BACKGROUND:Reports about relevance of three common and linked ABCB1 polymorphisms (c.2677G>T/A, c.1236C>T, c.3435C>T) for exposure to- and functional outcomes in tacrolimus-treated renal transplant patients are inconsistent. METHODS:Tacrolimus morning troughs/dose-corrected troughs and serum creatinine/estimated glomerular filtration rate (eGFR) were measured on 6th-7th and 8th-10th postoperative day in tacrolimus-mycophenolate-treated renal transplant patients. Exposure was defined as the number of ABCB1 variant alleles (three levels; 0-1 variant = control) or as diplotypes (three levels, wild-type = control). Four target trials were emulated (2 exposure definitions × 2 outcome categories) contrasting exposed and controls for ln-transformed outcomes, and for creatinine/eGFR also on natural scales. Complementary mediation analysis related exposure, troughs, and eGFR. RESULTS:The 173 enrolled patients provided 316 paired trough and creatinine/eGFR values. After correction for strong residual confounding, all GMRs (95% CrI) for troughs remained within the 0.75-1.33 range. All GMRs (95% CrI) for ln-trasformed creatinine/eGFR were within the 0.75-1.33 range. On the natural scale, creatinine/eGFR differences were within -26.5 to 26.5 μmol/L and -5.0 to 5.0 mL/min/1.73 m2, respectively. In mediation analysis, direct, indirect, and total effects were within the same ranges. CONCLUSIONS:Renal transplant recipients subsetted by genotypes across the three common ABCB1 polymorphisms display closely similar tacrolimus troughs and graft function early after transplantation.

The ATP-binding cassette subfamily G member 2 (ABCG2), also known as breast cancer resistance protein (BCRP), is an efflux transporter expressed in key pharmacokinetic tissues and biological barriers. It regulates exposure to many endogenous compounds, drugs, and environmental toxins. Genetic variability in ABCG2 has been recognised as an important contributor to interindividual variability in drug response, especially in terms of efficacy and toxicity. This narrative review summarises current knowledge on the clinical relevance of ABCG2 genetic variants, with a focus on their effects on pharmacokinetics, adverse drug reactions and drug–drug–gene interactions, as well as their potential implementation in personalised therapy. A literature search was performed in PubMed, Scopus and the Clinical Pharmacogenomics Database (ClinPGx), with an emphasis on clinically relevant studies and available pharmacogenomic guidelines. The most investigated ABCG2 variant, c.421C>A (rs2231142; p.Gln141Lys), is consistently associated with reduced transporter activity and increased systemic exposure to several substrate drugs, including statins, allopurinol and anticancer agents, which may influence both treatment response and the risk of toxicity. Although growing evidence supports the clinical relevance of ABCG2 genotyping, its routine implementation remains limited. Integration of ABCG2 variability into polygenic models and clinical decision-support tools may further improve individualised treatment, particularly in patients with multimorbidity and polypharmacy.

Personalised medicine has become a central paradigm in modern healthcare, aiming to tailor prevention, diagnosis, and therapy to each patient's unique molecular and clinical profile. This paper provides a comprehensive overview of the lectures presented at the 36th annual Symposium of the Croatian society of medical biochemistry and laboratory medicine. It highlights key topics including the role of disease-causing variants in hereditary disorders, the development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, the evolution of newborn screening programs and spinal muscular atrophy diagnostics, emphasizing early detection and timely initiation of therapy, advances in cancer genetics, pharmacogenetics, and the translation of other laboratory-based innovations into clinical practice. Altogether, these advances reaffirm the central role of laboratory diagnostics as the cornerstone of personalised medicine, bridging genetic discovery with clinical translation and transforming modern healthcare into a predictive, preventive, and truly patient-centred discipline.

AIM:To evaluate associations between polymorphisms in CYP3A4 (*1B, *22), CYP3A5 (*3), CYP2J2 (*7, rs11572325), ABCB1 (c.1236C>T, c.2677G>T/A, c.3435C>T, rs4148738) and ABCG2 (c.421C>A) and the occurrence of bleeding or occlusive events in patients receiving rivaroxaban in real-world clinical practice. METHODS:A nested case-control study, divided into two substudies (bleeding and thromboembolic events), was conducted within a prospective cohort of 385 adults receiving rivaroxaban at University Hospital Centre Zagreb (September 2021-September 2024). Bleeding events were classified per ISTH criteria, and genotyping was performed using TaqMan real-time PCR. Cases and controls were balanced using entropy balancing, and associations were estimated with Bayesian logistic regression under a skeptical prior N(0, 0.355); LASSO regression was used to identify clinical and genetic predictors of outcomes. RESULTS:In total, 71 patients (18.4%) experienced bleeding events, most frequently gastrointestinal (47.9%), while 314 patients served as controls. No pharmacogenomic variant showed a clear association with bleeding risk (raw and balanced odds ratios 0.80-1.35; 95% credible intervals crossing 1.0). LASSO regression identified age (OR 2.00 per decade), gastrointestinal comorbidity (OR 8.77), and eGFR as the dominant predictors of bleeding. Twenty-one patients experienced occlusive events (15 venous, 6 arterial); however, the low event count precluded meaningful pharmacogenomic analysis. CONCLUSIONS:Individual pharmacogenomic variants in CYP3A4, CYP3A5, CYP2J2, ABCB1, and ABCG2 together with pharmacogenetic-based phenotypes were not associated with clinically relevant bleeding in rivaroxaban-treated patients. Traditional clinical risk factors, particularly advanced age and gastrointestinal comorbidity, remain the dominant determinants of adverse outcomes. Routine pharmacogenomic testing to guide rivaroxaban dosing is not currently supported.

Adolescent patients with borderline personality traits present a significant clinical challenge due to their polymorphic symptomatology occurring together with ongoing psychological and physiological development. While psychotherapy remains the first-line treatment, it is often combined with different psychopharmacological medications. This case report presents a 17.5-year-old female adolescent who developed extrapyramidal symptoms (EPS) following the addition of fluphenazine to her therapy, which had been modified due to deteriorating psychiatric symptoms. After the resolution of the EPS, the patient developed anticholinergic syndrome within a few days. Pharmacogenetic testing showed genetic variations associated with modified drug and dopamine metabolism, which may have contributed to her increased predisposition to drug adverse effects. This case highlights the complexity of psychopharmacological management in adolescents with multidimensional symptomatology and emphasizes the potential value of integrating pharmacogenetic data to guide optimal treatment strategies.

Although the role of pharmacogenomics (PGx) in personalized pharmacotherapy has been well established, its implementation in clinical practice lags behind. In this article, we present an overview of important achievements in the field of PGx of cardiovascular drugs (CVDs), and identify gaps in the existing research. We also present an outline of the PGx-CardioDrug project (ClinicalTrials.gov: NCT05307718) focused on PGx of three major classes of CVDs: P2Y12 antiplatelets, direct oral anticoagulants (DOACs), and statins. The project intends to evaluate pharmacogenes, concomitant treatments, and their combinations as determinants of adverse drug reactions (ADRs). It is based on a pool of around 1200 consecutive adults who were accrued on the case-control principle defined with respect to the CVDs and ADRs of interest (bleeding related to antiplatelets and DOACs, skeletal muscle or liver toxicity related to statins, inefficiency). Possible perpetrator or victim roles of concomitantly used drugs are assessed using the Lexicomp® Clinical Decision Support System. The assembled data provide a basis for a series of case-control type analyses. Considering the mode of data generation and the nature of the exposures of interest (ie, present before the occurrence of the outcome), potentially observed outcome-exposure associations are likely to be causal, provided that confounding is reasonably controlled. The project enables the development of methods and procedures that better reflect the real-life situation of patients with comorbidities and polytherapy, and might better predict the interactions of multiple drugs and genes that affect the frequency and severity of CVD ADRs.

Background/Objectives: Lipoprotein (a) [Lp(a)] plays a significant role in atherosclerosis and cardiovascular disease (CVD). Genetic regulation of Lp(a) involves variations in the apo(a) LPA gene, as specific polymorphisms like rs10455872 and rs3798220, both linked to higher Lp(a) levels and CVD. CVD remains the leading global cause of death, with high Lp(a) levels increasingly recognized as a significant factor in younger patients with no other CVD risk factors. We aimed to evaluate the association of LPA genetic variations with Lp(a) levels and its effect on cardiovascular risk as there are existing inconsistent findings. Methods: This case–control study included 251 subjects with a median age of 52 years (interquartile range, IQR = 17) and elevated Lp(a) levels. Cases were subjects who experienced early cardiovascular incidents (women < 65, men < 55 years old), and the control group included subjects without such history. Genotyping of LPA gene polymorphisms (rs10455872 and rs3798220) was performed, and demographic data with Lp(a) levels were collected. To evaluate the association between the LPA genotypes and the risk of cardiovascular incidents (CVI), several logistic regression models were performed. The cut-off points for Lp(a) levels were determined using diagnostic test accuracy measures. Results: The rs3798220-C allele was associated with higher Lp(a) levels (288 ± 166 nmol/L in cases vs. 189 ± 102 nmol/L in controls, p < 0.001) and myocardial infarction (53% in cases vs. 36% in controls, p = 0.036). Among cases, 28.9% carried the rs3798220-C allele, compared to 18.7% in controls. The rs10455872-G allele was slightly more prevalent in controls (34.15% vs. 29.69%) but without further significant associations. In this study, the cut-off Lp(a) value of 151 nmol/L, for patients with a positive family history of early CVD, is associated with a higher chance of developing CVI. Conclusions: This study demonstrates an association between the LPA rs3798220-C allele and higher Lp(a) levels, as well as an increased risk of early onset myocardial infarction. However, the obtained association should further be evaluated at a much larger scale.

Background: Tacrolimus is a cornerstone of immunosuppressive therapy following heart transplantation. Despite routine therapeutic drug monitoring (TDM), substantial interindividual variability in tacrolimus pharmacokinetics presents a persistent challenge. Pharmacogenetic profiling—particularly of CYP3A5 and CYP3A4 polymorphisms—offers a promising approach to individualize tacrolimus dosing and improve clinical outcomes. Case Presentation: We describe a 54-year-old male heart transplant recipient with persistently subtherapeutic tacrolimus trough concentrations despite escalating standard doses. Tacrolimus dosing initially started at 3.5 mg twice daily, escalated to 7.0 mg twice daily, with final maintenance dosing at 6.5 mg twice daily. TDM values were persistently subtherapeutic at 3–5 ng/mL for over a month before achieving therapeutic targets >10 ng/mL. Pharmacogenetic testing revealed a CYP3A5 expresser genotype (*1/*3) and normal CYP3A4 activity (*1/*1), suggesting enhanced metabolic clearance. In accordance with CPIC guidelines, tacrolimus dosing was intensified and supported by co-administration of diltiazem (60 mg twice daily, later adjusted to 90 mg twice daily), a CYP3A4 inhibitor. Subsequent TDM confirmed achievement of therapeutic levels. At nine months post-transplant, the patient exhibited stable graft function and excellent clinical status. Discussion: This case underscores the value of genotype-informed tacrolimus dosing in clinical scenarios where standard TDM is insufficient. Pharmacogenetic variation—particularly involving CYP3A5 expression—has been consistently associated with altered tacrolimus exposure and dose requirements. The literature supports routine genotyping in solid organ transplant recipients, although implementation remains limited. Additional considerations include drug–drug interactions, notably with CYP3A-modulating agents such as diltiazem and antifungals, which may further influence tacrolimus pharmacokinetics. Current evidence suggests that the utility of CYP3A4 genotyping may be phase-dependent, being more impactful during early post-transplant periods. Conclusions: Incorporating pharmacogenetic data alongside TDM facilitates more precise and individualized tacrolimus therapy, optimizing immunosuppressive efficacy and minimizing risk. This case, supported by literature review, advocates for broader integration of genotype-guided strategies in transplant pharmacotherapy.

A recently discovered haplotype—CYP2C:TG—determines the ultrarapid metabolism of several CYP2C19 substrates. The platelet inhibitor clopidogrel requires CYP2C19-mediated activation: the risk of ischemic events is increased in patients with a poor (PM) or intermediate (IM) CYP2C19 metabolizer phenotype (vs. normal, NM; rapid, RM; or ultrarapid, UM). We investigated whether the CYP2C:TG haplotype affected efficacy/bleeding risk in clopidogrel-treated patients. Adults (n = 283) treated with clopidogrel over 3–6 months were classified by CYP2C19 phenotype based on the CYP2C19*2*17 genotype, and based on the CYP2C19/CYP2C cluster genotype, and regarding carriage of the CYP2:TG haplotype, and were balanced on a number of covariates across the levels of phenotypes/haplotype carriage. Overall, 45 (15.9%) patients experienced ischemic events, and 49 (17.3%) experienced bleedings. By either classification, the incidence of ischemic events was similarly numerically higher in PM/IM patients (21.6%, 21.8%, respectively) than in mutually similar NM, RM, and UM patients (13.2–14.8%), whereas the incidence of bleeding events was numerically lower (13.1% vs. 16.6–20.5%). The incidence of ischemic events was similar in CYP2C:TG carries and non-carries (14.1% vs. 16.1%), whereas the incidence of bleedings appeared mildly lower in the former (14.9% vs. 20.1%). We observed no signal to suggest a major effect of the CYP2C19/CYP2C cluster genotype or CYP2C:TG haplotype on the clinical efficacy/safety of clopidogrel.

Introduction: Considering conflicting previous reports, we aimed to evaluate whether the common ABCB1 polymorphisms (rs1128503, rs2032582, rs1045642, rs4148738) affected the risk of bleeding in rivaroxaban-treated patients. Materials and methods: We report preliminary data from a larger nested case-control study. Consecutive adults started on rivaroxaban for any indication requiring > 6 months of treatment were followed-up to one year. Patients who experienced major or non-major clinically relevant bleeding during the initial 6 months were considered cases, whereas subjects free of bleeding over > 6 months were controls. The polymorphisms of interest (rs1128503, rs2032582, rs1045642, rs4148738) were in a strong linkage disequilibrium, hence patients were classified regarding the "load" of variant alleles: 0-2, 3-5 or 6-8. The three subsets were balanced regarding a range of demographic, comorbidity, comedication and genetic characteristics. A logistic model was fitted to probability of bleeding. Results: There were 60 cases and 220 controls. Raw proportions of cases were similar across the subsets with increasing number of ABCB1 variant alleles (0-2, N = 85; 3-6, N = 133; 6-8, N = 62): 22.4%, 21.8%, and 19.4%, respectively. Fully adjusted probabilities of bleeding were also similar across the subsets: 22.9%, 27.5% and 17.7%, respectively. No trend was observed (linear, t = -0.63, df = 273, P = 0.529; quadratic, t = -1.10, df = 273, P = 0.272). Of the 15 identified haplotypes, the completely variant (c.1236T_c.2677T(A)_c.3435T_c.2482-2236A) (40.7%) and completely wild-type (C_G_C_G) (39.5%) haplotypes prevailed, and had a closely similar prevalence of cases: 21.1% vs. 23.1%, respectively. Conclusions: The evaluated common ABCB1 polymorphisms do not seem to affect the risk of early bleeding in patients started on rivaroxaban.

Aim. To estimate the effect of the reduced-function polymorphism SLCO1B1 c.521T>C on the renal graft function (estimated glomerular filtration rate, eGFR) over 12 months in patients treated with mycophenolic acid (MPA). Methods. Consecutive eligible adults (≥16 years of age) engrafted over a 6-year period who received MPA as a part of maintenance immunosuppression were assessed for eGFR on 9 occasions over 12 post-transplant months. The SLCO1B1 c.521C>T variant allele carriers (treated) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and the development of eGFR (slope) was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. Results. The adjusted eGFR slopes from day 1 to day 28 (peak), and from day 28 to day 365 were practically identical in treated (n=86) and control (n=168) patients (GMR=0.99, 95%CI 0.92-1.06, and GMR=0.98, 0.94-1.01, respectively). The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in treated and controls (adjusted RR=0.94, 0.49-1.84 and RR=1.08, 0.74-1.58, respectively). The pharmacokinetic substudy did not signal that treated and control patients differed with respect to MPA clearance, peak, trough or total exposure, overall (treated n=23, control n=45), if cotreated with cyclosporine (n=17 vs. n=26) or with tacrolimus (n=8 vs. n=17). Discussion. In patients treated with MPA, variant allele SLCO1B1 c.521T>C has no effect on the 12-month renal graft function. It does not seem to affect exposure to- and safety of MPA.

Statins, HMG CoA reductase inhibitors, are effective at lowering blood cholesterol levels and protecting against cardiovascular incidents. Their uptake into hepatocytes depends on the activity of the SLCO1B1 gene which codes for the OATP1B1 transporter protein. Pharmacogenomic testing provides us information about the activity level of a certain protein. Lowered activity level of OATP1B1 protein can prolong the bioavailability of some drugs, such as statins. This greater systemic exposure to statins carries a higher risk of intolerance symptoms when compared to normal function of the OATP1B1 protein.

Non-vitamin K antagonist oral anticoagulants’ interindividual trough concentration variability affects efficacy and safety, especially in bleeding events. Rivaroxaban is metabolised via CYP3A4/5-, CYP2J2-, and CYP-independent mechanisms and is a substrate of two transporter proteins: ABCB1 (MDR1, P-glycoprotein) and ABCG2 (BCRP; breast-cancer-resistance protein). The polymorphisms of these genes may possibly affect the pharmacokinetics of rivaroxaban and, consequently, its safety profile. Rivaroxaban variability may be associated with age, liver and kidney function, concomitant illness and therapy, and pharmacogenetic predisposition. This case series is the first, to our knowledge, that presents multiple risk factors for rivaroxaban-related bleeding (RRB) including age, renal function, concomitant diseases, concomitant treatment, and pharmacogenetic data. It presents patients with RRB, along with their complete clinical and pharmacogenetic data, as well as an evaluation of possible risk factors for RRB. Thirteen patients were carriers of ABCB1, ABCG2, CYP2J2, and/or CYP3A4/5 gene polymorphisms. Possible drug–drug interactions with increased bleeding risk were identified in nine patients. Six patients had eGFR <60 mL/min/1.73 m2. Our data suggest a possible role of multiple factors and their interactions in predicting RRB; however, they also indicate the need for further comprehensive multidisciplinary research to enable safer use of this product based on a personalised approach.

Fluoropyrimidines (FPs) are antineoplastic drugs widely used in the treatment of various solid tumors. Nearly 30% of patients treated with FP chemotherapy experience severe FP-related toxicity, and in some cases, toxicity can be fatal. Patients with reduced activity of DPD, the main enzyme responsible for the breakdown of FP, are at an increased risk of experiencing severe FP-related toxicity. While European regulatory agencies and clinical societies recommend pre-treatment DPD deficiency screening for patients starting treatment with FPs, this is not the case with American ones. Pharmacogenomic guidelines issued by several pharmacogenetic organizations worldwide recommend testing four DPD gene (DPYD) risk variants, but these can predict only a proportion of toxicity cases. New evidence on additional common DPYD polymorphisms, as well as identification and functional characterization of rare DPYD variants, could partially address the missing heritability of DPD deficiency and FP-related toxicity.

Purpose . To estimate whether epilepsy patients with variant UGT2B7 -161C>T (rs7668258) or UGT1A4*3 c.142T>G (rs2011425) alleles differ from their wild-type (wt) peers in exposure to lamotrigine. Methods . Consecutive adults on lamotrigine monotherapy or lamotrigine+valproate co-treatment undergoing routine therapeutic drug monitoring, otherwise generally healthy and free of interacting drugs, were genotyped for UGT2B7 -161C>T and UGT1A4*3 c.142T>G. Heterozygous, variant homozygous, or combined heterozygous/variant homozygous subjects were compared to their wt controls for dose-adjusted lamotrigine troughs with adjustment for age, sex, body weight, rs7668258/rs2011425, polymorphisms of efflux transporter proteins ABCG2 c.421C>A (rs2231142) and ABCB1 1236C>T (rs1128503), and level of exposure to valproate using covariate entropy balancing. Results . Of the 471 included patients, 328 (69.6%) were on monotherapy and 143 were co-treated with valproate. Dose-adjusted lamotrigine troughs in UGT2B7 -161C>T heterozygous (CT, n=237) or variant homozygous (TT, n=115) subjects were closely similar to those in their wt controls (CC, n=119): geometric means ratios (GMRs) (frequentist and Bayes) 1.00 (95%CI 0.86-1.16) and 1.00 (95%CrI 0.83-1.22) for CT vs. CC; and 0.97 (0.81-1.17) and 0.97 (0.80-1.20) for TT vs. CC subjects. Lamotrigine troughs were also closely similar in UGT1A4*3 c.142T>G variant carriers [n=106: 102 TG + 4 GG subjects) and wt controls (TT, n=365): GMR= 0.95 (0.81-1.12) frequentist, 0.96 (0.80-1.16) Bayes. GMRs for variant carriers vs. wt controls were around unity also at different levels of exposure to valproate. Conclusion . Dose-adjusted lamotrigine troughs in epilepsy patients with variant UGT2B7 -161C>T or UGT1A4*3 c.142T>G alleles are equivalent to those in their respective wt peers.

Although changes in dietary sodium intake alter blood pressure (BP) in salt-sensitive individuals, pathophysiological mechanisms are still unknown. It has been reported that uromodulin is involved in sodium tubular transport, and genome-wide association studies pointed to UMOD gene as one of the most important gene candidates for arterial hypertension. Our aim was to analyze urinary uromodulin, salt intake and BP in 326 young middle-aged subjects (mean age 36±8 years, 49.4% male). In a subgroup of 175 individuals, ambulatory blood pressure monitoring and echocardiogram were performed. Uromodulin was determined by ELISA. According to the JNC-7 criteria, subjects were classified as optimal BP (n=103, men 72%), prehypertension (PHT) (n=143, men 43%) and hypertension (HT) (n= 80, men 38%). There were no differences in age, salt intake, estimated glomerular filtration rate, sodium excretion and uromodulin among BP groups. However, in PHT subjects, uromodulin was positively associated with fractional sodium excretion and negatively with 24-h sodium excretion and diastolic BP dip. These findings point to the effect of uromodulin on sodium reabsorption along the nephron and consequently circadian BP alteration in prehypertensives.