Farmakogenoomika – teekond ravivastuse päriliku varieeruvuse baasteadusest kliinilisse meditsiini

Farmakogenoomika on farmakoloogiat ning genoomikat ühendav teadusharu. Farmakogenoomika eesmärk on tuvastada geneetilised markerid, mis mõjutavad ravimi efektiivsust ja toksilisust, ning kasutada seda infot suunatud ravitulemuse saavutamiseks. Viimastel aastatel on farmakogenoomilisi teadmisi rakendatud järjest suuremas mahus kliinilises meditsiinis. Artikli eesmärk on selgitada farmakogenoomika kui baasteadusharu põhimõtteid ning teekonda kliinilisse meditsiini. &nbsp

Farmakogeneetilise analüüsi kulutõhusus depressiooni ravis Eestis

Taust. Depressiooni ravis kasutatavate antidepressantide (AD) tarvitamine on Eestis viimastel aastatel suurenenud, kuid mitmete ADde efektiivsus ja kõrvaltoimete risk sõltub muu hulgas ka geneetilisest variatsioonist. Farmakogeneetika kombineerib teadmisi farmakoloogiast  ja geneetikast eesmärgiga muuta medikamentoosne ravi ohutumaks ja efektiivsemaks.Eesmärk. Hinnata teaduskirjanduse ja Eesti andmete alusel tervishoiu rahastaja perspektiivist farmakogeneetilise analüüsi (FGA) alusel juhitud AD-ravi kulutõhusust ja eelarvemõju Eestis võrreldes tavaraviga.Metoodika. Kulutõhususe arvutamiseks koostati otsustuspuu mudel, milles arvestati efektiivsuse näitajatena ravivastuse ja remissiooni tekkimisega, elukvaliteedi hinnangutega ning geenitesti hinnaga.Tulemused. FGA alusel juhitud AD-ravi võimaldab suurendada ravivastuse ja remissiooni tõenäosust ning vähendada kõrvaltoimete riski mõõduka ja raske depressiooniga patsientidel. FGA alusel juhitud AD-ravi ja tavaravi võrdluses oli täiendkulu tõhususe määr 30 700 eurot lisanduva kvaliteetse eluaasta kohta. Kõige enam mõjutas kulutõhususe hinnangut see, kui alates 12. nädalast eeldatakse FGA alusel juhitud AD-ravi ja tavaravi korral võrdset efektiivsust, ning geenitesti hind. Eeldades FGA alusel juhitud AD-ravi järkjärgulist rakendamist, oleks tõenäoline kumulatiivne lisakulu Tervisekassale 5,4 miljonit eurot viie aasta jooksul.Järeldused. FGA alusel juhitud AD-ravi võib Eesti kontekstis pidada kulutõhusaks, kuid selle rakendamine on ressursimahukas

Hybrid Modelling for Stroke Care: Review and suggestions of new approaches for risk assessment and simulation of scenarios

Stroke is an example of a complex and multi-factorial disease involving multiple organs, timescales, and disease mechanisms. To deal with this complexity, and to realize Precision Medicine of stroke, mathematical models are needed. Such approaches include: 1) machine learning, 2) bioinformatic network models, and 3) mechanistic models. Since these three approaches have complementary strengths and weaknesses, a hybrid modelling approach combining them would be the most beneficial. However, no concrete approach ready to be implemented for a specific disease has been presented to date. In this paper, we both review the strengths and weaknesses of the three approaches, and propose a roadmap for hybrid modelling in the case of stroke care. We focus on two main tasks needed for the clinical setting: a) For stroke risk calculation, we propose a new two-step approach, where non-linear mixed effects models and bioinformatic network models yield biomarkers which are used as input to a machine learning model and b) For simulation of care scenarios, we propose a new four-step approach, which revolves around iterations between simulations of the mechanistic models and imputations of non-modelled or non-measured variables. We illustrate and discuss the different approaches in the context of Precision Medicine for stroke

Personaalmeditsiini keskuse loomisest Eestis

Eesti Arst 2023; 102(2):76–7

A distinctive DNA methylation pattern in insufficient sleep

Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia. We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 +/- 7.3), and in relation to shift work disorder in an occupational cohort (26 men, aged 44.9 +/- 9.0). The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: "Nervous System Development" (FDR P value <0.05). We found that 78% of the DMPs were hypomethylated in cases in both cohorts, suggesting that insufficient sleep may be associated with loss of DNA methylation. A karyoplot revealed clusters of DMPs at various chromosomal regions, including 12 DMPs on chromosome 17, previously associated with Smith-Magenis syndrome, a rare condition comprising disturbed sleep and inverse circadian rhythm. Our findings give novel insights into the DNA methylation patterns associated with sleep loss, possibly modifying processes related to neuroplasticity and neurodegeneration. Future prospective studies are needed to confirm the observed associations.Peer reviewe

A data-driven medication score predicts 10-year mortality among aging adults

Health differences among the elderly and the role of medical treatments are topical issues in aging societies. We demonstrate the use of modern statistical learning methods to develop a data-driven health measure based on 21 years of pharmacy purchase and mortality data of 12,047 aging individuals. The resulting score was validated with 33,616 individuals from two fully independent datasets and it is strongly associated with all-cause mortality (HR 1.18 per point increase in score; 95% CI 1.14-1.22; p=2.25e-16). When combined with Charlson comorbidity index, individuals with elevated medication score and comorbidity index had over six times higher risk (HR 6.30; 95% CI 3.84-10.3; AUC=0.802) compared to individuals with a protective score profile. Alone, the medication score performs similarly to the Charlson comorbidity index and is associated with polygenic risk for coronary heart disease and type 2 diabetes.Peer reviewe

Variants in calcium voltage-gated channel subunit Alpha1 C-gene (CACNA1C) are associated with sleep latency in infants

Genetic variants in CACNA1C (calcium voltage-gated channel subunit alpha1 C) are associated with bipolar disorder and schizophrenia where sleep disturbances are common. In an experimental model, Cacna1c has been found to modulate the electrophysiological architecture of sleep. There are strong genetic influences for consolidation of sleep in infancy, but only a few studies have thus far researched the genetic factors underlying the process. We hypothesized that genetic variants in CACNA1C affect the regulation of sleep in early development. Seven variants that were earlier associated (genome-wide significantly) with psychiatric disorders at CACNA1C were selected for analyses. The study sample consists of 1086 infants (520 girls and 566 boys) from the Finnish CHILD-SLEEP birth cohort (geno-typed by Illumina Infinium PsychArray BeadChip). Sleep length, latency, and nightly awakenings were reported by the parents of the infants with a home-delivered questionnaire at 8 months of age. The genetic influence of CACNA1C variants on sleep in infants was examined by using PLINK software. Three of the examined CACNA1C variants, rs4765913, rs4765914, and rs2239063, were associated with sleep latency (permuted PPeer reviewe

Variation near MTNR1A associates with early development and interacts with seasons

First published: 07 October 201

Comprehensive genome-wide association study of different forms of hernia identifies more than 80 associated loci

Hernias are characterized by protrusion of an organ or tissue through its surrounding cavity and often require surgical repair. In this study we identify 65,492 cases for five hernia types in the UK Biobank and perform genome-wide association study scans for these five types and two combined groups. Our results show associated variants in all scans. Inguinal hernia has the most associations and we conduct a follow-up study with 23,803 additional cases from four study groups giving 84 independently associated variants. Identified variants from all scans are collapsed into 81 independent loci. Further testing shows that 26 loci are associated with more than one hernia type, suggesting substantial overlap between the underlying genetic mechanisms. Pathway analyses identify several genes with a strong link to collagen and/or elastin (ADAMTS6, ADAMTS16, ADAMTSL3, LOX, ELN) in the vicinity of associated loci for inguinal hernia, which substantiates an essential role of connective tissue morphology. Hernias involve protrusion of an organ or tissue through its surrounding cavity. Here the authors carry out GWAS for five types of hernia and find 81 variants, most of which are associated with inguinal hernia; downstream analysis suggests an important role for connective tissue morphology.Peer reviewe

Longitudinal proteomic profiling reveals increased early inflammation and sustained apoptosis proteins in severe COVID-19

SARS-CoV-2 infection has a risk to develop into life-threatening COVID-19 disease. Whereas age, hypertension, and chronic inflammatory conditions are risk factors, underlying host factors and markers for disease severity, e.g. requiring intensive care unit (ICU) treatment, remain poorly defined. To this end, we longitudinally profiled blood inflammation markers, antibodies, and 101 plasma proteins of hospitalized COVID-19 patients who did or did not require ICU admission. While essentially all patients displayed SARS-CoV-2-specific antibodies and virus-neutralization capacity within 12-15 days, a rapid, mostly transient upregulation of selective inflammatory markers including IL-6, CXCL10, CXCL11, IFN gamma, IL-10, and monocyte-attracting CCL2, CCL7 and CCL8, was particularly evident in ICU patients. In addition, there was consistent and sustained upregulation of apoptosis-associated proteins CASP8, TNFSF14, HGF, and TGFB1, with HGF discriminating between ICU and non-ICU cohorts. Thus, COVID-19 is associated with a selective inflammatory milieu within which the apoptotic pathway is a cardinal feature with potential to aid risk-based patient stratification.Peer reviewe