Tuberculosis (Edinb). 2022 Aug 8;136:102246. doi: 10.1016/j.tube.2022.102246. Online ahead of print.

ABSTRACT

Despite updated recommendations for weight-based isoniazid dosing in children with drug-susceptible tuberculosis (TB) and higher dose isoniazid in regimens for adults with drug-resistant TB, individual pharmacokinetic variability can lead to sub-target isoniazid exposure. Host pharmacogenetics and isoniazid exposure remain understudied, especially in the East African population. We therefore employed a real-time polymerase chain reaction (qPCR) assay system to test genomic DNA extracted from saliva samples targeting the NAT2 gene responsible for isoniazid metabolism to describe the frequency of human single nucleotide polymorphisms in NAT2 within populations of children and adults in Tanzania, ascribe those polymorphisms to acetylator phenotype, and correlate to serum isoniazid exposures. In adults treated with higher dose isoniazid, genotypes with a predicted allelic phenotype of slow or intermediate acetylation were able to achieve a 0.41 μg/mL higher Cmax (p = 0.018) and a 2.9h*μg/mL higher AUC0-12 (p = 0.003) per mg/kg increase in isoniazid dosage versus adults with rapid acetylation phenotype. A similar relationship was not found in the younger age population as predicted by timing of NAT2 maturation. This saliva based qPCR assay was fieldable to guide personalized isoniazid dosing in adults but not young children that may not have full NAT2 maturation and activity.

PMID:35961094 | DOI:10.1016/j.tube.2022.102246

High Blood Press Cardiovasc Prev. 2022 Aug 12. doi: 10.1007/s40292-022-00536-3. Online ahead of print.

ABSTRACT

INTRODUCTION: ABCB1 gene polymorphisms are associated with rivaroxaban distribution changes and adverse reactions but the data are controversial.

AIM: To evaluate the influence of ABCB1 (rs1045642 and rs4148738) gene polymorphisms on rivaroxaban pharmacokinetics in patients aged 80 years and older with nonvalvular atrial fibrillation (NAF).

METHODS: 128 patients aged 80 years and older (median [Me] age 87.5 [83.0-90.0] years) with NAF were included. We performed ABCB1 (rs1045642 and rs4148738) genotyping, measured the trough steady-state plasma concentration (Cmin,ss) of rivaroxaban and prothrombin time (PT) and analyzed prior medical records for clinically relevant non-major bleeding (CRNMB).

RESULTS: CC genotype carriers had no differences in Cmin,ss (p > 0.05) compared with the CT and TT rs1045642 and rs4148738 genotypes carriers. CC genotype carriers had no differences in PT (p > 0.05) compared with the CT rs1045642 and rs4148738 and TT rs4148738 genotypes carriers. In the TT genotype PT levels were higher than in the CC rs1045642 genotype: Me 14.2 [13.0-16.1] sec vs 13.3 [12.4-14.5] sec (p = 0.049). Incidence of CRNMB was higher in patients with the TT genotype compared with the CC rs1045642 (29.3% vs 4.5%, p = 0.021) and rs4148738 (39.3% vs 8.1%, p = 0.008) and the CT genotype rs4148738 (39.3% vs 14.3%, p = 0.002).

CONCLUSION: ABCB1 (rs1045642 and rs4148738) polymorphisms didn't influence rivaroxaban pharmacokinetics in patients aged 80 years and older with NAF. TT carriers developed CRNMB more frequently compared with the CC rs1045642 and the CC and CT rs4148738 genotypes. The haplotype TT-TT haplotype was associated with a higher frequency of CRNMB.

PMID:35960493 | DOI:10.1007/s40292-022-00536-3

Blood Cancer Discov. 2022 Aug 12:BCD-22-0011. doi: 10.1158/2643-3230.BCD-22-0011. Online ahead of print.

ABSTRACT

Despite the expanding portfolio of targeted therapies for adults with acute myeloid leukemia (AML), direct implementation in children is challenging due to inherent differences in underlying genetics. Here we established the pharmacological profile of pediatric AML by screening myeloblast sensitivity to approved and investigational agents, revealing candidates of immediate clinical relevance. Drug responses ex vivo correlated with patient characteristics, exhibited age-specific alterations, and concorded with activities in xenograft models. Integration with genomic data uncovered new gene-drug associations, suggesting actionable therapeutic vulnerabilities. Transcriptome profiling further identified gene expression signatures associated with on- and off-target drug responses. We also demonstrated the feasibility of drug screening-guided treatment for children with high-risk AML, with two evaluable cases achieving remission. Collectively, this study offers a high-dimensional gene-drug-clinical dataset that could be leveraged to research the unique biology of pediatric AML, and sets the stage for realizing functional precision medicine for clinical management of the disease.

PMID:35960210 | DOI:10.1158/2643-3230.BCD-22-0011

Am Heart J Plus. 2022 May;17:100152. doi: 10.1016/j.ahjo.2022.100152. Epub 2022 Jun 14.

ABSTRACT

BACKGROUND: Ischemic coronary heart disease (IHD) is the leading cause of death worldwide. Genetic variation is presumed to be a major factor underlying sex differences for IHD events, including mortality. The purpose of this study was to identify sex-specific candidate genes associated with all-cause mortality among people diagnosed with coronary artery disease (CAD).

METHODS: We performed a sex-stratified, exploratory genome-wide association (GWAS) screen using existing data from CAD-diagnosed males (n = 510) and females (n = 174) who reported European ancestry from the Duke Catheterization Genetics biorepository. Extant genotype data for 785,945 autosomal SNPs generated with the Human Omni1-Quad BeadChip (Illumina, CA, USA) were analyzed using an additive inheritance model. We estimated instantaneous risk of all-cause mortality by genotype groups across the 11-year follow-up using Cox multivariate regression, covarying for age and genomic ancestry.

RESULTS: The top GWAS hits associated with all-cause mortality among people with CAD included 8 SNPs among males and 15 among females (p = 1 × 10-6 or 10-7), adjusted for covariates. Cross-sex comparisons revealed distinct candidate genes. Biologically relevant candidates included rs9932462 (EMP2/TEKT5) and rs2835913 (KCNJ6) among males and rs7217169 (RAP1GAP2), rs8021816 (PRKD1), rs8133010 (PDE9A), and rs12145981 (LPGAT1) among females.

CONCLUSIONS: We report 20 sex-specific candidate genes having suggestive association with all-cause mortality among CAD-diagnosed subjects. Findings demonstrate proof of principle for identifying sex-associated genetic factors that may help explain differential mortality risk in people with CAD. Replication and meta-analyses in larger studies with more diverse samples will strengthen future work in this area.

PMID:35959094 | PMC:PMC9365120 | DOI:10.1016/j.ahjo.2022.100152

Int J Mol Sci. 2022 Aug 4;23(15):8686. doi: 10.3390/ijms23158686.

ABSTRACT

Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels. In addition to environmental risk factors, genetic predisposition increases the risk; this includes alterations in the vitamin D receptor gene (VDR). These alterations play a key role in modifying vitamin D uptake, being able to modify its function and increasing susceptibility to cardiovascular disorders. The aim of this study was to evaluate the association of polymorphisms in the VDR gene and risk of CVD in a Caucasian population. A retrospective case-control study was conducted comprising 246 CVD patients and 246 controls of Caucasian origin from Southern Spain. The genetic polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232), FokI (rs2228570) and Cdx2 (rs11568820) were determined by means of real-time polymerase chain reaction (PCR) for allelic discrimination using TaqMan® probes. The logistic regression analysis adjusted for body mass index and diabetes revealed that the TT genotype was associated with a higher risk of CVD in both the genotypic model (p = 0.0430; OR = 2.30; 95% CI = 1.06-5.37; TT vs. CC) and the recessive model (p = 0.0099; OR = 2.71; 95% CI = 1.31-6.07; TT vs. C). Haplotype analysis revealed that the haplotype GAC (p = 0.047; OR = 0.34; 95% CI = 0.12-0.98) was associated with increased risk of CVD. The VDR polymorphisms FokI (rs2228570) was significantly associated with the development of CVD. No influence was observed of the VDR polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232) and Cdx2 (rs11568820) on the risk of developing CVD in the patients studied.

PMID:35955825 | DOI:10.3390/ijms23158686

Int J Mol Sci. 2022 Jul 28;23(15):8360. doi: 10.3390/ijms23158360.

ABSTRACT

Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unluckily restricted to a small subgroup of patients. Much of the inter-individual variability in treatment efficacy is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. The nucleotide excision repair (NER) system is the main defense mechanism for repairing DNA damage caused by carcinogens and chemotherapy drugs. Single nucleotide polymorphisms (SNPs) of NER pathway key genes, altering mRNA expression or protein activity, can be significantly associated with response to chemotherapy, toxicities, tumor relapse or risk of developing cancer. In the present study, in a cohort of STS patients, we performed DNA extraction and genotyping by SNP assay, RNA extraction and quantitative real-time reverse transcription PCR (qPCR), a molecular dynamics simulation in order to characterize the NER pathway in STS. We observed a severe deregulation of the NER pathway and we describe for the first time the effect of SNP rs1047768 in the ERCC5 structure, suggesting a role in modulating single-stranded DNA (ssDNA) binding. Our results evidenced, for the first time, the correlation between a specific genotype profile of ERCC genes and proficiency of the NER pathway in STS.

PMID:35955506 | DOI:10.3390/ijms23158360

Int J Mol Sci. 2022 Jul 28;23(15):8364. doi: 10.3390/ijms23158364.

ABSTRACT

Statins are drugs widely prescribed in high-risk patients for cerebrovascular or cardiovascular diseases and are, usually, safe and well tolerated. However, these drugs sometimes may cause neuromuscular side effects that represent about two-third of all adverse events. Muscle-related adverse events include cramps, myalgia, weakness, immune-mediated necrotizing myopathy and, more rarely, rhabdomyolysis. Moreover, they may lead to peripheral neuropathy and induce or unmask a preexisting neuromuscular junction dysfunction. A clinical follow up of patients assuming statins could reveal early side effects that may cause neuromuscular damage and suggest how to better modulate their use. In fact, statin dechallenge or cessation, or the alternative use of other lipid-lowering agents, can avoid adverse events. This review summarizes the current knowledge on statin-associated neuromuscular adverse effects, diagnosis, and management. It is conceivable that the incidence of neuromuscular complications will increase because, nowadays, use of statins is even more diffused than in the past. On this purpose, it is expected that pharmacogenomic and environmental studies will help to timely predict neuromuscular complications due to statin exposure, leading to a more personalized therapeutic approach.

PMID:35955495 | DOI:10.3390/ijms23158364

Cells. 2022 Jul 29;11(15):2329. doi: 10.3390/cells11152329.

ABSTRACT

Prostate cancer (PCa) is the second most diagnosed cancer in the United States and is associated with metabolic reprogramming and significant disparities in clinical outcomes among African American (AA) men. While the cause is likely multi-factorial, the precise reasons for this are unknown. Here, we identified a higher expression of the metabolic enzyme UGT2B28 in localized PCa and metastatic disease compared to benign adjacent tissue, in AA PCa compared to benign adjacent tissue, and in AA PCa compared to European American (EA) PCa. UGT2B28 was found to be regulated by both full-length androgen receptor (AR) and its splice variant, AR-v7. Genetic knockdown of UGT2B28 across multiple PCa cell lines (LNCaP, LAPC-4, and VCaP), both in androgen-replete and androgen-depleted states resulted in impaired 3D organoid formation and a significant delay in tumor take and growth rate of xenograft tumors, all of which were rescued by re-expression of UGT2B28. Taken together, our findings demonstrate a key role for the UGT2B28 gene in promoting prostate tumor growth.

PMID:35954173 | DOI:10.3390/cells11152329

J Neurol Neurosurg Psychiatry. 2022 Aug 11:jnnp-2021-328516. doi: 10.1136/jnnp-2021-328516. Online ahead of print.

ABSTRACT

OBJECTIVES: Long COVID is a major public health issue. Whether long COVID is comorbid with psychiatric disorders remains unclear. Here, we investigate the association between long COVID, psychiatric symptoms and psychiatric disorders.

DESIGN: Cross-sectional.

SETTINGS: Bicêtre Hospital, France, secondary care.

PARTICIPANTS: One hundred seventy-seven patients admitted in intensive care unit during acute phase and/or reporting long COVID complaints were assessed 4 months after hospitalisation for an acute COVID.

MAIN OUTCOME MEASURES: Eight long COVID complaints were investigated: fatigue, respiratory and cognitive complaints, muscle weakness, pain, headache, paraesthesia and anosmia. The number of complaints, the presence/absence of each COVID-19 complaint as well as lung CT scan abnormalities and objective cognitive impairment) were considered. Self-reported psychiatric symptoms were assessed with questionnaires. Experienced psychiatrists assessed Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-based diagnoses of psychiatric disorders.

RESULTS: One hundred and fifteen (65%) patients had at least one long COVID complaint. The number of long COVID complaints was associated with psychiatric symptoms. The number of long COVID complaints was higher in patients with psychiatric disorders (mean (m) (SD)=2.47 (1.30), p<0.05), new-onset psychiatric disorders (m (SD)=2.41 (1.32), p<0.05) and significant suicide risk (m (SD)=2.67 (1.32), p<0.05) than in patients without any psychiatric disorder (m (SD)=1.43 (1.48)). Respiratory complaints were associated with a higher risk of psychiatric disorder and new-onset psychiatric disorder, and cognitive complaints were associated with a higher risk of psychiatric disorder.

CONCLUSIONS: Long COVID is associated with psychiatric disorders, new-onset psychiatric disorders and suicide risk. Psychiatric disorders and suicide risk should be systematically assessed in patients with long COVID.

PMID:35953265 | DOI:10.1136/jnnp-2021-328516

Adv Pharmacol. 2022;95:49-72. doi: 10.1016/bs.apha.2022.05.001. Epub 2022 Jul 20.

ABSTRACT

With the availability of detailed genomic data on all 57 human cytochrome P450 genes, it is clear that there is substantial variability in gene product activity with functionally significant polymorphisms reported across almost all isoforms. This article is concerned mainly with 13 P450 isoforms of particular relevance to xenobiotic metabolism. After brief review of the extent of polymorphism in each, the relevance of selected P450 isoforms to both adverse drug reaction and disease susceptibility is considered in detail. Bleeding due to warfarin and other coumarin anticoagulants is considered as an example of a type A reaction with idiosyncratic adverse drug reactions affecting the liver and skin as type B. It is clear that CYP2C9 variants contribute significantly to warfarin dose requirement and also risk of bleeding, with a minor contribution from CYP4F2. In the case of idiosyncratic adverse drug reactions, CYP2B6 variants appear relevant to both liver and skin reactions to several drugs with CYP2C9 variants also relevant to phenytoin-related skin rash. The relevance of P450 genotype to disease susceptibility is also considered but detailed genetic studies now suggest that CYP2A6 is the only P450 relevant to risk of lung cancer with alleles associated with low or absent activity clearly protective against disease. Other cytochrome P450 genotypes are generally not predictors for risk of cancer or other complex disease development.

PMID:35953163 | DOI:10.1016/bs.apha.2022.05.001

Adv Pharmacol. 2022;95:393-416. doi: 10.1016/bs.apha.2022.04.004. Epub 2022 Jul 18.

ABSTRACT

The cytochromes P450s can be divided in two groups, those of high importance for endogenous functions being evolutionary quite stable and those participating in detoxification of drugs and other xenobiotics having less important endogenous functions. In the latter group extensive genetic diversity has been allowed and in addition this is of high importance for survival in different environments. The genetic polymorphisms in these genes have evolved to some extent based on dietary restrictions and environmental factors and have not been subject of conservation due to less importance for survival. In cases of high dietary selection events, gene multiplication and amplification events have been seen. The different variants in genes encoding drug metabolizing enzymes can be used as genetic biomarkers (pharmacogenomic labels) for adjustment of drug treatment leading to less adverse drug reactions and better response. Indeed, this has improved the use of personalized medicine, although the missing heredity seen based on twin studies indicates that there are indeed many more genetic variants to be discovered before one can achieve a satisfactory relationship between genotype and phenotype with respect to drug metabolism and toxicity.

PMID:35953162 | DOI:10.1016/bs.apha.2022.04.004

Adv Pharmacol. 2022;95:365-391. doi: 10.1016/bs.apha.2022.05.006. Epub 2022 Jul 19.

ABSTRACT

Cytochrome P450 enzymes play an important role in the pharmacokinetics, efficacy, and toxicity of drugs. Age-dependent changes in P450 enzyme expression have been studied based on several detection systems, as well as by deconvolution of in vivo pharmacokinetic data observed in pediatric populations. The age-dependent changes in P450 enzyme expression can be important determinants of drug disposition in childhood, in addition to the changes in body size and the other physiological parameters, and effects of pharmacogenetics and disease on organ functions. As a tool incorporating drug-specific and body-specific factors, physiologically-based pharmacokinetic (PBPK) models have become increasingly used to characterize and explore mechanistic insights into drug disposition. Thus, PBPK models can be a bridge between findings from basic science and utilization in predictive science. Pediatric PBPK models incorporate additional system specific information on developmental physiology and ontogeny and have been used to predict pharmacokinetic parameters from preterm neonates onwards. These models have been advocated by regulatory authorities in order to support pediatric clinical trials. The purpose of this chapter is to highlight accumulated knowledge and findings from basic research focusing on P450 enzymes, as well as the current status and future challenges of expanding the utilization of pediatric PBPK modeling.

PMID:35953161 | DOI:10.1016/bs.apha.2022.05.006

J Psychiatr Res. 2022 Jul 31;154:209-218. doi: 10.1016/j.jpsychires.2022.07.049. Online ahead of print.

ABSTRACT

OBJECTIVE: Canada exhibits one of highest lifetime prevalence for post-traumatic stress disorder (PTSD), but the etiology of this debilitating mental health condition still remains largely unknown. This study aims to examine the genetics of PTSD in the Canadian Longitudinal Study on Aging (CLSA) to identify potential genetic factors involved in the development of PTSD.

METHOD: The CLSA sample was screened for primary (PTSD status) and secondary outcomes (avoidance, detachment, guardedness, and nightmares) based on the Primary Care PTSD Screen Scale (PC-PTSD). After GWAS quality control and whole-genome imputation, single-marker, gene-based, and polygenic risk score (PRS) analyses were performed.

RESULTS: Based on available genotype and phenotype data, N = 16,535 individuals were selected for the analyses. While genome-wide analyses did not show significant findings for our primary and secondary outcomes, PRS analyses showed variable levels of association between PC-PTSD items with trauma, major depressive disorder, schizophrenia, bipolar disorder, educational attainment, and insomnia (p < 5e-4).

CONCLUSION: This is the first GWAS of PTSD status and individual PC-PTSD items in a population sample of older adults from Canada. This study was also able to replicate findings from previous studies. Genetic investigations into individual symptom components of PTSD may help untangle the complex genetic architecture of PTSD.

PMID:35952521 | DOI:10.1016/j.jpsychires.2022.07.049

Health Sci Rep. 2022 Aug 8;5(5):e762. doi: 10.1002/hsr2.762. eCollection 2022 Sep.

ABSTRACT

BACKGROUND AND AIMS: Vitamin C has been predicted to be effective as an antioxidant in treating various ailments, including viral infections such as pervasive coronavirus disease (COVID-19). With this meta-analysis, we looked to ascertain the relationship between high-dose vitamin C administration and mortality, severity, and length of hospitalization of COVID-19 patients.

METHODS: We collected articles from PubMed, Google Scholar, ScienceDirect, SAGE, and Cochrane databases between January 1, 2020, and May 30, 2022. Odds ratio (ORs) with corresponding 95% confidence interval (CI) and p value were calculated to assess the connection of high-dose vitamin C in COVID-19 patients' mortality and severity. The length of hospitalization was calculated and pooled with the mean difference (MD), 95% CI, and p value. Review manager 5.3 was used to carry out this meta-analysis.

RESULTS: This meta-analysis included 15 complete studies involving 2125 COVID-19 patients. Our study demonstrated a significant correlation between vitamin C consumption and death. Vitamin C consumption significantly reduces mortality risk with COVID-19 patients (OR = 0.54, 95% CI = 0.42-0.69, p < 0.00001). Furthermore, there was a link between the severity of COVID-19 and the intake of vitamin C. Patients who consumed vitamin C showed 0.63 times less severity than those who did not take vitamin C (OR = 0.63, 95% CI = 0.43-0.94, p = 0.02). Patients taking vitamin C spent slightly more time in hospital than those who did not take vitamin C (MD = 0.19, 95% CI = -1.57 to 1.96, p = 0.83).

CONCLUSIONS: During COVID-19, there was a substantial advantage in taking supplementary vitamin C, at least in terms of severity and mortality.

PMID:35949675 | PMC:PMC9358542 | DOI:10.1002/hsr2.762

Exp Ther Med. 2022 Jul 19;24(3):584. doi: 10.3892/etm.2022.11521. eCollection 2022 Sep.

ABSTRACT

Vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) have been investigated over the past years with the aim of identifying any association with the development of Alzheimer's disease (AD). However, information regarding the potential association of VDR SNP haplotypes with AD is limited. The aim of the present study was to provide additional knowledge on the effects of VDR haplotypes on the development of late-onset AD in a cohort of Southeastern European Caucasians (SECs). The study sample included 78 patients with late-onset AD and 103 healthy subjects as the control group. VDR SNPs that were analyzed were TaqI (rs731236), BsmI (rs1544410) and FokI (rs2228570). The CAC (TaqI, BsmI and FokI) haplotype was found to be associated with a 53% lower risk of developing the disease (OR, 0.47; 95% CI, 0.23-0.96; P=0.04) and the TAC (TaqI, BsmI and FokI) haplotype was associated with an ~6-fold greater risk of developing AD (OR, 6.19; 95% CI, 1.91-20.13; P=0.0028). Female subjects carrying the TAC haplotype had a ~9-fold greater risk of developing AD in comparison to female control subjects (OR, 9.27; 95% CI, 1.86-46.28; P<0.05). The TaqI and BsmI polymorphisms were in high linkage disequilibrium (D'=0.9717, r=0.8467) and produced a haplotype with a statistically significant different frequency between the control and AD group. The TA (TaqI and BsmI) haplotype was associated with an ~8-fold greater risk of developing AD (OR, 8.27; 95% CI, 2.70-25.28; P<0.05). Female TA carriers had an ~14-fold greater risk of developing the disease in comparison to female control subjects (OR, 13.93; 95% CI, 2.95-65.87; P<0.05). On the whole, the present study demonstrates that in the SEC population, TAC and TA are risk haplotypes for AD, while the CAC haplotype may act protectively. SEC women carrying the TAC or TA haplotype are at a greater risk of developing AD, thus suggesting that women are markedly affected by the poor utilization of vitamin D induced by the VDR haplotype.

PMID:35949319 | PMC:PMC9353461 | DOI:10.3892/etm.2022.11521

Pediatr Pulmonol. 2022 Aug 10. doi: 10.1002/ppul.26109. Online ahead of print.

ABSTRACT

BACKGROUND: Mannose binding lectin (MBL) is an important component of the innate immune system. Polymorphisms in the MBL2 gene and promoter region are directly associated with MBL-deficiency. We sought to determine the association between MBL genotype on the frequency of common childhood respiratory infections, respiratory symptoms, and atopic outcomes in early childhood.

METHODS: MBL2 gene variants were analysed in newborns recruited to the GO-CHILD multi-centre prospective cohort study. Follow-up for respiratory infection and atopy diagnoses and symptoms, healthcare utilisation and medication prescription were conducted by postal questionnaires at 12 and 24-months.

RESULTS: Genotyping and follow-up were completed in 1004 children. Genotypes associated with MBL-deficiency were associated with an increased risk of bronchiolitis (relative risk (RR) 1.95, 95%CI 1.33-2.85)) and pneumonia (RR 2.46, 95%CI 1.16-5.22). MBL-deficient genotypes were associated with an increased risk of wheeze with shortness of breath episodes (RR 1.22, 95%CI 1.04-1.43), emergency department attendance (RR 1.90 95%CI 1.13-3.19) and hospital admission (RR 2.01, 95%CI 1.04-3.89) for wheeze. MBL-deficient genotypes were associated with a reduced risk of developing atopic dermatitis (RR 0.72, 95%CI 0.53-0.98).

CONCLUSION: The positive association between MBL-deficient genotypes and bronchiolitis and pneumonia, as well as a severe wheeze phenotype in some young children, supports the hypothesis that MBL is an important component of innate immunity in the vulnerable period prior to the maturation of the adaptive immune system. Identification of disease modifying genotypes may help target preventative strategies in high-risk infants. This article is protected by copyright. All rights reserved.

PMID:35949104 | DOI:10.1002/ppul.26109

J Clin Pharmacol. 2022 Aug 9. doi: 10.1002/jcph.2138. Online ahead of print.

ABSTRACT

The susceptibility of different individuals to anesthetics varies widely, and sevoflurane is no exception. We hypothesized that polymorphisms in genes involved in pharmacokinetics and pharmacodynamics may explain this variation. One hundred fifty-one individuals undergoing otorhinolaryngology surgery were included. The influence of genetic polymorphisms on sevoflurane sensitivity were investigated through SNaPshot technology. Individuals carrying KCNK2 rs6686529 G > C, MTRR rs3733784 TT, rs2307116 GG, or rs1801394 AA polymorphisms had a higher sensitivity to the sedative effect of sevoflurane than those without those polymorphisms. The univariate linear regression analysis indicated that MTRR rs3733784 TT, rs2307116 GG and rs1801394 AA were potentially significant predictors of higher sensitivity to the sedative effect of sevoflurane. Moreover, CYP2E1 rs3813867 G > C and rs2031920 C > T, GABRG1 rs279858 T > C, KCNK3 rs1275988 CC, GRIN2B rs1806201 GG, MTRR rs2307116 G > A and rs1801394 A > G were associated with a higher sensitivity to the cardiovascular effect of sevoflurane. Our results suggested that nine SNPs in genes involved in metabolizing enzymes, transport proteins, target proteins of sevoflurane and folate metabolism may help to explain individual differences in the susceptibility to the sedative or cardiovascular effect of sevoflurane. This article is protected by copyright. All rights reserved.

PMID:35943164 | DOI:10.1002/jcph.2138

Br J Clin Pharmacol. 2022 Aug 9. doi: 10.1111/bcp.15485. Online ahead of print.

ABSTRACT

AIMS: The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin.

METHODS: We conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n=159) and a cohort of previously published studies (n=88).

RESULTS: In the genome-wide association meta-analysis of a prospective study and a cohort of previously published studies with rosuvastatin pharmacokinetic data, the SLCO1B1 c.521T>C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax ) of rosuvastatin (P=1.8×10-12 and P=3.2×10-15 ). The candidate gene analysis suggested that the ABCG2 c.421C>A (rs2231142) SNV associates with increased rosuvastatin AUC (P=0.0079), while the SLCO1B1 c.388A>G (rs2306283) and SLCO2B1 c.1457C>T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P=0.0041 and P=0.0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased, and highly increased OATP1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6-2.8, P=4.69×10-5 ) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16%-62%; P=0.019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2-fold (1.5-3.0; P=2.6×10-4 ) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11-42%; P=0.01).

CONCLUSIONS: These data suggest roles for SLCO1B1, ABCG2, and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.

PMID:35942816 | DOI:10.1111/bcp.15485

Front Pharmacol. 2022 Jul 22;13:897951. doi: 10.3389/fphar.2022.897951. eCollection 2022.

ABSTRACT

A wide inter-individual variability in the therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) has been reported. We herein present a case series of five patients treated with either palbociclib or ribociclib referred to our clinical pharmacological counselling, including therapeutic drug monitoring (TDM), pharmacogenetics, and drug-drug interaction analysis to support clinicians in the management of CDKis treatment for metastatic breast cancer. Patients' plasma samples for TDM analysis were collected at steady state and analyzed by an LC-MS/MS method for minimum plasma concentration (Cmin) evaluation. Under and overexposure to the drug were defined based on the mean Cmin values observed in population pharmacokinetic studies. Polymorphisms in selected genes encoding for proteins involved in drug absorption, distribution, metabolism, and elimination were analyzed (CYP3A4, CYP3A5, ABCB1, SLCO1B1, and ABCG2). Three of the five reported cases presented a CDKi plasma level above the population mean value and were referred for toxicity. One of them presented a low function ABCB1 haplotype (ABCB1-rs1128503, rs1045642, and rs2032582), possibly causative of both increased drug oral absorption and plasmatic concentration. Two patients showed underexposure to CDKis, and one of them was referred for early progression. In one patient, a CYP3A5*1/*3 genotype was found to be potentially responsible for more efficient drug metabolism and lower drug plasma concentration. This intensified pharmacological approach in clinical practice has been shown to be potentially effective in supporting prescribing oncologists with dose and drug selection and could be ultimately useful for increasing both the safety and efficacy profiles of CDKi treatment.

PMID:35942220 | PMC:PMC9356076 | DOI:10.3389/fphar.2022.897951

Tuberculosis (Edinb). 2022 Jul 16;136:102233. doi: 10.1016/j.tube.2022.102233. Online ahead of print.

ABSTRACT

Single nucleotide polymorphisms (SNPs) in IRGM are reported to affect Mycobacterium tuberculosis (M.tb) degradation pathway. Here, we aim to screen promoter-region regulatory SNPs of IRGM in Pakistani population. DNA extracted from blood of cohort containing 70 TB patients (TB) and 30 controls subjects (Ctrl), was amplified for IRGM promoter region, followed by DNA sequencing. Group-specific variations were found in allelic frequencies at four loci. Allele T (p-value = 0.03) at -1161T/C, allele G (p-value = 0.027) at -1133G/A; allele C (p-value = 0.029) at -1049C/T; and allele G (p-value = 0.02) at -708G/A, showed higher associations with TB in our cohort. These SNPs display strong linkage disequilibrium (LD) in Pakistani population. Haplotype analysis showed a significant association of haplotype -1161T/-1133G/-1049C/-708G (p-value = 0.007) to TB. This 4-SNP haplotype also represents an expression quantitative trait locus (eQTL), associated with Crohn's disease and chronic inflammatory diseases. Our findings show that variants -1161T/C, -1133G/A, -1049C/T, and -708G/A are associated with IRGM expression and susceptibility to TB in a Pakistani population.

PMID:35939988 | DOI:10.1016/j.tube.2022.102233