Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 17, Issue 1, 2020

Previously, the association of human leukocyte antigen (HLA)-B27 with ankylosing spondylitis has been investigated as original and meta-analysis studies. However, the association of HLA-B27 with rheumatoid arthritis is not currently investigated as a meta-analysis. Hence, in this letter, a brief meta-analysis on this association will be performed. Although there were some studies on the association of RA and HLA-B27, however, there was not a pooled odds ratio reported in textbooks. Based on this brief metaanalysis, number 2.687 can be reported as the odds ratio of this association. It shows that this association is neither sensitive nor specific, but can be an idea for pharmacogenomics and personalized medicine as a potential risk factor. Such other associations should be reported numerically and updated in textbooks.

Background: Hu5F9-G4, a human immunoglobulin G4 (IgG4) monoclonal antibody (mAb) has recently been granted fast-track designation by the FDA for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Hu5F9-G4 has the ability to block CD47-SIRPα signaling along with anti- EGFR and anti-PD-L1 immune checkpoint activity that is involved in a variety of cancers like solid tumors, Non-Hodgkin’s Lymphoma (NHL), colorectal cancer (CRC), breast, ovarian and bladder cancers, and hematological malignancies. Thus, Hu5F9-G4 is an important biologic that has increasing clinical relevance in cancer care. Methods: We queried PubMed, Web of Science, Google Scholar, Science Direct and Scopus databases with keywords pertaining to Hu5F9-G4. In addition, we have included the Hu5F9-G4 data presented at the 60th American Society of Hematology (ASH) Annual Meeting, the American Society of Clinical Oncology (ASCO) Annual Meeting and 23rd Congress of the European Hematology Association (EHA). Results: We discuss the mechanistic basis and preclinical evidence for the anticancer activity of Hu5F9-G4. Further, we delineate clinical studies, alone and in combination with anti-CD20 mAb rituximab, anti-EGFR mAb cetuximab, PD-L1 checkpoint inhibitors avelumab and atezolizumab, and anti-HER2 mAb trastuzumab. Moreover, the potential adverse effects, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 with emphasis on the role of CD47-SIRPα signaling in phagocytosis are presented. Conclusion: Taken together, we review the pharmacokinetics and systems pharmacology of Hu5F9-G4 which appears to hold great promise for the future of cancer care.

Prenatal genetic diagnosis provides information for pregnancy and perinatal decision- making and management. Cytogenetic testing methods, including chromosomal microarray analysis and gene panels, have evolved to become a part of routine laboratory testing, providing valuable diagnostic and prognostic information for prenatal diagnoses. Despite this progress, however, cytogenetic analyses are limited by their resolution and diagnosis is only possible in around 40% of the dysmorphic fetuses. The advent of nextgeneration sequencing (NGS), whole-genome sequencing or whole-exome sequencing has revolutionized prenatal diagnosis and fetal medicine. These technologies have improved the identification of genetic disorders in fetuses with structural abnormalities and provide valuable diagnostic and prognostic information for the detection of genomic defects. Here, the potential future of prenatal genetic diagnosis, including a move toward NGS technologies, is discussed.

Objective: The purpose of the study was to analyze the association of allelic polymorphism of IL1B gene C>T loci -31 and +3953 with atherosclerotic changes of artries in patients with Metabolic Syndrome (MS). Materials and Methods: The main group of the study included 30 consecutive patients (24 women and 6 men, mean age - 51.7±2.2 years), for examination and treatment in the therapeutic Department of the Republican clinical hospital named "G. YA. Remishevskaya" (Abakan) about arterial hypertension or suspicion of type 2 diabetes. The criteria for inclusion in the core group included: compliance with the MS criteria according to the IDF criteria (2006); and the presence of ultrasound markers of Atherosclerosis (AS) according to the study of brachiocephalic arteries (presence of Atherosclerotic Plaques (ASP) and stenosis ≥30%). The control group included persons who underwent a planned medical examination in the Republican clinical hospital name "G. YA. Remishevskaya" (Abakan). A total of 35 patients (26 women and 9 men, mean age 44.7±1.5 years) were selected. The study involved the Russian population (Caucasians) living in the territory of the Republic of Khakassia. All the necessary examination and data collection were conducted including anamnestic data, anthropometric examination (measurements of length and body mass, waist circumference) body mass index, laboratory examination of blood biochemical parameters (glucose and lipid) and instrumental examination (blood pressure measurement, conducting ECG and ultrasound the brachiocephalic arteries). Single-nucleotide polymorphisms (SNP) of the promoter region of the IL1B gene at position-31C/T (rs1143627) and polymorphism in the coding part of the gene in exon 5 +3953C/T (rs 1143634) were studied by restriction analysis of amplification products (RFLP analysis). Results: The risk of development of AS in patients with MS may be higher in carriers of genotype TT (OR = 1,76; 95% CI: (0,96-3,24)) or T allele (OR = 1,44; 95% CI: (0,82- 2,53)) IL1B gene in the polymorphic locus of the T-31C and genotype CT (OR = 1,85; 95% CI: (0,92-3,37)) or T allele (OR = 1,35; 95% CI: (0,63-2,89)) IL1B gene in the polymorphic locus of C + 3953T. The most common combination of gene polymorphisms IL1B was haplotype (-31) TC/(+3953)CC in both the groups surveyed (40.6% to 36.8%, respectively). Variant (-31)TT/(+3953)CT in the main group was found significantly more often (15.8%, at χ2= 4.92, at p=0.03) than in the control group (3.1 %). The value of the odds ratio in this case was 3.99 (95% CI: (1.08-14.79), which indicates the risk of AS development against the background of MS in carriers of combined genotype inheritance (-31)TT/(+3953) CT. Conclusion: The risk of development of AS in the background of MS is increased in carriers of combinations of SNPs (-31)TT/(+3953)CT IL1B gene responsible for hyperproduction of this cytokine. In this connection, further studies of the association of genes with MS and AS components should focus on intergenic interactions.

Background: Identifying the genetic polymorphisms of drug metabolizing enzyme CYP2D6 is useful in pharmacogenomics. Unfortunately, until today, the prevalence of the CYP2D6 polymorphisms among Kurds is scarce. Objective: In this study, we explored the CYP2D6 polymorphisms among Kurds. Methods: Four hundred and fifty-nine unrelated healthy Kurds were recruited for the study. DNA was extracted from whole blood and was then used for genotyping CYP2D6*3, *4, *5, *6, *9, *10, *17, *114 and gene duplication using the nested allelespecific multiplex Polymerase Chain Reaction (PCR). Results: The most common alleles and genotypes identified were CYP2D6*1 (75.5%), gene duplication (10.0%), *4 (8.6%), *10 (3.4%) and CYP2D6*1/*1 (62.5%), *1/*4 (16.3%), *1/*1xN (8.3%) and *1/*10 (6.3%). Thirty-nine (8.5%) subjects had genotypes that predicted Ultrarapid Metaboliser (UM) phenotypes, whereas two (0.4%) showed genotypes that predicted Intermediate Metabolisers (IMs), and four (0.8%) subjects had genotypes that Predicted Poor Metabolism (PMs). Conclusion: The data add to our knowledge of CYP2D6 alleles, the genotypes and the distributions of predicted phenotypes in Kurds. Majority of the observed variant alleles confer no function and gene duplication. CYP2D6 polymorphisms were found to be very heterogeneous in relation to genotype frequencies. Further study in relation to the evaluation of drug therapy adjustment based on CYP2D6 genotype may help to understand the clinical consequences of CYP2D6 polymorphisms.

Background: Imatinib mesylate is the first tyrosine kinase inhibitor approved for chronic myeloid leukemia (CML) therapy. Imatinib is an effective drug. However, previous studies have shown that about 20-30% of patients eventually would develop resistance to imatinib. Approximately 40% of imatinib resistance is associated with BCRABL kinase domain mutation. One of the most common and serious variations account for imatinib response is T315I of ABL1 gene. Objective: The study aimed to examine the association of T315I mutation with the ABL1 gene and its relation to major molecular response (MMR) achievement in CML patients. This study also examined other mutations adjacent to T315I, i.e., F311I, F317L, and different possible variations in the ABL1 gene. Methods: This was a cross-sectional study on Indonesian CML patients in chronic phase. We analyzed 120 blood samples from patients in chronic phase who have received imatinib mesylate (IM) for ≥12 months. Results: There were no T315I, F311I, and F317L mutations found in this study. However, we found another variation, which was 36 substitutions from A to G at position 163816 of ABL1 gene (according to NG_012034.1). Conclusion: We found no T315I, F311I, and F317L mutations in this study. Our findings suggest that there might be other factors that influenced the MMR achievement in our study patients. However, there were 36 substitutions from A to G at position 163.816 (according to NG_012034.1) that needed further examination to explore the significance of this mutation in clinical practice.

Background: Personalized approach is one of the options to overcome treatment failure in psychiatry and increase the efficacy of antipsychotic treatment for an individual patient by using genetic tests. Objective: The aim of this study was to investigate the frequency of MDR1 (C3435T), CYP2D6, CYP2C19, and CYP1A2 genotypes in psychiatric patients with treatment failure to antipsychotics to compare the results with those published for the Russian population. Methods: A total number of 52 patients attending a psychiatry outpatient clinic were included in the study. All patients required changing the therapy with antipsychotics due to treatment failure. Results: We revealed the higher frequency of T/T MDR1 (C3435T) homozygotes among study patients as compared with the Russian healthy population. For CYP1A2, the higher frequency of normal metabolizers (*1A/*1A) and lower frequency of slow metabolizers (*1F/*1F) were observed. No difference was found for intermediate metabolizers (*1A/*1F) and one patient had *1A/*1C genotype with decreased activity. For the majority of CYP2D6 genotypes, the observed frequencies were similar to those reported for the Russian healthy population except for CYP2D6 *3/*4 (slow metabolizers), for which higher frequency among study patients was found. The frequencies of CYP2C19 genotypes were comparable to the Russian population, however, no slow metabolizers (*2/*2, *2/*3, *3/*3 genotypes) were identified. Conclusion: Psychiatric patients with treatment failure to antipsychotics demonstrated a high frequency of T/T MDR1 (C3435T) and CYP2D6 *3/*4 genotypes coding inactive proteins. The frequency of CYP1A2 wild type genotype *A/*A was higher with a simultaneous decrease in the frequency of *F/*F genotype compared with the healthy Russian population. Further studies of MDR1 (C3435T) genotype as well as CYP2D6, CYP2C19, and CYP1A2 genotypes frequency should be conducted in patients with treatment failure to antipsychotics.

Background: The opioid receptor μ-1 (OPRM1) has become one of the most studied genes in pharmacogenetics, as this gene encodes the μ-opioid receptor (MOR), which plays a role in opioid drugs response, as well as in various disorders. One of its variants, A118G, which is found at a high frequency in the Asian population, has been associated with loss of sensitivity to and an increased requirement for analgesics in the treatment of pain, increased pain sensitivity, various types of substance dependencies, and the development of breast cancer. However, there are still limited reports about this gene polymorphism in the Indonesian population. Objective: The study aimed to determine the allele frequencies of the OPRM1 A118G polymorphism among the Indonesian population. Method: A cross-sectional study of 158 subjects, comprising 79 males and 79 females, was conducted among Indonesians, and genotype analysis was carried out by a modified allele-specific Polymerase Chain Reaction (PCR) method. Results: A frequency of 60.4% was found for the G allele among Indonesian samples, with a higher frequency being present in males (66.5%). The A allele was found at frequencies of 33.5% and 45.6% in males and females, respectively. A significant difference in allele frequency was found between males and females (p = 0.029, OR = 1.659, 95% CI [1.052–2.614]), while there was no significant difference in genotype frequencies between groups. Conclusion: A high prevalence of the OPRM1 A118G polymorphism was found in the Indonesian population, with the G allele frequency tending to be higher in males.