Pharmacogenomic biomarker information differences between drug labels in the United States and Hungary: implementation from medical practitioner view.

Pharmacogenomic biomarker availability of Hungarian Summaries of Product Characteristics (SmPC) was assembled and compared with the information in US Food and Drug Administration (FDA) drug labels of the same active substance (July 2019). The level of action of these biomarkers was assessed from The Pharmacogenomics Knowledgebase database. From the identified 264 FDA approved drugs with pharmacogenomic biomarkers in drug label, 195 are available in Hungary. From them, 165 drugs include pharmacogenomic data disposing 222 biomarkers. Most of them are metabolizing enzymes (46%) and pharmacological targets (41%). The most frequent therapeutic area is oncology (37%), followed by infectious diseases (12%) and psychiatry (9%) (p < 0.00001). Most common biomarkers in Hungarian SmPCs are CYP2D6, CYP2C19, estrogen and progesterone hormone receptor (ESR, PGS). Importantly, US labels present more specific pharmacogenomic subheadings, the level of action has a different prominence, and offer more applicable dose modifications than Hungarians (5% vs 3%). However, Hungarian SmPCs are at 9 oncology drugs stricter than FDA, testing is obligatory before treatment. Out of the biomarkers available in US drug labels, 62 are missing completely from Hungarian SmPCs (p < 0.00001). Most of these belong to oncology (42%) and in case of 11% of missing biomarkers testing is required before treatment. In conclusion, more factual, clear, clinically relevant pharmacogenomic information in Hungarian SmPCs would reinforce implementation of pharmacogenetics. Underpinning future perspective is to support regulatory stakeholders to enhance inclusion of pharmacogenomic biomarkers into Hungarian drug labels and consequently enhance personalized medicine in Hungary.

Interethnic variability of CYP4F2 (V433M) in admixed population of Roma and Hungarians.

AIMS: Pharmacogenetic based dosing recommendations are provided in FDA-approved warfarin label for Caucasians. Evidence of notable difference in dosing algorithms of under-represented populations forced us to explore the genetic variability of CYP4F2 gene in Roma and Hungarian populations. PATIENTS AND METHODS: 484 Roma, 493 Hungarian untreated subjects were genotyped for the CYP4F2*3 (rs2108622) variant by PCR-RFLP assay. RESULTS AND DISCUSSION: We firstly report, that frequencies of the CYP4F2 rs2108622 GG, GA, AA genotypes and A allele in the Roma population were 46.5%, 42.6%, 10.9% and 32.2%; in Hungarians 50.1%, 42.2%, 7.7% and 22.8%, respectively. Bearing of two minor alleles of CYP4F2 missense variant (AA genotype) modestly explains inter-ethnic differences of studied populations (p<0.08). CYP4F2*3 (V433M) risk allele frequency of Roma (0.32) was in higher range, and of Hungarians (0.23) in lower range, as compared with other world populations. CONCLUSIONS: Roma have an elevated chance for higher mean warfarin dose, besides a decreased risk of major bleeding events in long-term warfarin use.

Lower carrier rate of GJB2 W24X ancestral Indian mutation in Roma samples from Hungary: implication for public health intervention.

The purpose of this work was to characterise the W24X mutation of the GJB2 gene in order to provide more representative and geographicaly relevant carrier rates of healthy Roma subisolates and the Hungarian population. 493 Roma and 498 Hungarian healthy subjects were genotyped for the GJB2 c.71G>A (rs104894396, W24X) mutation by PCR-RFLP assay and direct sequencing. This is the first report on GJB2 W24X mutation in geographically subisolated Roma population of Hungary compared to local Hungarians. Comparing the genotype and allele frequencies of GJB2 rs104894396 mutation, significant difference was found in GG (98.4 vs. 99.8 %), GA (1.62 vs. 0.20 %) genotypes and A (0.8 vs. 0.1 %) allele between the Roma and Hungarian populations, respectively (p < 0.02). None of the subjects of Roma and Hungarian samples carried the GJB2 W24X AA genotype. Considerable result of our study, that the proportion of GJB2 W24X GA heterozygotes and the A allele frequency was eight times higher in Roma than in Hungarians. Considering the results, the mutant allele frequency both in Roma (0.8 %) and in Hungarian (0.1 %) populations is lower than expected from previous results, likely reflecting local differentiated subisolates of these populations and a suspected lower risk for GJB2 mutation related deafness. However, the significant difference in GJB2 W24X carrier rates between the Roma and Hungarians may initiate individual diagnostic investigations and effective public health interventions.

High prevalence of CYP2C19*2 allele in Roma samples: study on Roma and Hungarian population samples with review of the literature.

The purpose of our study was to characterise the CYP2C19*2 and CYP2C19*3 alleles in healthy Roma and Hungarian populations. DNA of 500 Roma and 370 Hungarian subjects were genotyped for CYP2C19*2 (G681A, rs4244285) and CYP2C19*3 (G636A, rs4986893) by PCR-RFLP assay and direct sequencing. Significant differences were found comparing the Roma and Hungarian populations in CYP2C19 681 GG (63.6 vs. 75.9%), GA (31.8 vs. 23.0%), AA (4.6 vs. 1.1%), GA+AA (36.4 vs. 24.1%) and A allele frequencies (0.205 vs. 0.125) (p<0.004). Striking differences were found between Roma and Hungarian samples in CYP2C19*1 (79.5 vs. 87.4%) and CYP2C19*2 (20.5 vs. 12.6%) alleles, respectively (p<0.001). None of the subjects was found to carry the CYP2C19*3 allele. Frequencies of the intermedier metabolizer phenotype defined by the *1/*2 genotype (0.318 vs. 0.230, p<0.005) and poor metabolizer predicted by the *2/*2 genotype (0.046 vs. 0.011, p<0.005) was significantly higher in Roma than in Hungarians, respectively. Genotype distribution of the Roma population was similar to those of the population of North India, however, a major difference was found in the frequency of the CYP2C19*2 allele, which is likely a result of admixture with European lineages. In conclusion, the frequencies of the CYP2C19 alleles, genotypes and corresponding extensive, intermediate and poor metabolizer phenotypes studied here in the Hungarian population are similar to those of other European Caucasian populations, but display clear differences when compared to the Roma population.

[Significance of thiopurine s-methyltransferase gene test in a clinical case]. / Thiopurin s-metil-transzferáz gén vizsgálatának jelentosége egy eset kapcsán.

Thiopurine s-methyltransferase enzyme is responsible for the metabolism of immunosuppressant thiopurines, which are used in inflammatory bowel diseases, acute lymphoblastic leukemia and autoimmune diseases. Because of the relative narrow therapeutic index of thiopurines serious or life threatening side effects can occur. A total of 28 variant alleles of the gene coding for the thiopurine s-methyltransferase enzyme are responsible for altered catalytic activity of the enzyme. Patients with one non-functional (heterozygous) allele have intermediate, while those with two non-functional (homozygous) alleles have low enzyme activity. Using polymerase chain reaction/restriction fragment length polymorphism and direct DNA sequencing the authors determined the G238C, G460A and A719G polymorphisms of the thiopurine s-methyltransferase gene in a child with Crohn's disease who developed thiopurine-induced severe agranulocytosis. The presence of the G460A and A719G polymorphic alleles in homozygous forms were detected which corresponded to the *3A variant allele. This variant has been shown to be associated with lower enzyme activity and low amount of the enzyme resulting in thiopurine toxicity and agranulocytosis. These findings underline the need for genotyping of the thiopurine s-methyltransferase variants prior to thiopurine treatment.