Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 19, Issue 2, 2022

Background: PCSK9 (Proprotein convertase subtilisin/kexin type 9) plays a key role in cholesterol homeostasis and Coronary artery disease (CAD). Many studies have extrapolated the association of the PCSK9 gene with low-density lipoprotein cholesterol (LDL-C) levels and CAD but with contradicting results. No such study is available stating the intergenotypic variations in the levels of expression of PCSK9 and LDL-C and their correlations with CAD risk factors in patients with CAD. Objective: We aim to explore the association of PCSK9 A/G (rs505151) polymorphism and its expression at mRNA and protein levels in patients with CAD. It also investigates how LDL-C, PCSK9, BMI, and systolic blood pressure (SBP) levels in patients with CAD and in healthy participants relate to the PCSK9 intergenotypic variation. Methods: Angiographically confirmed CAD patients [n=250] and controls [n=250] were genotyped by PCR followed by RFLP techniques. Real-time PCR and Western Blot methods were used to investigate PCSK9's differential expression. Results: Odds ratio being the index of association, revealed a statistically significant association of PCSK9 A/G (rs505151), A Vs G= 4.94 [1.37-7.79] polymorphism with CAD. In patients with the GG genotype, there is a correlation between higher PCSK9 gene expression and circulating LDL-C levels. Conclusion: Our study shows a significant association of PCSK9 gene polymorphism with CAD. We also observed an increased expression of the PCSK9 gene in patients with the G allele. In our study, PCSK9 A/G (rs505151) gene and LDL-C emerged as independent risk factors. More follow-up research is required to determine whether upregulated PCSK9 gene expression can act as a prognostic marker for CAD.

Aims: This pilot study aimed to make head-to-head comparisons of multiple classes of drugs used in the management of neuropathic pain in North Indian older adult patients presenting to the geriatric clinic of a tertiary medical institution. Background: Chronic neuropathic pain is a condition affecting nearly one third of older adults. There is paucity of data on head-to-head comparisons of drugs used in neuropathic pain in older adults. Real world studies may be a useful tool to study diverse neuropathic pain medications in this population. Objectives: The study objective was to measure NPRS (numeric pain rating scale), GDS (geriatric depression scale), IADL (instrumental activities of daily living), HMSE (Hindi mental state examination) scores at baseline, and 4- and 12-week follow-ups in all older adult patients receiving neuropathic pain medications. Methods: A prospective observational study was conducted involving older adult patients ≥ 50 years of age with painful peripheral neuropathy of any etiology (n=60; mean age 63±8.4 years). The patients received either gabapentin, pregabalin, duloxetine, amitriptyline, or methyl- cobalamin complex. NPRS, GDS, IADL, and HMSE scores were measured at baseline and post-therapy. Results: All groups except amitriptyline showed statistically significant improvement in NPRS at 4 weeks and 12 weeks compared to baseline. 30% response rate at 4 weeks was maximum for pregabalin (72%) and 50% response rate at 12 weeks was maximum for gabapentin (58%). Numerically maximum improvement in depression was seen with duloxetine. There was no statistically significant difference in the measured parameters between the drug groups across time. Mean daily dose was 172 mg (gabapentin group), 75 mg (pregabalin group) and 20 mg (duloxetine group). The adverse drug reaction rate was 10.5%. Conclusion: All drug groups showed beneficial effects on neuropathic pain at much lower doses than those described in the literature. The effectiveness at these low doses and the lower rates of adverse effects sets the foundation for larger studies in the future in diverse ethnic and aged populations.

Background: Tamoxifen (TAM) is commonly prescribed as adjuvant therapy in women with estrogen receptor-positive breast cancer. Unfortunately, not all patients respond adequately to this drug. This variation in pharmacological response has been associated with different factors, including genetic polymorphisms of enzymes responsible for the metabolism of TAM. Objective: To determine the concentrations of tamoxifen (TAM) and its main metabolites in Mexican women with breast cancer and to evaluate its relationship with genetic, demographic and anthropometric characteristics. Methods: Eighty-four patients with a mean age of 49.3 (± 8.8) years were included in the study. Plasma concentrations of TAM and its metabolites N-desmethyl-tamoxifen (NDT), 4- hydroxy-tamoxifen (4HT) and endoxifen (END) were determined in predose for each patient. CYP2D6 * 4, * 10 and CYP3A5 * 3 genetic polymorphisms were characterized. Demographic, anthropometric, biochemical and clinical data were recorded for each patient. Results: Plasma concentrations of 4HT and END were higher in the extensive metabolizer (EM) phenotype than in the intermediate metabolizer (IM) phenotype (p<0.05). The metabolic ratio (MR) [END+4HT]/[TAM+NDT] was lower in patients with the CYP2D6 IM phenotype than those with the EM phenotype (p= 0.014). Regarding anthropometric factors, a positive correlation was found for 4HT and the END concerning age (R = 0.256 and 0.232, respectively). The body mass index (BMI) presented a statistically significant correlation with the concentrations of NDT (R=-0.351) and 4HT (R=-0.298). Conclusion: CYP2D6 phenotype, age and BMI could help to explain part of the interindividual variability of TAM plasma levels and its metabolites in the Mexican population.

Background: Type 2 Diabetes Mellitus (T2DM) is a complex metabolic disease that is caused by insulin dysfunction. It is an output of oxidative stress that results from defective redox reactions and increased Reactive Metabolites (RMs) and is neutralized by antioxidant enzymes. It has been reported that decreased levels of antioxidant enzymes are due to genetic alterations in the respective genes. Therefore, the present study has undertaken a genetic analysis of antioxidant genes and their interaction in the family to assess T2DM risk. Objective: This study aimed to investigate the individual susceptibility/risk to T2DM using antioxidant gene variants and their interactions in family members with a diabetic history. Methods: Genotypic analysis of antioxidant genes was done by polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP), haplotype analysis, and gene-gene interactions using statistical tools. Pedigrees were constructed by face-to-face interviews with members of nine families. Results: Genotypes AT (CAT-21A>T), IV (GSTP1+313(105I>V), and CT (GPx1 +599C>T) were found to be frequent in diabetic individuals. For instance, in one family, if only the mother had diabetes, all siblings were found to have the risk genotypes AT (CAT- 21A>T) and CT (GPx1 +599C>T) with 2.12- and 2.11-folds risk of developing T2DM. The risk haplotypes, NNV (GSTM1 N>P(Null>Present), GSTT1 N>P(Null>Present), GSTP1105I>V and TCC (CAT-21A>T, SOD2+47C>T, GPx1+599C>T) were observed in most of the diabetic individuals and non-diabetics possessing the risk haplotypes manifested altered BMI. Conclusion: The present study suggests that the GSTP1105I>V, CAT-21A>T, SOD2+47C>T and GPx1+599C>T gene variants can be prognostic biomarkers for the assessment of T2DM risk in healthy individuals.

Background: Juvenile myelomonocytic leukemia (JMML) is a rare childhood disease characterized by hepatosplenomegaly, monocytosis, anemia, increased white blood cell count, thrombocytopenia, skin infiltration, and elevated fetal hemoglobin. Mutation in specific genes, including KRAS, NRAS, PTPN11, and NF1, can lead to the development of JMML. Case Presentation: A two-year-old boy with a history of inguinal abscess at the age of 12 months and surgery due to infectious lymphadenitis was referred to the hospital. His parents also reported a history of oral candidiasis, recurrent otitis media, and lymphadenopathy in the patient. The physical examination showed splenomegaly, macular rash, lymphadenopathy in the neck region, and rashes in the inguinal region and on the hands and feet. Laboratory and flow cytometry data showed lymphocytosis, low hemoglobin, thrombocytopenia, monocytosis, eosinophilia, and a shift to the left in the peripheral blood. The bone marrow aspiration showed a cellular marrow with myeloid hyperplasia. Whole-exome sequencing revealed a rare heterozygous ENST00000351677.2:c.1508G>C, p.Gly503Ala variant in PTPN11. The patient was diagnosed with JMML but, unfortunately, passed away. Conclusion: We report a rare heterozygous mutation in the PTPN11 gene in a two-year-old boy diagnosed with JMML. This uncommon mutation should be considered in the mutational screening protocol of JMML. Management of JMML with RAS pathway targeted therapy may also have promising results and needs further investigations.