Diabetes Care. 2021 Apr 16:dc202700. doi: 10.2337/dc20-2700. Online ahead of print.

ABSTRACT

OBJECTIVE: Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals.

RESEARCH DESIGN AND METHODS: ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D would reduce CVD outcomes. Using a novel approach to cluster HbA1c trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality.

RESULTS: We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD (hazard ratio [HR] 0.34; P = 2.01 × 10-3) and microvascular outcomes (HR 0.86; P = 0.015) than those receiving standard treatment. A single-nucleotide polymorphism, rs220721, in MAS1 reached suggestive significance in C4 (P = 4.34 × 10-7). PS predicted C4 with high accuracy (area under the receiver operating characteristic curve 0.98), and this predicted C4 displayed reduced CVD risk with intensive versus standard glycemia treatment (HR 0.53; P = 4.02 × 10-6), but not reduced risk of microvascular outcomes (P < 0.05). Mendelian randomization indicated causality between PS, on-trial HbA1c, and reduction in CVD outcomes (P < 0.05).

CONCLUSIONS: We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership in this group could be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development in this landmark clinical trial warranting further investigation.

PMID:33863751 | DOI:10.2337/dc20-2700

Breast Cancer Res Treat. 2021 Apr 15. doi: 10.1007/s10549-021-06191-x. Online ahead of print.

ABSTRACT

PURPOSE: Genomic tests can guide the decision to administer adjuvant chemotherapy in women with hormone receptor (HR)-positive, Human Epidermal growth Factor 2 (HER2)-negative breast cancer (BC) at intermediate risk of recurrence. We assessed the decision-making and economic impact of the Prosigna test in a real-life setting.

METHODS: Retrospective cohort study of HR + , HER2- BC patients managed from 2016 to 2020, potential candidates for adjuvant chemotherapy, at intermediate risk of recurrence, in whom a Prosigna test was performed according to contemporary guidelines. The additional cost of chemotherapy over one year in terms of direct medical and non-medical costs was estimated in this study to be €9,737 (derived from a previous study, NCT02813317). The cost of the Prosigna test, as defined by the reimbursement system, was €1,849.

RESULTS: Among the 809 patients included in this study, 2.3 Prosigna tests had to be performed to avoid adjuvant chemotherapy for one patient. The number of tests that had to be performed to avoid chemotherapy for one patient was higher for patients with grade 3 tumors and pN1mic axillary node involvement and lower for grade 1 tumors or in the absence of axillary node involvement (pN0), but did not vary according to the 10-year overall survival gain predicted by the Predict online test. The cost saving related to withholding of adjuvant chemotherapy for one patient on the basis of the Prosigna test results was €5,485.

CONCLUSION: We present one of the largest cohorts of HR + , HER2- BC patients at intermediate risk of recurrence, in whom a Prosigna test was used to guide the adjuvant therapy decision in a real-life setting, resulting in a 44% decrease in the indication for chemotherapy.

PMID:33860387 | DOI:10.1007/s10549-021-06191-x

Endosc Int Open. 2021 Apr;9(4):E562-E571. doi: 10.1055/a-1353-4849. Epub 2021 Apr 12.

ABSTRACT

Background and study aims Adherence to colorectal cancer (CRC) screening is still unsatisfactory in many countries, thereby limiting prevention of CRC. Colon capsule endoscopy (CCE), a minimally invasive procedure, could be an alternative to fecal immunochemical tests or optical colonoscopy for CRC screening, and might increase adherence in CRC screening. This systematic review and meta-analysis evaluates the diagnostic accuracy of CCE compared to optical colonoscopy (OC) as the gold standard, adequacy of bowel preparation regimes and the patient perspective on diagnostic measures. Methods We conducted a systematic literature search in PubMed, EMBASE and the Cochrane Register for Clinical Trials. Pooled estimates for sensitivity, specificity and the diagnostic odds ratio with their respective 95 % confidence intervals (CI) were calculated for studies providing sufficient data. Results Of 840 initially identified studies, 13 were included in the systematic review and up to 9 in the meta-analysis. The pooled sensitivities and specificities for polyps ≥ 6 mm were 87 % (95 % CI: 83 %-90 %) and 87 % (95 % CI: 76 %-93 %) in 8 studies, respectively. For polyps ≥ 10 mm, the pooled estimates for sensitivities and specificities were 87 % (95 % CI: 83 %-90 %) and 95 % (95 % CI: 92 %-97 %) in 9 studies, respectively. A patients' perspective was assessed in 31 % (n = 4) of studies, and no preference of CCE over OC was reported. Bowel preparation was adequate in 61 % to 92 % of CCE exams. Conclusions CCE provides high diagnostic accuracy in an adequately cleaned large bowel. Conclusive findings on patient perspectives require further studies to increase acceptance/adherence of CCE for CRC screening.

PMID:33860073 | PMC:PMC8041571 | DOI:10.1055/a-1353-4849

Sci Rep. 2021 Apr 15;11(1):8298. doi: 10.1038/s41598-021-87921-5.

ABSTRACT

Two 3-oxo-Δ4 fetal bile acids, 3-oxachola-4,6-dien-24-oic acid (1) and 7α-hydroxy-3-oxochol-4-en-24-oic acid (2), occur normally in the human fetus but remain elevated in neonates and children with severe cholestatic liver disease due to an autosomal recessive inborn error of metabolism affecting Δ4-3-oxo-steroid 5β-reductase (AKR1D1). Relatively little is known about 1 and 2 in adult patients with liver disease. The chemical synthesis of 1 and 2 is therefore described and their quantitation in plasma by ultrarapid chromatography-triple quadrupole mass spectrometry. Plasma concentrations of 1 and 2 were investigated in 25 adult patients with varying degrees of liver cirrhosis with and without hepatocellular carcinoma (HCC). Highly statistically significant correlations (P < 0.0001) were found between severity of liver cirrhosis, determined by the Child-Pugh and MELD scores, with plasma 1 and 2 concentrations, both alone and combined. The presence of HCC did not influence these correlations. Plasma cholic, chenodeoxycholic, deoxycholic, lithocholic or ursodeoxycholic acids, free and as their glycine or taurine conjugates, did not correlate with Child-Pugh or MELD score when corrected for multiple comparisons. These findings demonstrate that plasma levels of fetal bile acids 3-oxachola-4,6-dien-24-oic acid and 7α-hydroxy-3-oxochol-4-en-24-oic acid and likely deteriorating AKR1D1 activity indicate the severity of liver cirrhosis measured by the Child-Pugh and MELD scores.

PMID:33859329 | DOI:10.1038/s41598-021-87921-5

J Transl Med. 2021 Apr 15;19(1):151. doi: 10.1186/s12967-021-02816-3.

ABSTRACT

BACKGROUND: Pharmacogenomics describes the link between gene variations (polymorphisms) and drug responses. In view of the implementation of precision medicine in personalized healthcare, pharmacogenetic tests have recently been introduced in the clinical practice. However, the translational aspects of such tests have been limited due to the lack of robust population-based evidence.

MATERIALS: In this paper we present a novel pharmacogenetic panel (iDNA Genomics-PGx-CNS or PGx-CNS), consisting of 24 single nucleotide polymorphisms (SNPs) on 13 genes involved in the signaling or/and the metabolism of 28 approved drugs currently administered to treat diseases of the Central Nervous System (CNS). We have tested the PGx-CNS panel on 501 patient-derived DNA samples from a southeastern European population and applied biostatistical analyses on the pharmacogenetic associations involving drug selection, dosing and the risk of adverse drug events (ADEs).

RESULTS: Results reveal the occurrences of each SNP in the sample and a strong correlation with the European population. Nonlinear principal component analysis strongly indicates co-occurrences of certain variants. The metabolization efficiency (poor, intermediate, extensive, ultra-rapid) and the frequency of clinical useful pharmacogenetic, associations in the population (drug relevance), are also described, along with four exemplar clinical cases illustrating the strong potential of the PGx-CNS panel, as a companion diagnostic assay. It is noted that pharmacogenetic associations involving copy number variations (CNVs) or the HLA gene were not included in this analysis.

CONCLUSIONS: Overall, results illustrate that the PGx-CNS panel is a valuable tool supporting therapeutic medical decisions, urging its broad clinical implementation.

PMID:33858454 | DOI:10.1186/s12967-021-02816-3

Pharmacogenomics. 2021 Apr 16. doi: 10.2217/pgs-2021-0004. Online ahead of print.

ABSTRACT

Aim: Teaching of genetics and pharmacogenetics with personal genotyping (PGT) is becoming commonplace. We aimed to perform a systematic review and meta-analysis to understand the effects of PGT on student outcomes. Methods: A systematic review was performed on studies that reported the effects of PGT on student attitudes, perceptions or knowledge. Extracted data were summarized qualitatively and when possible, quantitatively. Results: Student PGT has a positive effect on student attitude and perceptions survey responses in studies without a control group (p = 0.009) and in studies with a control group (p = 0.025). Knowledge increased after the use of PGT (p < 0.001) in studies without a control group. Conclusion: The findings here suggest that perceptions, attitudes and knowledge increase with PGT in the classroom.

PMID:33858193 | DOI:10.2217/pgs-2021-0004

Pharmacogenomics. 2021 Apr 16. doi: 10.2217/pgs-2020-0171. Online ahead of print.

ABSTRACT

Aim: Explore the possible association between clinical factors and genetic variants of the dopamine pathways and negative symptoms. Materials & methods: Negative symptoms were assessed in 206 patients with schizophrenia using the Arabic version of the self-evaluation of negative symptoms scale and the Positive and Negative Syndrome Scale. Genotyping for COMT, DRD2, MTHFR and OPRM1 genes was performed. Results: Multivariable analysis showed that higher self-evaluation of negative symptoms scale scores were significantly associated with higher age, higher chlorpromazine-equivalent daily dose for typical antipsychotics and in married patients. Higher negative Positive and Negative Syndrome Scale scores were significantly associated with women and having the CT genotype for MTHFR c.677C>T (β = 4.25; p = 0.008) compared with CC patients. Conclusion: Understanding both clinical/genetic factors could help improve the treatment of patients.

PMID:33858192 | DOI:10.2217/pgs-2020-0171

Pharmacogenomics. 2021 Apr 16. doi: 10.2217/pgs-2020-0197. Online ahead of print.

ABSTRACT

Although statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) have proven effective in reducing plasma low-density lipoprotein levels and risk of cardiovascular disease, their lipid lowering efficacy is highly variable among individuals. Furthermore, statin treatment carries a small but significant risk of adverse effects, most notably myopathy and new onset diabetes. Hence, identification of biomarkers for predicting patients who would most likely benefit from statin treatment without incurring increased risk of adverse effects can have a significant public health impact. In this review, we discuss the rationale for the use of subject-derived lymphoblastoid cell lines in studies of statin pharmacogenomics and describe a variety of approaches we have employed to identify novel genetic markers associated with interindividual variation in statin response.

PMID:33858191 | DOI:10.2217/pgs-2020-0197

Pharmacol Res. 2021 Apr 12:105610. doi: 10.1016/j.phrs.2021.105610. Online ahead of print.

ABSTRACT

During pregnancy, various physiological changes occur that can alter the pharmacokinetics of antiepileptic drugs, such as lamotrigine (LTG). Anticipating the change in LTG dose required to achieve a pre-pregnancy target concentration is challenging. This study aimed to develop a refined population pharmacokinetic (PopPK) model of LTG in pregnant women with epilepsy (WWE) to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen. On that basis, a coarsened model containing only clinical variables was also developed to examine its predictive performance compared to the refined model. In total, 322 concentration-time points from 51 pregnant WWE treated with LTG were employed to establish a refined PopPK model that included endogenous estrogen profiles, variants of candidate genes for LTG-metabolizing enzymes and -transporter proteins, and other clinical variables and a coarsened model that included only clinical variables, respectively. Data from an additional 11 patients were used for external validation of these two models. A nonlinear mixed-effect modeling approach was used for PopPK analysis of LTG. The standard goodness-of-fit method, bootstrap, normalized prediction distribution errors and external evaluation were adopted to estimate the stability and predictive performance of the candidate models. Akaike information criterion (AIC) was used to compare the goodness of fit between these two models. A lower AIC indicates a better fit of the data and the preferred model. Recommended dosing regimens for pregnant WWE were selected using Monte Carlo simulation based on the established optimal model. In the refined PopPK model, the population mean of apparent LTG clearance (CL/F) in pregnant WWE was estimated to be 2.82L/h, with an inter-individual variability of 23.6%. PopPK analysis indicated that changes in estrogen profile during pregnancy were the predominant reason for the significant variations in LTG-CL/F. Up to the 3rd trimester, the concentration accumulation effect of E2 increased LTG-CL/F by 5.109L/h from baseline levels. Contrary to effect of E2, E3 as the main circulating estrogen in pregnancy with a peak value of 34.41ng/mL is 1000-fold higher than that in non-pregnancy reduced LTG-CL/F by 1.413L/h. In addition, the UGT2B7 rs4356975 C>T and ABCB1 rs1128503 A>G variants may contribute to a better understanding of the inter-individual variability in LTG-CL/F. LTG-CL/F was 1.66-fold higher in UGT2B7 rs4356975 CT or TT genotype carriers than in CC genotype carriers. In contrast, ABCB1 rs1128503 GG genotype carriers had only 71.9% of the LTG-CL/F of AA or AG genotype carriers. In the coarsened PopPK model, the gestational age was a promising predictor of changes in LTG-CL/F. When comparing these two models, the refined PopPK model was favored over the coarsened PopPK model (AIC = -30.899 vs. -20.017). Monte Carlo simulation based on optimal PopPK model revealed that the LTG dosage administered to carriers of the UGT2B7 rs4356975 CT or TT genotype required a 33% to 50% increase to reach the pre-pregnancy target concentration, and carriers of the ABCB1 rs1128503 GG genotype required a 33% to 66% lower dose of LTG than carriers of the ABCB1 rs1128503 AA or AG genotype. Changes in estrogen profile during pregnancy was a better predictor of variations in LTG-CL/F than gestational age. The developed model based on estrogen profile and pharmacogenetics can serve as a foundation for further optimization of dosing regimens of LTG in pregnant WWE.

PMID:33857625 | DOI:10.1016/j.phrs.2021.105610

Commun Biol. 2021 Apr 14;4(1):370. doi: 10.1038/s42003-021-01897-6.

ABSTRACT

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.

PMID:33854168 | DOI:10.1038/s42003-021-01897-6

J Oncol Pharm Pract. 2021 Apr 15:10781552211005529. doi: 10.1177/10781552211005529. Online ahead of print.

ABSTRACT

INTRODUCTION: Pharmacogenetics, in hand with precision medicine in oncology, represents an opportunity to holistically tailor a patient's treatment regimen using both somatic and germline variants to improve efficacy and decrease toxicity. Colorectal cancer patients represent a population with frequent use of fluoropyrimidine and irinotecan and are an ideal opportunity for implementation of preemptive pharmacogenetics as evidence supports pharmacogenetic testing for DPYD and UGT1A1 to reduce fluoropyrimidine and irinotecan toxicities.

METHODS: This was a single arm proof-of-concept study at a large community-based health system. Participants provided samples for pharmacogenetic testing via an external vendor prior to chemotherapy initiation and an oncology pharmacist was responsible for pharmacogenetic interpretation and pharmacogenetic-guided therapeutic recommendation to the treating provider.

RESULTS: A total of 24 (60%) participants had a UGT1A1 variant. All participants (100%) were DPYD*1/*1. Results were available and interpreted for 29/40 (72.5%) participants prior to scheduled chemotherapy initiation (p value <0.014). Of the participants whose results were available in 5 weekdays or less (n = 23), 20 (87%) were communicated with the treating provider prior to scheduled chemotherapy administration. A total turnaround time of 5 days or less was significantly associated with PGx feasibility in a community-based oncology clinic (p = 0.03).

CONCLUSIONS: In conclusion, we were able to show that implementation of preemptive pharmacogenetic testing into a community oncology clinic with results interpretation available prior to scheduled initiation of chemotherapy was feasible. As pharmacogenetic testing in oncology expands, pharmacists should be prepared to optimize supportive medication regimens as well as chemotherapy with pharmacogenetic results.

PMID:33853470 | DOI:10.1177/10781552211005529

Pharmacogenet Genomics. 2021 Apr 12. doi: 10.1097/FPC.0000000000000434. Online ahead of print.

ABSTRACT

OBJECTIVE: Inhaled bronchodilators are the first-line treatment for asthma exacerbations, but individual bronchodilator response (BDR) varies by race and ethnicity. Studies have examined BDR's genetic underpinnings, but many did not include children or were not conducted during an asthma exacerbation. This pilot study tested single-nucleotide polymorphisms' (SNPs') association with pediatric African American BDR during an acute asthma exacerbation.

METHODS: This was a study of pediatric asthma patients in the age group 2-18 years treated in the emergency department for an asthma exacerbation. We measured BDR before and after inhaled bronchodilator treatments using both the Pediatric Asthma Severity Score (PASS) and asthma severity score. We collected genomic DNA and examined whether 21 candidate SNPs from a review of the literature were associated with BDR using crude odds ratios (OR) and adjusted analysis.

RESULTS: The final sample population was 53 children, with an average age of 7.2 years. The average initial PASS score (scale of ascending severity from 0 to 6) was 2.5. After adjusting for BMI, age category, gender and smoke exposure, rs912142 was associated with decreased odds of having low BDR (OR, 0.20; 95% confidence interval (CI), 0.02-0.92), and rs7081864 and rs7903366 were associated with decreased odds of having high BDR (OR, 0.097; 95% CI, 0.009-0.62).

CONCLUSIONS: We found three SNPs significantly associated with pediatric African American BDR that provide information regarding a child's potential response to emergency asthma exacerbation treatment. Once validated in larger studies, such information could guide pharmacogenomic evidence-based emergency asthma treatment to improve patient outcomes.

PMID:33851947 | DOI:10.1097/FPC.0000000000000434

Pharmacogenomics J. 2021 Apr 13. doi: 10.1038/s41397-021-00235-7. Online ahead of print.

ABSTRACT

Recently, the use of antiretroviral drug tenofovir disoproxil fumarate (TDF) is increased, thanks to the new co-formulation with doravirine, the availability of booster-free regimens, and its advantageous lipid-lowering effect. The aim of our study was to identify genetic markers that contribute to assess the risk of TDF-related renal toxicity. We have retrospectively investigated, in 179 HIV positive patients treated with TDF, the association between the main variants in ABCC2, ABCC4, and ABCC10 genes and four safety endpoints, three clinically relevant as renal outcomes and a higher tenofovir plasma concentration. In patients with an annual eGFR decline >5 mL/min/1.73 m2 a difference in genotype frequencies was observed for ABCC10 c.1875 + 526 G>A (3 subjects AA vs. 44 GG + GA, p = 0.045). In patients with an eGFR decrement >25%, plus a decline in GFR category and TDF discontinuation, a difference was observed for ABCC4 c.*38T>G (35 subjects TG + GG vs. 18 TT, p = 0.052). At univariate analysis OR was 1.39 [(95% CI 1.00-1.96) p = 0.054] and at multivariate analysis OR was 1.49 [(95% CI 1.00-2.22) p = 0.049]. The stronger associations were found between the tenofovir accumulation and ABCC4 c.*38T>G and c.3348G>A: the percentage of these patients was higher in the TG + GG (p = 0.011) and in the AA (p = 0.004) genotype, respectively. The logistic regression analysis confirmed these significant relationships. No significant association was observed in patients with eGFR < 60 mL/min/1.73m2 and with the studied ABCC2 polymorphisms. Our results show a major role for a combined determination of ABCC4/ABCC10 variants as an indicator of tenofovir toxicity in the clinical practice.

PMID:33850298 | DOI:10.1038/s41397-021-00235-7

Pharmacogenomics J. 2021 Apr 13. doi: 10.1038/s41397-021-00236-6. Online ahead of print.

ABSTRACT

The aim of this study was to perform a systematic overview of the pharmacogenetic studies conducted in Jordan. A structured search of Medline was conducted for articles over the last decade (January 2010-July 2020). Studies were classified by design, sample size, drug-gene combination, and the significance of the results. Thirty-two studies met the criteria for review. Most pharmacogenomic studies had a case-only design (n = 23). Only five studies included >500 participants. The total number of genetic variants in all studies was one hundred fifteen, which were found in forty genes, including dynamic (n = 27), and kinetic (n = 9) genes. The most commonly studied drugs were within the hematology and cardiology therapeutic areas and included statins, warfarin, aspirin, and clopidogrel. Most studies (n = 18) reported results with mixed p values [<0.05 and >0.05]. Pharmacogenomic research in Jordan is still in its infancy and is limited mainly to replication attempts. The need for standardization is imperative, especially in developing countries with scarce funding resources.

PMID:33850297 | DOI:10.1038/s41397-021-00236-6

Sci Rep. 2021 Apr 13;11(1):8478. doi: 10.1038/s41598-021-88212-9.

NO ABSTRACT

PMID:33850257 | DOI:10.1038/s41598-021-88212-9

Pharmacogenomics. 2021 Apr 14. doi: 10.2217/pgs-2020-0177. Online ahead of print.

ABSTRACT

Background: Despite the expansion of pharmacogenetics (PGx), the views of pediatric patients remain unknown. This study explores adolescents' understanding and perceptions of PGx testing. Methods: Adolescents who had PGx testing were interviewed and their electronic health records were reviewed. Results: Adolescents accurately described reason for testing and most felt the results impacted their current and future care. None perceived risks to securing future employment or insurance. All felt PGx would benefit their peers. Conclusion: Adolescents understand the reasons for PGx and perceive testing to be useful, low risk and applicable to peers. Findings from this study advocate for the inclusion of adolescents in shared decision-making regarding testing and for active engagement in the discussion of results.

PMID:33849282 | DOI:10.2217/pgs-2020-0177

Pharmacogenomics. 2021 Apr 14. doi: 10.2217/pgs-2021-0036. Online ahead of print.

NO ABSTRACT

PMID:33849279 | DOI:10.2217/pgs-2021-0036

J Clin Pharmacol. 2021 Apr 13. doi: 10.1002/jcph.1873. Online ahead of print.

ABSTRACT

Morphine is an opioid analgesic indicated in the treatment of acute and chronic moderate to severe pain. From a pharmacodynamic standpoint, morphine exerts its effects by agonizing mu-opioid receptors (OPRM1) predominantly, resulting in analgesia and sedation. Pharmacokinetically, morphine is primarily metabolized in the liver via glucuronidation by the enzyme uridine diphosphate glucuronosyltransferase family 2-member B7 (UGT2B7) and encounters the transporter proteins organic cation transporter isoform 1 (OCT1) and p-glycoprotein (ABCB1) as it is being distributed throughout the body. The genes coding for the proteins impacting either the pharmacokinetics or pharmacodynamics of morphine may bear genetic variations, also known as polymorphisms, which may alter the function of the proteins in such a manner that an individual may have disparate treatment outcomes. The purpose of this review is to highlight some of the genes coding for proteins that impact morphine pharmacokinetics and pharmacodynamics and present some treatment considerations. This article is protected by copyright. All rights reserved.

PMID:33847389 | DOI:10.1002/jcph.1873

Acta Derm Venereol. 2021 Apr 13. doi: 10.2340/00015555-3794. Online ahead of print.

ABSTRACT

Biological drugs targeting tumour necrosis factor are effective for psoriasis. However, 30-50% of patients do not respond to these drugs and may even develop paradoxical psoriasiform reactions. This study search-ed for DNA copy number variations that could predict anti-tumour necrotic factor drug response or the appearance of anti-tumour necrotic factor induced psoriasiform reactions. Peripheral blood samples were collected from 70 patients with anti-tumour necrotic factor drug-treated moderate-to-severe plaque psoriasis. Samples were analysed with an Illumina 450K methylation microarray. Copy number variations were obtained from raw methylation data using conumee and Chip Analysis Methylation Pipeline (ChAMP) R packages. One copy number variation was found, harbouring 1 gene (CPM) that was significantly associated with adalimumab response (Bonferroni-adjusted p-value < 0.05). Moreover, 1 copy number variation was identified harbouring 3 genes (ARNT2, LOC101929586 and MIR5572) related to the development of paradoxical psoriasiform reactions. In conclusion, this study has identified DNA copy number variations that could be good candidate markers to predict response to adalimumab and the development of anti-tumour necrotic factor paradoxical psoriasiform reactions.

PMID:33846759 | DOI:10.2340/00015555-3794

Scand J Public Health. 2021 Apr 12:14034948211004421. doi: 10.1177/14034948211004421. Online ahead of print.

ABSTRACT

Aim: This case study aimed to investigate the process of integrating resources of multiple biobanks and health-care registers, especially addressing data permit application, time schedules, co-operation of stakeholders, data exchange and data quality. Methods: We investigated the process in the context of a retrospective study: Pharmacogenomics of antithrombotic drugs (PreMed study). The study involved linking the genotype data of three Finnish biobanks (Auria Biobank, Helsinki Biobank and THL Biobank) with register data on medicine dispensations, health-care encounters and laboratory results. Results: We managed to collect a cohort of 7005 genotyped individuals, thereby achieving the statistical power requirements of the study. The data collection process took 16 months, exceeding our original estimate by seven months. The main delays were caused by the congested data permit approval service to access national register data on health-care encounters. Comparison of hospital data lakes and national registers revealed differences, especially concerning medication data. Genetic variant frequencies were in line with earlier data reported for the European population. The yearly number of international normalised ratio (INR) tests showed stable behaviour over time. Conclusions: A large cohort, consisting of versatile individual-level phenotype and genotype data, can be constructed by integrating data from several biobanks and health data registers in Finland. Co-operation with biobanks is straightforward. However, long time periods need to be reserved when biobank resources are linked with national register data. There is a need for efforts to define general, harmonised co-operation practices and data exchange methods for enabling efficient collection of data from multiple sources.

PMID:33845693 | DOI:10.1177/14034948211004421