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Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3–4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3–4) was seen in 54.9% of patients. The NUDT15c.415T allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5–6.1); p = 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by considering FPGS variant (rs1544105’T’) carrier status along with NUDT15c.415T allele [HR = 2.7 (1.5–4.7, p = 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15c.415T allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT.

Patients on antituberculosis therapy (ATT) are more prone to drug interactions in the presence of coexisting illnesses which require drug therapy. Rifampicin is a pleiotropic inducer of CYP enzymes, and isoniazid is an enzyme inhibitor. Genetic variations are common in the gene coding for CYP2C19 enzyme. These variations would be important in predicting the individual variations in CYP2C19 activity. The objectives of the study were to find the net effect of 1-month ATT on CYP2C19 enzyme activity and its association with CYP2C19 genetic polymorphisms. Newly diagnosed tuberculosis patients (n = 125) were included in the study. Before commencing ATT, they were given a single dose of omeprazole 20 mg as a probe drug for CYP2C19. Blood sample was collected after 3 h to carry out phenotyping for CYP2C19 enzyme by measuring omeprazole hydroxylation index (OHI) using LC-MS/MS. The phenotyping procedure was repeated after 1 month of ATT. CYP2C19 genotyping was carried out by PCR-RFLP method. Significant reduction in OHI was observed after 1 month of ATT in all the metabolizer groups. The percentage reduction in OHI was maximum with poor metabolizers, 84.1 (IQR - 74.6, 86.6), and minimum with ultra-rapid metabolizers, 39.6 (IQR - 12.7, 54.7). CYP2C19 enzyme induction is predominant in patients after 1 month of antituberculosis treatment (ATT). Genetic variations in the enzyme could not clearly explain the interindividual differences in induction. There is a potential risk of drug failure/adverse effect in poor metabolizers regardless of their genotype after ATT.

The aim of the study was to look for the association of FPGS 2752 G > A (rs1544105), FPGS 1994 A > G (rs10106), and GGH 452 C > T (rs 11545078), GGH −401C > T (rs 3758149) gene polymorphisms with methotrexate (MTX) treatment response and MTX-induced adverse events in South Indian Tamil patients with rheumatoid arthritis (RA). Further the influence of these gene polymorphisms on MTX polyglutamate levels was analyzed. A total of 330 patients with RA were investigated. FPGS gene polymorphisms were analyzed by TaqMan 5ʹnuclease assay and GGH gene polymorphisms were analyzed by PCR-RFLP. Methotrexate polyglutamates (nmol/L of packed erythrocytes) were measured by liquid chromatography mass spectrometry (LCMS/MS) method. We found that the heterozygous genotype of FPGS rs1544105 [p = 0.02, OR 1.93, 95% CI (1.15–3.35)] and FPGS rs10106 AG genotype [p = 0.01, OR 2.11, 95% CI (1.20–3.71)] were associated with MTX adverse events. FPGS rs1544105 and GGH −401C > T SNPs influenced the polyglutamate levels. None of the investigated SNPs seems to be associated with MTX treatment outcome.

Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). Therapeutic drug monitoring (TDM) and pharmacogenetic screening is warranted for better management of imatinib therapy. The present study was framed to explore the influence of common drug transporter gene polymorphisms of ABCB1, ABCG2, OCT1 and trough level concentration on commonly occurring adverse events in CML patients treated with imatinib mesylate. A total number of 111 patients in chronic phase (Philadelphia chromosome +ve) were included in the study. The plasma drug concentration of imatinib was estimated using LC–MS/MS method. The mean ± SD trough level concentration of imatinib mesylate was found to be 1430.7 ± 438.7 ng/ml. The trough level concentration at steady state (Cmin.ss) was significantly higher in patients with grade 2–4 thrombocytopenia compared with patients without the adverse event (P value 0.033). The drug level of imatinib in plasma correlates with the severity of thrombocytopenia, which adds to the utility of TDM in the management of CML patients.

Summary: CYP2C19 is expressed polymorphically with about 21 variant alleles. Genotype-phenotype association studies of CYP2C19 have shown marked deviations, suggesting the 5´ regulatory region affecting its expression. This study aims to identify the genetic polymorphisms and construction of haplotypes of variations in 5' regulatory region of CYP2C19 among the South Indian population. CYP2C19 5 ´ regulatory region was amplified and sequenced from the DNA of 58 healthy volunteers of South Indian origin. Genetic analysis revealed the existence of 14 variations including eight novel ones in the 5´ regulatory region. Identified novel variations and their percentage frequencies were: − 779A > C (16.4), − 828 T > A (2.6), − 934del > T (3.5), − 1051 T > C (1.72), − 1289 T > G (3.4), − 1442 T > C (12.1), − 1498 T > G (25.0) and -1558 T > G (2.6). The reported variations found in the study population and their frequencies were: − 98 T > C (28.4), − 806C > T (2.6), − 833del > T (9.5), 889 T > G (10.3), − 1041A > G (100.0) and -1418C > T (1.7). The two known non synonymous single nucleotide polymorphisms, 681G > A (*2 allele) and 636G > A (*3 allele) were detected at 0.371 and 0.025 frequencies, respectively. Forty three haplotypes were constructed and linkage disequilibrium analysis showed strong linkage between several variations identified in the gene. Fourteen polymorphisms including 8 novel ones in CYP2C19 5´ flanking region are reported for the first time in an Indian population from South India. Results from this study provide additional information for genotyping of CYP2C19 in the South Indian population and probably in the Indian population.

Only 30% of major depressive disorder (MDD) patients achieve complete remission with a serotonergic antidepressant (selective serotonin reuptake inhibitor). We investigated the potential of serotonin (5-HT) and interleukin-6 (IL-6) to serve as functional biomarkers of fluoxetine response.Serum IL-6 and 5-HT were measured in 73 MDD patients (39 responders and 34 non-responders) pre- and 6 weeks post-treatment and in 44 normal controls with ELISA. Fluoxetine and norfluoxetine were measured using LC MS/MS.IL-6 levels were significantly higher in MDD patients when compared with controls (p 0.01), and 5-HT levels were significantly lower in non-responders compared with controls (p = 0.0131). Pre- and post-treatment levels of both biomarkers individually and in combination did not significantly differ between responders and non-responders. Area under the receiver operating characteristics curve for the biomarkers was 0.5. Significant correlation was seen between the percentage change in IL-6 and percentage change in Hamilton Rating Scale for Depression score in responders. Fluoxetine and norfluoxetine concentrations were not significantly different in responders and non-responders, and there was no correlation between fluoxetine concentrations and percentage reduction in 5-HT from week 0 to 6.5-HT and IL-6 may not serve as useful markers of response to fluoxetine because of inconsistent results across different studies. Copyright © 2016 John WileySons, Ltd.

Imatinib mesylate is currently considered the first-line treatment for chronic myeloid leukemia (CML). Sokal, Hasford and EUTOS are the three major risk categorization scores available for CML patients. The present study aimed to explore the influence of three risk score, genetic polymorphisms of ABCB1, OCT1, ABCG2 and trough level concentration on complete cytogenetic response at 1 year and overall survival. The mean time period of follow-up was 53.05 months, and the overall survival was 94.6 %. The Sokal score (P 0.014), Hasford score (P 0.016) and MDR1 C3435T (P 0.001) tend to influence the overall survival in the patients. The patients who had better overall survival had early complete cytogenetic response (P 0.0003). The ABCG2 C421A was the covariate which had correlation with the complete cytogenetic response. A perceptive approach incorporating pharmacogenetic evaluation with major risk categorization score at the initial stage will help in ensuring better treatment success in CML patients treated with imatinib.

Glu298 Asp polymorphism of endothelial nitric oxide synthase (eNOS) gene has been recently implicated as a genetic marker for coronary artery disease (CAD) in some studies. There is no information on the prevalence of this polymorphism and its relationship with CAD in south Indian population.A case control study was performed for the determination of the influence of Glu298 Asp polymorphism of eNOS gene in Tamilian population of south India. The study subjects comprised of 100 angiographically proven CAD patients and 100 age- and sex-matched volunteers asymptomatic for CAD, with a low coronary risk score. Genotyping of the eNOS gene was done by the polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) method.The genotype distribution was not significantly different between CAD (GG; 72, GT; 26, TT; 2) and control subjects (GG; 79, GT; 18, TT; 3). The corresponding allele frequencies were G 0.85, T 0.15 and G 0.88, T 0.12, respectively. The odds ratio for the association of CAD with the Asp variant failed to achieve statistical significance (OR = 0.66; 95% CI: 0.11-4.04, P = 1.0).No significant association was observed between the Glu298 Asp polymorphism and CAD in this population group.