thinner shell. The sense organ test suggested that M18 had higher taste quality regardless of partial replacement of rice through the improvement of preponderant indicators related to cereal taste quality, including lower values of total protein, albumin, glutelin, globulin, pasting temperature, cool paste viscosity, and setback. Meanwhile, M18 contained high levels of flavonoids, including rutin and quercetin, but presented a positive summary appraisal of cooking with 25% rice. Additionally, 92 metabolites were positively identified by GC-MS, including 59 differentially expressed metabolites (DEMs) between M18 and JQ2. Typically, M18 exhibited lower levels of 20 amino acids and higher levels of 6 sugars and 4 polyols. These DEMs might partly explain the superior eating quality of M18. In addition, M18 was abundant in 4-aminobutyric acid, which is beneficial to human health. The current findings offer a theoretical foundation for breeding rice-Tartary buckwheat with high yield and quality and promoting the cultivation and consumption of rice-Tartary buckwheat as a daily functional cereal.

Characterization of a Novel Creeping Tartary Buckwheat (Fagopyrum tataricum) Mutant lazy1.

Gravity is known as an important environmental factor involved in the regulation of plant architecture. To identify genes related to the gravitropism of Tartary buckwheat, a creeping line was obtained and designated as lazy1 from the mutant bank by 60Co-γ ray radiation. Genetic analysis indicated that the creeping phenotype of lazy1 was attributed to a single recessive locus. As revealed by the horizontal and inverted suspension tests, lazy1 was completely lacking in shoot negative gravitropism. The creeping growth of lazy1 occurred at the early seedling stage, which could not be recovered by exogenous heteroauxin, hormodin, α-rhodofix, or gibberellin. Different from the well-organized and equivalent cell elongation of wild type (WT), lazy1 exhibited dilated, distorted, and abnormally arranged cells in the bending stem. However, no statistical difference of indole-3-acetic acid (IAA) levels was found between the far- and near-ground bending sides in lazy1, which suggests that the asymmetric cell elongation of lazy1 was not induced by auxin gradient. Whereas, lazy1 showed up-expressed gibberellin-regulated genes by quantitative real-time PCR (qRT-PCR) as well as significantly higher levels of gibberellin, suggesting that gibberellin might be partly involved in the regulation of creeping growth in lazy1. RNA sequencing (RNA-seq) identified a number of differentially expressed genes (DEGs) related to gravitropism at stages I (before bending), II (bending), and III (after bending) between WT and lazy1. Venn diagram indicated that only Pectate lyase 5 was down-expressed at stages I [Log2 fold change (Log2FC): -3.20], II (Log2FC: -4.97), and III (Log2FC: -1.23) in lazy1, compared with WT. Gene sequencing revealed that a fragment deletion occurred in the coding region of Pectate lyase 5, which induced the destruction of a pbH domain in Pectate lyase 5 of lazy1. qRT-PCR indicated that Pectate lyase 5 was extremely down-expressed in lazy1 at stage II (0.02-fold of WT). Meanwhile, lazy1 showed the affected expression of lignin- and cellulose-related genes and cumulatively abnormal levels of pectin, lignin, and cellulose. These results demonstrate the possibility that Pectate lyase 5 functions as the key gene that could mediate primary cell wall metabolism and get involved in the asymmetric cell elongation regulation of lazy1.

Ethylene response factors 15 and 16 trigger jasmonate biosynthesis in tomato during herbivore resistance.

Jasmonates (JAs) are phytohormones with crucial roles in plant defense. Plants accumulate JAs in response to wounding or herbivore attack, but how JA biosynthesis is triggered remains poorly understood. Here we show that herbivory by cotton bollworm (Helicoverpa armigera) induced both ethylene (ET) and JA production in tomato (Solanum lycopersicum) leaves. Using RNA-seq, ET mutants, and inhibitors of ET signaling, we identified ET-induced ETHYLENE RESPONSE FACTOR 15 (ERF15) and ERF16 as critical regulators of JA biosynthesis in tomato plants. Transcripts of ERF15 and ERF16 were markedly upregulated and peaked at 60 and 15 min, respectively, after simulated herbivore attack. While mutation in ERF16 resulted in the attenuated expression of JA biosynthetic genes and decreased JA accumulation 15 min after the simulated herbivory treatment, these changes were not observed in erf15 mutants until 60 min after treatment. Electrophoretic mobility shift assays and dual-luciferase assays demonstrated that both ERFs15 and 16 are transcriptional activators of LIPOXYGENASE D, ALLENE OXIDE CYCLASE, and 12-OXO-PHYTODIENOIC ACID REDUCTASE 3, key genes in JA biosynthesis. Furthermore, JA-activated MYC2 and ERF16 also function as the transcriptional activators of ERF16, contributing to dramatic increases in ERF16 expression. Taken together, our results demonstrated that ET signaling is involved in the rapid induction of the JA burst. ET-induced ERF15 and ERF16 function as powerful transcriptional activators that trigger the JA burst in response to herbivore attack.

Genetic profiles of 103,106 individuals in the Taiwan Biobank provide insights into the health and history of Han Chinese.

Personalized medical care focuses on prediction of disease risk and response to medications. To build the risk models, access to both large-scale genomic resources and human genetic studies is required. The Taiwan Biobank (TWB) has generated high-coverage, whole-genome sequencing data from 1492 individuals and genome-wide SNP data from 103,106 individuals of Han Chinese ancestry using custom SNP arrays. Principal components analysis of the genotyping data showed that the full range of Han Chinese genetic variation was found in the cohort. The arrays also include thousands of known functional variants, allowing for simultaneous ascertainment of Mendelian disease-causing mutations and variants that affect drug metabolism. We found that 21.2% of the population are mutation carriers of autosomal recessive diseases, 3.1% have mutations in cancer-predisposing genes, and 87.3% carry variants that affect drug response. We highlight how TWB data provide insight into both population history and disease burden, while showing how widespread genetic testing can be used to improve clinical care.

Spatial Topological Relation Analysis for Cluttered Scenes.

The spatial topological relations are the foundation of robot operation planning under unstructured and cluttered scenes. Defining complex relations and dealing with incomplete point clouds from the surface of objects are the most difficult challenge in the spatial topological relation analysis. In this paper, we presented the classification of spatial topological relations by dividing the intersection space into six parts. In order to improve accuracy and reduce computing time, convex hulls are utilized to represent the boundary of objects and the spatial topological relations can be determined by the category of points in point clouds. We verified our method on the datasets. The result demonstrated that we have great improvement comparing with the previous method.

Towards a reference genome that captures global genetic diversity.

The current human reference genome is predominantly derived from a single individual and it does not adequately reflect human genetic diversity. Here, we analyze 338 high-quality human assemblies of genetically divergent human populations to identify missing sequences in the human reference genome with breakpoint resolution. We identify 127,727 recurrent non-reference unique insertions spanning 18,048,877 bp, some of which disrupt exons and known regulatory elements. To improve genome annotations, we linearly integrate these sequences into the chromosomal assemblies and construct a Human Diversity Reference. Leveraging this reference, an average of 402,573 previously unmapped reads can be recovered for a given genome sequenced to ~40X coverage. Transcriptomic diversity among these non-reference sequences can also be directly assessed. We successfully map tens of thousands of previously discarded RNA-Seq reads to this reference and identify transcription evidence in 4781 gene loci, underlining the importance of these non-reference sequences in functional genomics. Our extensive datasets are important advances toward a comprehensive reference representation of global human genetic diversity.

Viperin Inhibits Enterovirus A71 Replication by Interacting with Viral 2C Protein.

Enterovirus A71 (EVA71) is a human enterovirus belonging to the Picornaviridae family and mostly causes hand-foot-and-mouth disease in infants. Viperin is an important interferon-stimulated gene with a broad antiviral activity against various viruses. However, the effect of viperin on human enteroviruses and the interaction mechanism between EVA71 and viperin remains elusive. Here, we confirmed the EVA71-induced expression of viperin in a mouse model and cell lines and showed that viperin upregulation by EVA71 infection occurred on both the mRNA and protein level. Viperin knockdown and overexpression in EVA71-infected cells indicated that this protein can markedly inhibit EVA71 infection. Interestingly, immunofluorescent confocal microscopy and co-immunoprecipitation assays indicated that viperin interacts and colocalizes with the EVA71 protein 2C in the endoplasmic reticulum. Furthermore, amino acids 50⁻60 in the N-terminal domain of viperin were the key residues responsible for viperin interaction with 2C. More importantly, the N-terminal domain of viperin was found responsible for inhibiting EVA71 replication. Our findings can potentially aid future research on the prevention and treatment of nervous system damage caused by EVA71 and may provide a potential target for antiviral therapy.

MiR-16-5p mediates a positive feedback loop in EV71-induced apoptosis and suppresses virus replication.

Enterovirus 71 (EV71) is the predominant causative pathogen of hand-foot-and-mouth disease (HFMD). Contrary to other HFMD-causing enterovirus, EV71 can lead to severe neurological complications, even death. MicroRNAs (miRNAs) are small non-coding RNAs that constitute the largest family of gene regulators participating in numerous biological or pathological processes. We previously reported that miR-16-5p increases with severity of HFMD by investigating the expression patterns of host miRNAs in patients with HFMD. However, the mechanisms by which EV71 induces miR-16-5p expression are not clear, and the interaction between EV71 and miR-16-5p is not yet fully understood. Here, we confirmed EV71-induced expression of miR-16-5p both in vitro and in vivo and show that upregulation of miR-16-5p by EV71 infection may occur at the posttranscriptional level. Moreover, EV71-induced caspase activation facilitates the processing of pri-miR-16-1. We also revealed that miR-16-5p can promote EV71-induced nerve cells apoptosis through activating caspase-3. In addition, we found that miR-16-5p can inhibit EV71 replication. CCNE1 and CCND1, two important cell cycle regulators, play an important role in the suppression of EV71 replication by miR-16-5p. Therefore, miR-16-5p is a positive feedback regulator in EV71-induced apoptosis and a suppressor of virus replication. These results help in understanding the interaction network between miRNA and EV71 infection and provide a potential target for the development of antiviral therapy.

Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage.

Cutaneous adverse reactions (CARs) from antiepileptic drugs (AEDs) are common, ranging from mild to life-threatening, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The identification of subjects carrying the HLA-B*15:02, an inherited allelic variant of the HLA-B gene, and the avoidance of carbamazepine (CBZ) therapy in these subjects are strongly associated with a decrease in the incidence of carbamazepine-induced SJS/TEN. In spite of the strong genetic associations, the initiation of hypersensitivity for AEDs is still not very well characterized. Predicting the potential for other AEDs to cause adverse reactions will be undoubtedly beneficial to avoid CARs, which is the focus of this report. Here, we explore the use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to distinguish AEDs associated with and without CARs by examining the binding relationship of AEDs to HLA-B*15:02 and data from extensive reviews of medical records. We also evaluate the lack of benefit from a Hong Kong population policy on the effects of screening for HLA-B*15:02 and previous incorrect structure-activity hypotheses. Our analysis concludes that BDDCS class 2 AEDs are more prone to cause adverse cutaneous reactions than certain BDDCS class 1 AEDs and that BDDCS Class 3 drugs have the lowest levels of cutaneous adverse reactions. We propose that BDDCS Class 3 AEDs should be preferentially used for patients with Asian backgrounds (i.e., Han Chinese, Thai, and Malaysian populations) if possible and in patients predisposed to skin rashes.

Pharmacogenomics of adverse drug reactions: implementing personalized medicine.

Pharmacogenomics aims to investigate the genetic basis of inter-individual differences in drug responses, such as efficacy, dose requirements and adverse events. Research in pharmacogenomics has grown over the past decade, evolving from a candidate-gene approach to genome-wide association studies (GWASs). Genetic variants in genes coding for drug metabolism, drug transport and more recently human-leukocyte antigens (HLAs) have been linked to inter-individual differences in the risk of adverse drug reactions (ADRs). The tight association of specific HLA alleles with Stevens-Johnson syndrome, toxic epidermal necrolysis, drug hypersensitivity syndrome and drug-induced liver injury underscore the importance of HLA in the pathogenesis of these idiosyncratic drug hypersensitivity reactions. However, as with the search for the genetic basis for common diseases, pharmacogenomic research, including GWAS, has so far been a disappointment in discovering major gene variants responsible for the efficacy of drugs used to treat common diseases. This review focuses on the pharmacogenomics of ADRs, the underlying mechanisms and the potential use of genomic biomarkers in clinical practice for dose adjustment and the avoidance of drug toxicity. We also discuss obstacles to the implementation of pharmacogenomics and the direction of future translational research.