Interindividual differences in drug disposition are important causes for adverse drug reactions and lack of drug response. The majority of phase I and phase II drug-metabolizing enzymes (DMEs) are ...polymorphic and constitute essential factors for the outcome of drug therapy. Recently, both genome-wide association (GWA) studies with a focus on drug response, as well as more targeted studies of genes encoding DMEs have revealed in-depth information and provided additional information for variation in drug metabolism and drug response, resulting in increased knowledge that aids drug development and clinical practice. In addition, an increasing number of meta-analyses have been published based on several original and often conflicting pharmacogenetic studies. Here, we review data regarding the pharmacogenomics of DMEs, with particular emphasis on novelties. We conclude that recent studies have emphasized the importance of CYP2C19 polymorphism for the effects of clopidogrel, whereas the CYP2C9 polymorphism appears to have a role in anticoagulant treatment, although inferior to VKORC1. Furthermore, the analgesic and side effects of codeine in relation to CYP2D6 polymorphism are supported and the influence of CYP2D6 genotype on breast cancer recurrence during tamoxifen treatment appears relevant as based on three large studies. The influence of CYP2D6 polymorphism on the effect of antidepressants in a clinical setting is yet without any firm evidence, and the relation between CYP2D6 ultrarapid metabolizers and suicide behavior warrants further studies. There is evidence for the influence of CYP3A5 polymorphism on tacrolimus dose, although the influence on response is less studied. Recent large GWA studies support a link between CYP1A2 polymorphism and blood pressure as well as coffee consumption, and between CYP2A6 polymorphism and cigarette consumption, which in turn appears to influence the lung cancer incidence. Regarding phase II enzyme polymorphism, the anticancer treatment with mercaptopurines and irinotecan is still considered important in relation to the polymorphism of TPMT and UGT1A1, respectively. There is a need for further clarification of the clinical importance and use of all these findings, but the recent research in the field that encompasses larger studies and a whole genome perspective, improves the possibilities be able to make firm and cost-effective recommendations for drug treatment in the future.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background The B cell-activating factor (BAFF) promotes the maturation, differentiation, and survival of B lymphocytes, which play an important role in the pathogenesis of systemic lupus ...erythematosus (SLE). This cytokine has been associated with SLE disease activity, hence TNFSF13B gene, which encodes BAFF, along with its diverse single-nucleotide polymorphisms (SNPs) might also be associated with more severe SLE activity. The aim of this study was to explore the association between TNFSF13B genetic polymorphisms with disease activity, as well as serum soluble BAFF (s-BAFF) levels in SLE patients. Methods This cross-sectional study included SLE patients in rheumatology clinic and in-patient wards of Dr. Hasan Sadikin General Hospital, Bandung, between February 2020 -March 2022. One single nucleotide rs9514828 (C>T -871) polymorphism in the 5’ regulatory region of the TNFSF13B gene were identified by PCR-sequencing. Serum BAFF levels were measured by ELISA and disease activity was measured by MEX-SLEDAI score. The active disease was determined by MEX-SLEDAI 2. The statistical analysis was performed using Mann-Whitney, Chi-Square, and Spearman test for the correlation. Results There were 107 SLE patients, all female with median age of 32 years old (interquartile range IQR, 15–64). The median disease duration was 5 years (IQR 0.5–22), whereas the median s-BAFF levels was 846.9 pg/mL (IQR 185–6979.88). The s-BAFF levels were significantly elevated in active disease patients compared to inactive disease (953.17 pg/ml vs 781.4 pg/mL; p 0.008). There was a weak positive correlation between s-BAFF levels and disease activity (r 0.311; p 0.001). There were no differences in genotype TNFSF13B polymorphisms with the disease activity. Conclusions Although the rs9514828 (C>T -871) of TNFSF13B gene promoter does not seem to be related with SLE activity, s-BAFF levels is, however, correlated with disease activity. Further study to explore other polymorphisms in TNFSF13B gene is of great interest.
Objective To analyze the distribution of ApoE and SLCO1B1 genetic polymorphisms of patients with cardiovascular and cerebrovascular diseases in Han nationality of Hebei region. Methods Patients with ...cardiovascular and cerebrovascular diseases admitted to our hospital corresponding department from June 2019 to October 2020 were selected. The polymorphisms of ApoE and SLCO1B1 genes in 4193 patients with cardiovascular and cerebrovascular diseases were detected qualitatively by polymerase chain reaction (PCR)⁃fluorescence probe technique, to analyze the distribution characteristics of polymorphism and compare the genotype distribution difference between male and female. Results The observed mutation frequencies of ApoE and SLCO1B1 gene polymorphism of Han nationality in Hebei region were consistent with the Hardy⁃Weinberg genetic balance. Moreover, there was no significant difference in the distribution of ApoE gene polymorphism at 388T>C and 526C>T and SLCO1B1 gene polymorphism at 388A>G and 521T>C between men
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FFLJ, NUK, ODKLJ, UL, UM, UPUK, VSZLJ
Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit inter-individual differences in effect, termed 'variable penetrance'. Here, we study ...how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.
This study investigated the incidence of sulfonylurea-induced hypoglycemia and its predictors in Type 2 diabetes (T2D) patients.
In this prospective, observational study, T2D patients on maximal ...sulfonylurea-metformin therapy >1 year were enrolled. Hypoglycemia was defined as having symptoms or a blood glucose level <3.9 mmol/l.
Of the 401 patients, 120 (29.9%) developed sulfonylurea-induced hypoglycemia during the 12-month follow-up. The
rs757110,
rs5219,
rs7756992 and
rs2237892 gene polymorphisms were not associated with sulfonylurea-induced hypoglycemia (p > 0.05). Prior history of hypoglycemia admission (odds ratio = 16.44; 95% CI: 1.74–154.33, p = 0.014) independently predicted its risk.
Sulfonylurea-treated T2D patients who experienced severe hypoglycemia are at increased risk of future hypoglycemia episodes.
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