Role of CYP2C19 gene polymorphism in acute alcohol withdrawal treatment with loading dose of diazepam in a South Indian population.

PURPOSE: Alcohol dependence is a public health problem worldwide, commonly associated with withdrawal symptoms for which diazepam is a frequently used drug. We studied the effect of CYP2C19 gene polymorphisms on diazepam loading dose requirement and time to reversal of acute alcohol withdrawal symptoms. We also studied the influence of the polymorphism in this gene on the persistent symptoms after loading dose of diazepam. METHODS: Sixty-nine patients who reported to the psychiatry department with symptoms of alcohol withdrawal diagnosed by DSM-IV criteria were included for the study. A 10-mg loading dose of diazepam was administered iv after baseline assessment of withdrawal severity using CIWA-Ar scoring. The patients were assessed for improvement of the symptoms every two hourly and 20 mg oral diazepam was given based on improvement of symptoms. Genotyping for CYP2C19*2, CYP2C19*3 and CYP2C19*17 was done by PCR-RFLP and RT-PCR methods. RESULTS: The diazepam dose requirement as well as the time required for reversal of acute symptoms was not statistically different among the different genotype groups. Similarly, the frequency of patients with persistent symptoms after successful treatment of the acute episode was not different among the groups. However, the total diazepam dose requirement was influenced by baseline CIWA-Ar scores (adjusted OR 0.21, p = 0.026). In addition, the odds of treatment with a lower dose (10 mg) of diazepam were higher in smokers (adjusted OR 5.22, p = 0.025) and patients with other addiction (adjusted OR 9.26, p = 0.026). CONCLUSION: We found that CYP2C19 polymorphism did not have any significant effect on the diazepam dose requirement, time duration needed for successful treatment or on the persistent symptoms after loading dose of diazepam in South Indian population. However, diazepam dose requirement was influenced by baseline CIWA-Ar score, smoking status and other comorbid addictions.

Prehypertension status, cardiometabolic risks, and decreased baroreflex sensitivity are linked to sympathovagal imbalance in salt-preferring individuals.

Salt preference has been reported to cause sympathovagal imbalance (SVI) and prehypertension. We investigated the role of inflammation, insulin resistance (IR), hyperlipidemia, and oxidative stress (OS) in genesis of SVI and cardiovascular (CV) risks in salt-preferring prehypertensives. The subjects were divided into no-salt-preferring (NSP, n = 87) and salt-preferring (SP, n = 89) group based on their preference for salted food. Body mass index (BMI), blood pressure (BP) variability parameters including baroreflex sensitivity (BRS), heart rate variability (HRV) indices, autonomic function tests, IR, lipid risk factors, inflammatory and OS markers, and renin were measured in both the groups. Based on the contribution of various cardiometabolic risks to low-frequency-high-frequency (LF-HF) ratio of HRV, the marker of SVI was assessed by multiple-regression analysis. Prediction of prehypertension status by the LF-HF ratio was assessed by bivariate logistic regression. BMI, heart rate, BP parameters, cardiac output, total peripheral resistance, LF-HF ratio, IR, atherogenic index, inflammatory, and OS markers were significantly increased, and BRS was significantly decreased in the SP group compared with the NSP group. There was an independent association of IR, atherogenic index, markers of inflammation and OS, and BRS with the LF-HF ratio in SP subjects, and the LF-HF ratio had significant prediction of prehypertension status in these subjects. It was concluded that IR, low-grade inflammation, atherogenic lipid profile, and OS contribute to SVI in SP subjects. Decreased BRS (the marker of CV risk) is linked to SVI, and SVI predicts prehypertension status in SP subjects.

Computational identification and analysis of deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in the human POR gene: a structural and functional impact.

Cytochrome P450 oxidoreductase (POR) protein is essential for steroidogenesis, and POR gene mutations are frequently associated with P450 Oxidoreductase Deficiency (PORD), a disorder of hormone production. To our knowledge, no previous attempt has been made to identify and analyze the deleterious/pathogenic non-synonymous single nucleotide polymorphisms (nsSNPs) in the human POR gene through an extensive computational approach. Computational algorithms and tools were employed to identify, characterize, and validate the pathogenic SNPs associated with certain diseases. To begin with, all the high-confidence SNPs were collected, and their structural and functional impacts on the protein structures were explored. The results of various in silico analyses affirm that the A287P and R457H variants of POR could destabilize the interactions between the amino acids and the hydrogen bond networks, resulting in functional deviations of POR. The literature study further confirms that the pathogenic mutations (A287P and R457H) are associated with the onset of PORD. Molecular dynamics simulations (MDS) and essential dynamics (ED) studies characterized the structural consequences of prioritized deleterious mutations, representing the structural destabilization that might disrupt POR biological function. The identified deleterious mutations at the cofactor's binding domains might interfere with the essential interactions between the protein and cofactors, thus inhibiting POR catalytic activity. The consolidated insights from the computational analyses can be used to predict potential deleterious mutants and understand the disease's pathological basis and the molecular mechanism of drug metabolism for the application of personalized medication. HIGHLIGHTSNADPH cytochrome P450 oxidoreductase (POR) mutations are associated with a broad spectrum of human diseasesIdentified and analyzed the most deleterious nsSNPs of POR through the sequence and structure-based prediction toolsInvestigated the structural and functional impacts of the most significant mutations (A287P and R457H) associated with PORDMolecular dynamics and PCA-based FEL analysis were utilized to probe the mutation-induced structural alterations in PORCommunicated by Ramaswamy H. Sarma.

Body mass index contributes to sympathovagal imbalance in prehypertensives.

BACKGROUND: The present study was conducted to assess the nature of sympathovagal imbalance (SVI) in prehypertensives by short-term analysis of heart rate variability (HRV) to understand the alteration in autonomic modulation and the contribution of BMI to SVI in the genesis of prehypertension. METHODS: Body mass index (BMI), basal heart rate (BHR), blood pressure (BP), rate pressure product (RPP) and HRV indices such as total power (TP), low-frequency power (LF), normalized LF (LFnu), high-frequency power (HF), normalized HF (HFnu), LF-HF ratio, mean heart rate (mean RR), square root of the mean squared differences of successive normal to normal intervals (RMSSD), standard deviation of normal to normal RR interval (SDNN), the number of interval differences of successive NN intervals greater than 50 ms (NN50) and the proportion derived by dividing NN50 by the total number of NN intervals (pNN50) were assessed in three groups of subjects: normotensives having normal BMI (Group 1), prehypertensives having normal BMI (Group 2) and prehypertensives having higher BMI (Group 3). SVI was assessed from LF-HF ratio and correlated with BMI, BHR, BP and RPP in all the groups by Pearson correlation. The contribution of BMI to SVI was assessed by multiple regression analysis. RESULTS: LF and LFnu were significantly increased and HF and HFnu were significantly decreased in prehypertensive subjects in comparison to normotensive subjects and the magnitude of these changes was more prominent in subjects with higher BMI compared to that of normal BMI. LF-HF ratio, the sensitive indicator of sympathovagal balance had significant correlation with BMI (P=0.000) and diastolic blood pressure (DBP) (P=0.002) in prehypertensives. BMI was found to be an independent contributing factor to SVI (P=0.001) in prehypertensives. CONCLUSIONS: It was concluded that autonomic imbalance in prehypertensives manifested in the form of increased sympathetic activity and vagal inhibition. In prehypertensives with higher BMI, vagal withdrawal was predominant than sympathetic overactivity. Magnitude of SVI (alteration in LF-HF ratio) was linked to changes in BMI and DBP. BMI had an independent influence on LF-HF ratio. It was advised that life-style modifications such as yoga and exercise would enable achieve the sympathovagal balance and blood pressure homeostasis in prehypertensives.

Functional characterization of promoter region polymorphisms of human CYP2C19 gene.

CYP2C19 is an enzyme involved in the metabolism of several clinically important drugs. The variations in the CYP2C19 promoter region may alter the transcription of the gene by altering the interaction between the trans and cis-acting elements. In the present study, CYP2C19 promoter region with different variant alleles were cloned into a pGL-3 basic luciferase reporter vector and transfected into HepG2 cell lines. Subsequently, dual luciferase activity was measured to evaluate the activity of the promoter region. Gel shift assays with predicted binding sites for CCAAT displacement protein, activating transcription factor-2 and glucocorticoid receptor were performed. Results from this study indicate that few variations present in the putative cis-acting elements of the CYP2C19 promoter region such as -1442T>C, -779A>C and -98T>C -1498T>G and -828del>T alter the transcription of the gene. Specific binding with nuclear proteins was also observed in gel shift assays. This may account for the interindividual variations in gene expression and genotype dependant differences in gene transcription. The results also suggest the role of activating transcription factor-2 and CCAAT displacement repressor protein on CYP2C19 gene transcription.

Prothrombotic Factors Have Significant Association with Arterial and Venous Strokes in Indian Tamilians.

BACKGROUND: Prothrombotic factors have been correlated with vascular events in young patients, with recurrent strokes, and with venous thromboembolisms. However, their prevalence in adult strokes, in healthy populations, and in specific ethnic groups is not well defined. We investigated the association of prothrombotic factors with strokes in a South Indian Tamil population. METHODS: In this hospital-based cross-sectional study, plasma homocysteine (Hcys), protein C and protein S activity levels, activated protein C resistance (APCR) as a surrogate for factor V Leiden (FVL), fibrinogen, and antithrombin III (ATIII) were determined from 75 consecutive patients with ischemic stroke (IS), 25 with cortical venous thrombosis (CVT), and 75 healthy control participants. The Student t test or Mann-Whitney U test was used for comparing prothrombotic factor levels between the stroke and control groups. The χ2 or Fisher exact test was used for comparisons of proportions of thrombophilia and estimation of odds ratios. Mid-P correction was done for multiple estimations. RESULTS: Hcys levels in patients with IS were significantly higher compared with those in healthy control participants (P = 0.02). Proportions of ATIII deficiency and hyperfibrinogenemia were significantly higher in the IS group, and no healthy control participants had hyperfibrinogenemia. Protein C deficiency was more frequent in those with IS (17%; P < 8 × 10-5) and CVT (P < 10-7) compared with healthy control participants, and protein C activity levels (P = 0.016) were also significantly lower in patients with CVT. Other parameters had no significant associations with IS and CVT. The frequency of protein S deficiency was high in healthy control participants (60%) and in both patients with IS (45%; P = 0.1) and patients with CVT (48%; P = 0.4). No patients or control participants had abnormal APCR. CONCLUSIONS: In Tamilian participants, several prothrombotic factors were associated with IS. Protein C deficiency alone was associated with CVT. Replication of the pattern in genetically linked populations around the world may affect management of stroke in those populations.

Influence of CYP2C9 genetic polymorphism and undernourishment on plasma-free phenytoin concentrations in epileptic patients.

The objective of this study was to study the effect of CYP2C9 genetic polymorphism and undernourishment on free phenytoin concentrations in epileptic patients. The study was done in 70 patients who were taking phenytoin therapy for the treatment of epileptic seizures. Genotyping of CYP2C9 (*2 and *3) was determined by the polymerase chain reaction-restriction fragment length polymorphism method. Bound and free plasma phenytoin was separated using equilibrium dialysis technique. Total and free phenytoin concentrations were measured by the reverse-phase high-performance liquid chromatography method. Patients were broadly classified into well-nourished and undernourished and further subclassified by CYP2C9 genotypes. In well-nourished groups (G1 to G3 group), free phenytoin concentrations were significantly higher in the heterozygous poor metabolizer of CYP2C9 genotype (G2) group (3.1 ± 0.62 µg/mL) and homozygous poor metabolizer of CYP2C9 genotype (G3) group (4.3 ± 1.76 µg/mL) when compared with patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 µg/mL). Similarly, in undernourished patient groups (G4-G6 group), free phenytoin concentrations were significantly higher in the wild-type CYP2C9 (G4) group (2.5 ± 0.52 µg/mL), heterozygous poor metabolizer of CYP2C9 genotype (G5) group (4.3 ± 1.76 µg/mL), and homozygous poor metabolizer of CYP2C9 genotype (G6) group (8.2 ± 1.08 µg/mL) when compared with well-nourished patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 µg/mL). The percentage increase in free phenytoin concentration by undernourishment, CYP2C9 allelic variants, and undernourishment cum CYP2C9 allelic variants were 127%, 290%, and 472%, respectively, compared with well-nourished patients with the wild-type CYP2C9 genotype (G1) group. The contribution of undernourishment and genetic factors (CYP2C9 allelic variant) for developing phenytoin toxicity was calculated to have an odds ratio of 37.3 (P < 0.0001). Undernourishment and variant CYP2C9 alleles elevate free phenytoin concentrations individually and in combination show additive effects.

Insight into the structural and functional analysis of the impact of missense mutation on cytochrome P450 oxidoreductase.

Cytochrome P450 oxidoreductase (POR) is a steroidogenic and drug-metabolizing enzyme. It helps in the NADPH dependent transfer of electrons to cytochrome P450 (CYP) enzymes for their biological activity. In this study, we employed integrative computational approaches to decipher the impact of proline to leucine missense mutation at position 384 (P384L) in the connecting/hinge domain region which is essential for the catalytic activity of POR. Analysis of protein stability using DUET, MUpro, CUPSAT, I-Mutant2.0, iStable and SAAFEC servers predicted that mutation might alter the structural stability of POR. The significant conformational changes induced by the mutation to the POR structure were analyzed by long-range molecular dynamics simulation. The results revealed that missense mutation decreased the conformational stability of POR as compared to wild type (WT). The PCA based FEL analysis described the mutant-specific conformational alterations and dominant motions essential for the biological activity of POR. The LIGPLOT interaction analysis showed the different binding architecture of FMN, FAD, and NADPH as a result of mutation. The increased number of hydrogen bonds in the FEL conformation of WT proved the strong binding of cofactors in the binding pocket as compared to the mutant. The porcupine plot analysis associated with cross-correlation analysis depicted the high-intensity flexible motion exhibited by functionally important FAD and NADPH binding domain regions. The computational findings unravel the impact of mutation at the structural level, which could be helpful in understanding the molecular mechanism of drug metabolism.

Effects of genetic polymorphisms in Vitamin D metabolic pathway on Vitamin D level and asthma control in South Indian patients with bronchial asthma.

OBJECTIVES: The study was designed to evaluate the single-nucleotide polymorphisms (SNPs) of genes involved in Vitamin D actions (rs2228570) and metabolic pathways (rs2248137 and rs10766197) and their associations with serum 25-hydroxy Vitamin D (25(OH)D) level and asthma control in South Indian patients with bronchial asthma. MATERIALS AND METHODS: One hundred and two patients of South Indian origin with bronchial asthma either naive to inhaled corticosteroids (ICSs) or not receiving ICS for ≥1 month were included and were treated with ICS (beclomethasone 200 µg twice daily) for 8 weeks. One hundred and one unrelated healthy South Indians were used as controls. Pulmonary function test and fractional exhaled nitric oxide were used to assess asthma control. Serum 25(OH)D levels (chemiluminescence immunoassay) and SNPs in Vitamin D pathway (real-time polymerase chain reaction) were assessed. The associations of SNPs and serum 25(OH)D with asthma control was determined using linear regression. All analyses were performed using SPSS (version 19) and "SNPStats." P < 0.05 was considered as statistically significant. RESULTS: Vitamin D receptor (VDR) polymorphism (rs2228570) was found to be protective against asthma (P = 0.022), while there were no significant associations between the other two SNPs and asthma. Similarly, poor correlation and insignificant associations between the SNPs and serum 25(OH)D levels were observed in both cases and controls. There were also insignificant associations between the SNPs and asthma control. CONCLUSION: VDR polymorphism (rs2228570) was found to be protective against asthma in South Indians, while other genes involved in the metabolic pathway of Vitamin D did not show associations with asthma.

Gender specific association of endothelial nitric oxide synthase gene (Glu298Asp) polymorphism with essential hypertension in a south Indian population.

BACKGROUND: Endothelial derived nitric oxide (NO) plays a major role in blood pressure regulation. The role of missense variant eNOS-Glu298Asp has been demonstrated by many studies with conflicting results. Our objective was to investigate the association of eNOS gene polymorphism with essential hypertension in a south Indian population. METHODS: We carried out a case control study in 438 hypertensive patients and 444 healthy control subjects in a homogenous population. Genotyping was done by PCR-RFLP method. Multiple logistic regression analysis was used to detect the association between genotype and hypertension. RESULTS: The homozygous variant genotype Asp298Asp was significantly associated with hypertension (odds ratio 2.4; 95% CI, 1.23-5.0, p<0.01). Gender specific analysis showed both the heterozygous (odds ratio, 2.0; 95% CI, 1.3-2.9, p<0.01) and homozygous variants (odds ratio, 7.9; 95% CI, 2.0-4.1, p<0.001) were positively associated with hypertension in females. The variant allele Asp was higher in female hypertensives when compared to male hypertensive cases (22% vs. 16%). CONCLUSION: The eNOS gene polymorphism is a candidate gene for hypertension and the association to be gender specific with respect to females in a south Indian Tamilian population.

Lack of association between Glu(298) asp polymorphism of endothelial nitric oxide synthase (eNOS) gene and coronary artery disease in Tamilian population.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: No significant association was observed between the Glu298 Asp polymorphism and CAD in this population group.

Severe phenytoin toxicity in a CYP2C9*3*3 homozygous mutant from India.

The authors report an Indian adult female patient with a history of generalized tonic clonic seizures who developed severe features of phenytoin (DPH) toxicity on therapeutic dosage of this antiepileptic drug. Administration of 300 mg/day of DPH in this patient resulted in toxic symptoms associated with an excessive serum DPH concentration of 33 microg/ml. The PCR-RFLP analysis revealed a homozygosity involving CYP2C9*3*3. This mutation results in a marked decrease in the enzymatic activity (CYP2C9) and leads to a decreased clearance of the drug which can lead to severe acute and chronic toxicity. On switching the antiepileptic therapy from DPH to sodium valproate, there was reversal of both.

Vascular endothelial growth factor (VEGF) gene polymorphisms (rs699947, rs833061, and rs2010963) and psoriatic risk in South Indian Tamils.

BACKGROUND: Psoriasis is a chronic inflammatory disease of the skin. Vascular endothelial growth factor (VEGF), a pro-angiogenic factor, is involved in the pathogenesis of psoriasis. Being highly polymorphic, several SNPs of VEGF have been reported to be associated with increased risk of psoriasis. OBJECTIVES: We determined the association of VEGF gene polymorphisms with risk of psoriasis in South Indian Tamils. METHODS: 300 cases of psoriasis and 300 controls were recruited in this case-control study. Genotyping of SNPs of VEGF gene was done using Taqman 5' allele discrimination assay. Estimation of VEGF levels in plasma was done by ELISA. RESULTS: VEGF (rs2010963) polymorphism and the CTC haplotype were found to confer an increased risk of psoriasis. However, two other VEGF SNPs, rs833061, and rs699947, showed no association with psoriasis susceptibility. VEGF levels were higher in patients with psoriasis, as compared with controls and significantly correlated with disease severity. CONCLUSIONS: Our results indicate that VEGF (rs2010963) polymorphism and CTC haplotype of the VEGF SNPs (rs699947, rs833061, and rs2010963) confer an increased risk of psoriasis in the South Indian Tamil population. Plasma VEGF levels are higher in patients with psoriasis, as compared with controls and are significantly correlated with disease severity.

Drug information center as referral service in a South Indian tertiary care hospital.

OBJECTIVE: The objective of this study is to assess the various aspects of drug information services (DISs) provided in the DI center of a tertiary care hospital. MATERIALS AND METHODS: DI queries received from various departments from April 2013 to May 2017 were included in the study. Various aspects such as year- and department-wise distribution, reason for sending the queries, mode of receipt and reply, time taken for reply, number of visit for bedside examination of patients, and number of references given per query were analyzed. All the results are expressed in numbers and percentages. RESULTS: Fifty-five DI queries were received during the study period. Most of the queries were received from Department of Orthopedics (26, 47.27%), followed by Neurology (4, 7.27%). Most common mode of receipt of queries (41, 74.55%) was by Cross-reference form not case record form followed by phone calls (8, 14.55%) and outpatient department (OPD) case sheet (6, 10.9%). CRF with attached opinion was the most common mode of reply (41, 74.55%) followed by phone calls (7, 12.73%), and OPD case sheets (6, 10.9%). The most common reason for sending queries was antimicrobials-related problem (25, 45.46%), followed by the use of anticoagulants (13, 23.63%). Most of the queries were replied within 24 h (31, 56.36%), followed by 48 h (14, 25.45%). Out of 41 CRF received for in-patients, bedside examination was requested in 23 (56.09%) CRF. There was an increasing trend in the number of queries received every year with more queries received during 2016 (23, 41.82%). CONCLUSIONS: DIS if utilized properly can be used as a referral service such as other specialties in a tertiary care hospital.

Allele and genotype frequency of MDR1 C3435T in Tamilian population.

The allele and genotype frequencies of MDR1 C3435T polymorphism were determined in 185 unrelated healthy Tamilians. The genomic DNA was extracted from peripheral leucocytes using phenol chloroform method and genotyped by PCR-RFLP method. The frequencies of MDR1 C3435 and T3435 alleles in Tamilian population were 0.46 and 0.54 respectively. The distribution of T3435 in this population was found to be greater than Africans and almost similar to Caucasians and Orientals. The distribution of CC, CT and TT genotypes was 0.18, 0.56 and 0.26 respectively. The frequency distribution of the CC genotype was lower in them when compared with Chinese and Africans whereas CT genotype was higher in comparison with all the major ethnic groups.

Relation between serum prolactin levels and antipsychotic response to risperidone in patients with schizophrenia.

BACKGROUND: Hyperprolactinemia is commonly seen in patients with schizophrenia on risperidone. Dopamine receptor blockade plays a major role in risperidone induced hyperprolactinemia. However, limited studies are available with inconsistent results on antipsychotic response to risperidone and prolactin elevation. Therefore, we aimed to study the change in serum prolactin levels and response to risperidone and to test the association between DRD2 genetic variants and prolactin levels in schizophrenic patients treated with risperidone. METHODS: A prospective study comprising of 102 patients with schizophrenia were recruited. Prolactin levels and Positive and Negative Syndrome Scale (PANSS) score were recorded at baseline and after four weeks of risperidone treatment. Prolactin concentrations were measured by standard method Advia-Centaur® Chemiluminescence immuno assay method. Taq1A DRD2 genotyping was performed by qRT-PCR. RESULTS: The mean±SD prolactin levels (ng/ml) were increased after four weeks of treatment in both responders (males 21.66±15.15 to 41.63±18.73; p<0.01 females 51.92±40.89 to 122.35±52.16; p<0.01) and non-responders group (males 23.89±14.85 to 37.45±13.5; p<0.01 females 39.25±26.94 to 91.13±54.31; p<0.01). Patients with increased prolactin concentration were 4.6 fold higher in responders (OR 4.60; 95%CI 1.376-15.389; p-value 0.01) compared to non-responders. Ninety-six patients were genotyped for Taq1A DRD2 gene (AA=9, AG=46, GG=41) and found no association (p=0.6) between genetic variants and response to risperidone. CONCLUSION: Patients were showing more than 20% increase in prolactin levels had a better chance of responding to risperidone therapy. Taq1A DRD2 gene did not show any association with prolactin elevation and response to risperidone.

Clinical Utility of Fractional exhaled Nitric Oxide (FeNO) as a Biomarker to Predict Severity of Disease and Response to Inhaled Corticosteroid (ICS) in Asthma Patients.

INTRODUCTION: Bronchial asthma is a common chronic inflammatory airway disease diagnosed and is based on symptomatic history and Pulmonary Function Tests (PFT). Fractional exhaled Nitric Oxide (FeNO) is exclusively a non-invasive biomarker of on-going eosinophilic airway inflammation which remains unpredictable only with PFTs. FeNO measurement is recommended in predicting asthma severity and Inhaled Corticosteroid (ICS) response but further research is required to understand its clinical utility and agreement with current recommendations in a specific population. AIM: To estimate FeNO levels in Tamilian patients with mild-to-moderate persistent asthma and to correlate with disease severity and ICS response. MATERIALS AND METHODS: The study was a prospective cohort with a single group of 102 persistent asthma patients under standard ICS regimen for 8 weeks (follow-up period). PFT and FeNO were measured using portable spirometry and chemiluminescence based exhaled breath analyser, at baseline and during follow-up visits. Based on PFT and FeNO parameters, the study population was sub-grouped with respect to asthma severity (as mild, moderate and moderately severe), FeNO cut-off (> or < 50ppb) and ICS response classification (good vs poor ICS responders). RESULTS: Significant decrease in mean FeNO levels were found in mild, moderate and moderately severe asthmatic groups following ICS treatment (90.15±27.36, 75.74±31.98 and 77.18±32.79 ppb) compared to similar baseline FeNO levels (103.03±34.08, 91.38±37.60 and 97.90±43.84 ppb) in all the above groups. Similarly, significant decrease in mean FeNO levels was found - FeNO>50ppb, good and poor ICS responders groups, in post- ICS treatment (89.63±24.04, 77.90±31.12 and 86.49±32.57 ppb) compared to baseline levels (110.183±1.23, 97.12±42.04 and 99.68±34.71 ppb). CONCLUSION: The observed baseline FeNO values in all groups as stated above did not show significant difference to differentiate asthma severity or ICS responders groups. The present study results do not support the predictive association of baseline FeNO levels with asthma severity and future ICS response, but the decrements in FeNO levels on ICS treatment, supports its clinical utility in monitoring of ongoing airway inflammation and understanding treatment response rate.

Association of C-Reactive Protein (rs1205) Gene Polymorphism with Susceptibility to Psoriasis in South Indian Tamils.

INTRODUCTION: Psoriasis is a multi-factorial heritable T-helper Th-1/Th-17 mediated inflammatory disease, affecting the skin. It is associated with co-morbidities such as Cardiovascular Disease (CVD). C-Reactive Protein (CRP) is a good inflammatory marker. CRP rs1205 polymorphism is associated with circulating plasma CRP levels. Although there is association between the rs1205 Single Nucleotide Polymorphism (SNP) and CVD, there are no prior reports regarding the association of CRP rs1205 SNP with psoriasis susceptibility. AIM: To study the association of the genetic variant rs1205 in the CRP gene with susceptibility to the disease and protein levels in South Indian Tamils with psoriasis. MATERIALS AND METHODS: In this case-control genetic study, 300 cases of psoriasis and 300 age and gender matched controls were genotyped for CRP SNP rs1205 using Taq Man 5'allele discrimination assay at Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India from February 2014 to January 2016. Plasma high sensitivity (hs)-CRP levels were estimated by ELISA. Disease severity was assessed by Psoriasis Area Severity Index (PASI). RESULTS: CRP genetic variation rs1205 was not associated with psoriasis risk in our South Indian Tamil population. However, the circulating levels of hs-CRP was significantly higher in patients with psoriasis, as compared with controls (p < 0.0001) and the protein levels were significantly associated with disease severity, as assessed by PASI scoring. No genotype was found significantly associated with PASI or CRP levels. CONCLUSION: Our results suggest that plasma CRP levels are higher in patients with psoriasis and correlate with disease severity, whilst CRP rs1205 is not associated with susceptibility to psoriasis in South Indian Tamils.

CYP2C9 and CYP2C19 genetic polymorphisms: frequencies in the south Indian population.

The aim of the study was to establish the frequencies of CYP2C9*1, *2, *3 and CYP2C19*1, *2 and *3 in the south Indian population and to compare them with the inter-racial distribution of the CYP2C9 and CYP2C19 genetic polymorphisms. Genotyping analyses of CYP2C9 and CYP2C19 were conducted in unrelated, healthy volunteers from the three south Indian states of Andhra Pradesh, Karnataka and Kerala, by the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP). The allele frequencies of the populations of these three states were then pooled with our previous genotyping data of Tamilians (also in south India), to arrive at the distribution of CYP2C9 and CYP2C19 alleles in the south Indian population. Frequencies of CYP2C9 and CYP2C19 alleles and genotypes among various populations were compared using the two-tailed Fisher's exact test. The frequencies of CYP2C9*1, *2 and *3 in the south Indian population were 0.88 (95% CI 0.85-0.91), 0.04 (95% CI 0.02-0.06) and 0.08 (95% CI 0.06-0.11), respectively. The frequencies of CYP2C9 genotypes *1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 were 0.78 (95% CI 0.74-0.82), 0.05 (95% CI 0.03-0.07), 0.15 (95% CI 0.12-0.18), 0.01 (95% CI 0.0-0.02), 0.01 (95% CI 0.0-0.02) and 0.0, respectively. CYP2C19*1, *2 and *3 frequencies were 0.64 (95% CI 0.60-0.68), 0.35 (95% CI 0.31-0.39) and 0.01 (95% CI 0.0-0.03), respectively. As a result of a significant heterogeneity, the data on CYP2C19 genotype frequencies were not pooled. The frequency of CYP2C9*2 mutant alleles in south Indians was higher than in Chinese and Caucasians, while CYP2C9*3 was similar to Caucasians. CYP2C19*2 was higher than in other major populations reported so far. The relatively high CYP2C19 poor-metabolizer genotype frequency of 12.6% indicates that over 28 million south Indians are poor metabolizers of CYP2C19 substrates.

A study to explore the correlation of ABCB1, ABCG2, OCT1 genetic polymorphisms and trough level concentration with imatinib mesylate-induced thrombocytopenia in chronic myeloid leukemia patients.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.