Corrigendum: Global Text Mining and Development of Pharmacogenomic Knowledge Resource for Precision Medicine.

[This corrects the article DOI: 10.3389/fphar.2019.00839.].

Global Text Mining and Development of Pharmacogenomic Knowledge Resource for Precision Medicine.

Understanding patients' genomic variations and their effect in protecting or predisposing them to drug response phenotypes is important for providing personalized healthcare. Several studies have manually curated such genotype-phenotype relationships into organized databases from clinical trial data or published literature. However, there are no text mining tools available to extract high-accuracy information from such existing knowledge. In this work, we used a semiautomated text mining approach to retrieve a complete pharmacogenomic (PGx) resource integrating disease-drug-gene-polymorphism relationships to derive a global perspective for ease in therapeutic approaches. We used an R package, pubmed.mineR, to automatically retrieve PGx-related literature. We identified 1,753 disease types, and 666 drugs, associated with 4,132 genes and 33,942 polymorphisms collated from 180,088 publications. With further manual curation, we obtained a total of 2,304 PGx relationships. We evaluated our approach by performance (precision = 0.806) with benchmark datasets like Pharmacogenomic Knowledgebase (PharmGKB) (0.904), Online Mendelian Inheritance in Man (OMIM) (0.600), and The Comparative Toxicogenomics Database (CTD) (0.729). We validated our study by comparing our results with 362 commercially used the US- Food and drug administration (FDA)-approved drug labeling biomarkers. Of the 2,304 PGx relationships identified, 127 belonged to the FDA list of 362 approved pharmacogenomic markers, indicating that our semiautomated text mining approach may reveal significant PGx information with markers for drug response prediction. In addition, it is a scalable and state-of-art approach in curation for PGx clinical utility.

Association of Angiotensin-Converting Enzyme Gene Polymorphisms and Nephropathy in Diabetic Patients at a Tertiary Care Centre in South India.

BACKGROUND: Genetic polymorphisms of the angiotensin-renin pathway have been thought to influence the development of diabetic nephropathy. However, there are conflicting results regarding this association in previous studies on populations with varying ethnicity. AIMS: Primary aim was to compare the frequency of distribution of angiotensin-converting enzyme (ACE) gene (insertion/deletion [I/D]) polymorphism in Tamilian Indian type 2 diabetic individuals with and without microalbuminuria. Secondary objective was to compare the frequency of distribution of the 3 genotypes in diabetic patients with urinary albumin/creatinine ratio (ACR) < 30 mg/dL, urinary ACR = 30 to 300 mg/dL, and urinary ACR > 300 mg/dL. METHODS: A total of 179 consecutive diabetic individuals between 40 and 70 years, from Puducherry and Tamilnadu of Dravidian descent participated in the study conducted from 2012 to 2014. Inclusion criteria were as follows: age ≥ 40 years and duration of type 2 diabetes mellitus for ≥5 years. Patients were divided into 2 groups based on ACR values. Group 1 consisted of 50 individuals with urinary ACR < 30 mg/g of creatinine, and group 2 consisted of 129 individuals with urinary ACR > 30 mg/g. Angiotensin I-converting enzyme (ACE) gene polymorphism was determined by allele-specific polymerase chain reaction method using a primer pair flanking the polymorphic region of its intron 16. Furthermore, group 2 patients were subdivided into those with urinary ACR = 30 to 300 mg/g of creatinine and those with urinary ACR > 300 mg/g of creatinine, and distribution of ACE gene polymorphism was compared in the three groups. STATISTICS: Statistical analysis was done using SPSS version 17.0. Independent Student t test was used to compare mean values between the 2 groups. Odds ratio was calculated for testing association between ACE gene (I/D) polymorphism and presence of microalbuminuria. P < .05 was considered significant. Comparison of ACE genotypes among 3 groups of patients (ACR < 30 mg/g, ACR = 30-300 mg/g, and ACR > 300 mg/g) was done using 1-way analysis of variance with Bonferroni multiple comparison test as post hoc analysis. CONCLUSIONS: Heterozygous I/D genotype was more frequent in the study population (45.8%) than the other genotypes. There was no difference in the genotype distribution in patients with varying levels of albuminuria.

Frequency of single nucleotide platelet receptor gene polymorphism (P2Y12-i744T>C) in coronary artery disease patients among Tamilian population.

Several factors contribute to the development of coronary artery disease (CAD). Adenosine diphosphate (ADP) activated P2Y12 receptor also plays a key role in platelet activation and aggregation. It has been found that common variation in the P2Y12 gene was associated with increased platelet aggregation resulting in adverse cardiovascular outcomes. Thus, polymorphisms in the ADP receptor P2Y12 may contribute to the development of CAD. This study aims to determine the frequency distribution of platelet receptor polymorphism P2Y12 (i744T>C) in Tamilian population and to predict its possible role in CAD. Three hundred seventy-one subjects were recruited comprising of 221 healthy volunteers and 150 patients with CAD belonging to either sex, aged 18-60 years of Tamilian origin. Genomic DNA was extracted using phenol-chloroform method. Genotyping was done by PCR-RFLP (Polymerase chain reaction-restriction fragment length polymorphism). The C allele frequency of P2Y12 polymorphism in controls and cases was 8.4% and 17.7%, respectively. The TT, TC, and CC genotype frequencies in controls and cases were 83.7%, 15.8%, 0.5% and 66.7%, 31.3%, 2%, respectively. The genotype frequencies were in Hardy-Weinberg equilibrium. There was a significant association (p < 0.05) between the mutant genotypes of P2Y12 (i744T>C) polymorphism  and risk of CAD. The odds ratio was found to be 2.6. The variant allele frequency of P2Y12-i744T>C was significantly different from other populations. There was a significant association between the mutant genotypes of P2Y12 (i744T>C) polymorphism  and risk of developing CAD. Thus, the present study will emphasize on the relevance of pharmacogenetic testing of P2Y12 (i744T>C)  receptor gene polymorphism in CAD patients.

Decreased baroreflex sensitivity is linked to sympathovagal imbalance, low-grade inflammation, and oxidative stress in pregnancy-induced hypertension.

Pregnancy-induced hypertension (PIH) has been reported as a cardiovascular (CV) risk. We assessed the sympathovagal imbalance (SVI) and the association of inflammation and oxidative stress (OS) with CV risks in PIH. A total of 125 pregnant women having a risk factor for PIH were followed till term and the incidence of PIH was observed. Retrospectively, they were divided into two groups: Group I (those who did not develop PIH, n = 82) and Group II (those who developed PIH, n = 43). Blood pressure variability (BPV) parameters including baroreflex sensitivity (BRS), spectral heart rate variability (HRV), autonomic function tests (AFTs), inflammatory markers (interleukin-6, TNF-α, interferon-γ), and OS markers were measured in both the groups. Alterations in parasympathetic and sympathetic components of AFTs were analyzed. Link of various parameters to BRS was assessed by correlation and multiple regression analysis. Parasympathetic components of AFTs were decreased from the early part of pregnancy and sympathetic components were increased toward the later part of pregnancy. Decreased BRS, the marker of CV risk, was more prominent in Group II subjects. Independent contribution of interleukin-6 (ß = 0.276, P = 0.020), TNF-α (ß = 0.408, P = 0.002), interferon-γ (ß = 0.355, P = 0.008), and thiobarbituric-acid reactive substance (ß = 0.287, P = 0.015) to BRS was found to be significant. It was concluded that sympathetic overactivity that develops more in the later part (third trimester) of pregnancy contributes to SVI and genesis of PIH. In PIH women, CV risks are present from the beginning of pregnancy that intensifies in the later part of pregnancy. Retrograde inflammation and oxidative stress contribute to the decreased BRS in PIH.

Antimicrobial resistance in India: A review.

Antimicrobial resistance is an important concern for the public health authorities at global level. However, in developing countries like India, recent hospital and some community based data showed increase in burden of antimicrobial resistance. Research related to antimicrobial use, determinants and development of antimicrobial resistance, regional variation and interventional strategies according to the existing health care situation in each country is a big challenge. This paper discusses the situational analysis of antimicrobial resistance with respect to its problem, determinants and challenges ahead with strategies required in future to reduce the burden in India. Recent data from Google search, Medline and other sources were collected which was reviewed and analyzed by the authors. Hospital based studies showed higher and varied spectrum of resistance in different regions while there are limited number of community based studies at country level. There exists lacunae in the structure and functioning of public health care delivery system with regard to quantification of the problem and various determining factors related to antimicrobial resistance. There is an urgent need to develop and strengthen antimicrobial policy, standard treatment guidelines, national plan for containment of AMR and research related to public health aspects of AMR at community and hospital level in India.

P-glycoprotein expression as a predictor of response to neoadjuvant chemotherapy in breast cancer.

BACKGROUND: Chemoresistance is an important factor determining the response of tumor to neoadjuvant chemotherapy (NACT). P-glycoprotein (P-gp) expression-mediated drug efflux is one of the mechanisms responsible for multi-drug resistance. Our study was aimed to determine the role of P-gp expression as a predictor of response to NACT in locally advanced breast cancer (LABC) patients. MATERIALS AND METHODS: P-gp expression was performed by real-time quantitative polymerase chain reaction [qRT-PCR] in 76 patients with LABC. Response to adriamycin-based regimen was assessed both clinically and with contrast enhanced computed tomography (CECT) scan before and after NACT. The significance of correlation between tumor and P-gp levels was determined with Chi-square test. RESULTS: Twenty-one had high and 55 had low P-gp expression. On analyzing P-gp expression with response by World Health Organization (WHO) criteria, statistical significance was obtained (P = 0.038). Similarly, assessment of P-gp expression with response by Response Evaluation in Solid Tumors (RECIST) criteria in 48 patients showed statistical significance (P = 0.0005). CONCLUSION: This study proves that P-gp expression is a determinant factor in predicting response to NACT. Finally, detection of P-gp expression status before initiation of chemotherapy can be used as a predictive marker for NACT response and will also aid in avoiding the toxic side effects of NACT in non-responders.

Preference for salt contributes to sympathovagal imbalance in the genesis of prehypertension.

BACKGROUND/OBJECTIVES: As salt preference is known to cause hypertension (HTN), the present study was conducted to assess the impact of preference for salt on sympathovagal imbalance in prehypertensives by spectral analysis of heart rate variability (HRV). SUBJECTS/METHODS: Body mass index (BMI), basal heart rate, blood pressure (BP), rate pressure product and spectral indices of HRV such as total power (TP), normalized low frequency power (LFnu), normalized high frequency power (HFnu), ratio of low frequency power to high frequency power (LF-HF ratio), mean heart rate, square root of the mean squared differences of successive normal to normal (NN) intervals, the number of interval differences of successive NN intervals >50 ms (NN50) and the proportion derived by dividing NN50 by the total number of NN intervals were assessed in 555 subjects divided into four groups: Group 1, normotensives no-salt-preference subjects (n=260); Group 2, normotensives salt-preference subjects (n=185); Group 3, prehypertensives no-salt-preference subjects (n=25); and Group 4, prehypertensives salt-preference subjects (n=89). Sympathovagal balance was analyzed and contribution of individual factor to sympathovagal imbalance was assessed by regression analysis. RESULTS: LFnu was significantly increased (P=0.009), whereas TP and HFnu were significantly decreased (P=0.024 and 0.007, respectively) in the salt-preference groups compared with the no-salt-preference groups. LF-HF ratio, the sensitive indicator of sympathovagal balance, was significantly increased (P<0.0001) in salt-preference subjects compared with no-salt-preference subjects. In regression analysis, the link of LF-HF ratio to HTN status was found to be more prominent in the salt-preference group (P=0.000) compared with the no-salt-preference group (P=0.004). BMI had no significant contribution (P=0.818) to LF-HF ratio in salt-preference subjects. CONCLUSIONS: Salt preference is associated with sympathovagal imbalance caused by sympathetic overactivity and vagal withdrawal. Sympathovagal imbalance is more intense in salt-preferring prehypertensives compared with salt-preferring normotensives. Sympathovagal imbalance in salt-preferring subjects is independent of BMI. Thus, salt-preferring subjects should be encouraged to restrict salt intake to maintain their sympathovagal balance and BP homeostasis.

Genetic polymorphisms of CYP2C19 influences the response to clopidogrel in ischemic heart disease patients in the South Indian Tamilian population.

BACKGROUND: The antiplatelet activity of clopidogrel is variable among patients suffering from ischemic heart disease. Variation in the cytochrome P450 2C19 (CYP2C19) gene coding for the CYP2C19 enzyme is one of the major determinants of this variable response to clopidogrel. The activity of the CYP2C19 enzyme, which plays a role in the conversion of the prodrug clopidogrel to its active metabolite, is genetically influenced by polymorphisms in its gene. The aim of our study was to evaluate the association of CYP2C19 polymorphisms and the antiplatelet effect of clopidogrel in the South Indian Tamilian population. MATERIALS AND METHODS: Genotyping and platelet aggregation results of 149 ischemic heart disease patients on clopidogrel maintenance therapy (75 mg daily dose) were analyzed in this study. CYP2C19 polymorphisms were genotyped by the PCR-restriction fragment length polymorphism method. We measured residual platelet activities in these patients on clopidogrel therapy in terms of impedance (expressed as ohms). The study subjects were divided into two metabolizer phenotype groups [group 1: poor/intermediate metabolizers (PM/IM); group 2: extensive/ultra-rapid metabolizers (EM/URM)] based on CYP2C19 genotype, and the residual platelet activities were compared. Higher values of impedance denote increased residual platelet activity. RESULTS: Poor/intermediate metabolizers had significantly higher impedance values than EM/URM [(median; range) 4.0; 0-13 vs. 2.0; 0-11, respectively; p = 0.04]. These higher impedance values denote higher residual platelet activities among the carriers of loss-of-function alleles (CYP2C19*2,*3) than among non-carriers. However, residual platelet activities were lower among the carriers of the gain-of-function allele (CYP2C19*17) than among non-carriers, although this difference was not significant. CONCLUSION: Patients with CYP2C19 (*2 or *3) genetic polymorphisms had higher residual platelet activities and were associated with a reduced antiplatelet response to clopidogrel. As the South Indian Tamilian population is characterized with higher frequencies of these genetic polymorphisms, our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy.

Increased vascular tone due to sympathovagal imbalance in normotensive and prehypertensive offspring of hypertensive parents.

AIM: Prehypertension has recently been observed as a potent cardiovascular risk factor. Though prehypertension has a strong familial predisposition, the pathophysiological mechanisms that cause its progression to prehypertension in normotensive sibling of hypertensive parents have not yet been fully elucidated. Therefore, the present study was conducted in normotensive and prehypertensive sibling by spectral analysis of heart rate variability (HRV) to understand the nature of change in sympathovagal balance (SVB) in this condition. METHODS: Body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), basal heart rate (BHR), blood pressure (BP), rate pressure product (RPP) and spectral indices of HRV were assessed in three groups of subjects: Group I (normotensive offspring of normotensive parents, N.=231); Group II (normotensive offspring of hypertensive parents, N.=113); and Group III (prehypertensives offspring of hypertensive parents, N.=52). SVB was analyzed and correlated with BMI, WHR, BHR, BP and RPP in all the groups. RESULTS: Sympathovagal imbalance (SVI) was observed to be present in both normotensive and prehypertensive sibling of hypertensive parents. In normotensive sibling, SVI was mild in the form of proportionate increase in sympathetic and decreased vagal activity. In prehypertensive sibling, SVI was prominent with more of vagal withdrawal. Though LF-HF ratio, the indicator of SVB was correlated with all parameters in groups II and III, the significance was more with diastolic pressure and WHR. CONCLUSION: It was concluded that vagal inhibition plays a critical role in modulation of SVB for progression into prehypertension in normotensive sibling of hypertensive parents and WHR is a prominent marker of SVI in these subjects.

Distribution of CYP2C19*17 allele and genotypes in an Indian population.

WHAT IS KNOWN AND OBJECTIVE: CYP2C19*17 allele increases the metabolic activity of CYP2C19 resulting in decreased therapeutic levels of CYP2C19 substrates. There exist inter-ethnic differences in the distribution of this allele. The present study was aimed at establishing the allele and genotype frequencies of CYP2C19*17 in a South Indian Tamilian population. Furthermore, we describe the haplotype structure of the three common variant alleles of CYP2C19 in the Tamilian population. METHODS: Two hundred and six subjects of South Indian Tamilian origin were genotyped for CYP2C19*17 allele by nested polymerase chain reaction and restriction fragment length polymorphism. A subset of 87 subjects were also genotyped for CYP2C19*2 and CYP2C19*3 alleles. After ascertaining linkage disequilibrium (LD), haplotypes were constructed. Allele and genotype frequencies, LD pattern and haplotype frequency were compared with those of the HapMap populations. RESULTS AND DISCUSSION: The CYP2C19*17 allele frequency in the Tamilian population (n = 206) was found to be 19·2% (95% CI: 15·4 - 20·3). The CYP2C19*2 allele frequency (n = 87) was found to be 40·2% (95% CI: 32·9 - 47·5), whereas the CYP2C19*3 allele was not detected in the study subjects (n = 97). The high frequency of the CYP2C19*17 allele in the study population has resulted in a revision of frequencies for CYP2C19*1/*2 (31·0%) and CYP2C19*1/*1 (16·1%) genotypes in the Tamilian population. We also observed significant differences in haplotype structure and frequencies of these variant alleles in the HapMap population compared to Tamilian population. WHAT IS NEW AND CONCLUSION: CYP2C19*17 allele is present at high frequency in the Tamilian population. This study also demonstrates the need for reassessment of wild-type allele frequencies in view of CYP2C19*17 allele. The estimated high frequency of CYP2C19*17 allele will aid in genotype-phenotype association studies in the Tamilian population. Further genotype-phenotype association studies are required to evaluate the clinical utility of this allele in South Indians.

Genetic polymorphisms of drug-metabolizing phase I enzymes CYP2E1, CYP2A6 and CYP3A5 in South Indian population.

CYP2E1, CYP2A6 and CYP3A5 enzymes belong to phase I group of drug-metabolizing enzymes, which are involved in the metabolism of various compounds and xenobiotics. Presence of polymorphisms in the genes coding for these enzymes results in interindividual variations in drug metabolism, therapeutic response and susceptibility towards various diseases. The frequencies of these variants in genes differ considerably between ethnic groups. This study was carried out to estimate the allele and genotype frequencies of common variants in CYP2E1, CYP2A6 and CYP3A5 in South Indian population. Six hundred and fifty-two unrelated healthy volunteers of South Indian origin (Andhra Pradesh, Karnataka, Kerala and Tamil Nadu) were included in this study. Polymerase chain reaction-restriction fragment length polymorphism, allele-specific PCR, real-time PCR, SNaPshot and gene sequencing methods were used for the identification of gene polymorphisms. The frequencies of CYP2E1*1B, CYP2E1*5B and CYP2E1*6 alleles in South Indian population were 14.3, 1.3 and 22.4%, respectively. The frequencies of CYP2A6*2, CYP2A6*4A and CYP2A6*5 alleles were found to be 1, 8.9 and 0.7%, respectively. The distribution of CYP3A5*3 allele was 63.5%. There were no variant alleles of CYP3A5*2, CYP3A5*4 and CYP3A5*6 in South Indian population. The frequencies of CYP2E1, CYP2A6 and CYP3A5 in the South Indian population are distinct from Caucasians, Chinese, Japanese, African Americans and other compared populations. This is the first study conducted in the South Indian population with a larger sample size. The findings of our study provide the basic genetic information for further pharmacogenomic investigations in the population.

Role of ventromedial hypothalamus on energy homeostasis in albino rats: effect of gender.

Various brain areas like the ventromedial hypothalamus (VMH) are known to influence food intake and body weight. Though obesity is more common in females, the reports on gender difference in the neural regulation of energy homeostasis are not adequate. Therefore, the present study was conducted to assess the gender difference in the effect of VMH lesion on food intake (FI), body weight (BW), serum lipid profile, thyroid profile, glucose and insulin levels and glucose-insulin ratio (GIR) in Wistar albino rats. Twenty-four Wistar albino rats were divided equally into control and experimental groups with 6 male and 6 female rats in each. In the experimental group, bilateral electrolytic lesion of VMH was performed by stereotaxy and post-lesion parameters were recorded. In the control group, VMH sham lesion was made. Male-female difference in each parameter was determined. Following VMH lesion, FI was increased (females, P < 0.01) and BW (males, P < 0.05) and GIR decreased in males (P < 0.001), which was significantly correlated with BW. T3 was more significantly correlated with FI and BW in females (P < 0.000 and P < 0.001). Following VMH lesion, male rats exhibited significant weight gain in the absence of proportionate hyperphagia indicating that weight-gain was mainly metabolic in nature. Also, the male rats developed more susceptibility to insulin resistance. The female rats developed resistance to weight-gain inspite of hyperphagia, which could be due to the higher T3 level.

Effect of lesion of nucleus septal medialis on energy homeostasis in Wistar rats.

Mesolimbic areas such as nucleus accumbens, amygdala and septal nuclei are known to influence food intake and body weight. However, the reports on gender difference in the neural regulation of obesity and energy homeostasis are incomplete. Therefore, the present study was conducted to assess the effect of lesions of nucleus septal medialis (NSM) and the gender difference of lesion on food intake (FI), body weight (BW), serum lipid profile, thyroid profile, glucose and insulin levels and glucose-insulin ratio (GIR) in Wistar albino rats. Twenty-four rats were divided equally into control and experimental groups having 6 male and 6 female rats in each group. In the experimental group, bilateral electrolytic lesion of NSM was performed by stereotaxy and post-lesion parameters were recorded. In the control group, sham-lesions of NSM were produced. Following lesion, blood glucose and serum insulin levels were decreased and GIR was increased significantly in female rats, but not in male rats. It was concluded that NSM is involved in energy homeostasis, especially in female rats.

Sympathovagal Imbalance in Prehypertensive Offspring of Two Parents versus One Parent Hypertensive.

Objective. Though prehypertension has strong familial predisposition, difference in pathophysiological mechanisms in its genesis in offspring of both parents and single parent hypertensive have not been elucidated. Methods. Body mass index (BMI), waist-hip ratio (WHR), basal heart rate (BHR), blood pressure (BP), HR and BP response to standing, deep breathing difference, BP response to handgrip and spectral indices of heart rate variability (HRV) were analyzed in normotensive offspring of two parents hypertensive (Group I), normotensive offspring of one parent hypertensive (Group II), prehypertensive offspring of two parents hypertensive (Group III) and prehypertensive offspring of one parent hypertensive (Group IV). Results. Sympathovagal imbalance (SVI) in prehypertensive offspring was observed due to increased sympathetic and decreased vagal activity. In group III, SVI was more prominent with greater contribution by vagal withdrawal. LF-HF ratio, the marker of SVI was correlated more with diastolic pressure, 30 : 15 ratio and E : I ratio in prehypertensives and the degree of correlation was more in group III prehypertensives. Conclusion. Vagal withdrawal plays a critical role in development of SVI in prehypertensive offspring of hypertensive parents. The intensity of SVI was more in offspring of two parents hypertensive compared to single parent hypertensive.

Assessment of sympathovagal imbalance by spectral analysis of heart rate variability in prehypertensive and hypertensive patients in Indian population.

Though the incidence of hypertension has increased considerably in recent years, the pathophysiologic mechanism that causes progression from stage of prehypertension to hypertension has not been fully elucidated. Therefore, the present study was conducted to assess the sympathovagal imbalance in prehypertensives and hypertensives by spectral analysis of heart rate variability (HRV) to understand the nature of change in autonomic balance in this common dysfunction of mankind. Body mass index (BMI), basal heart rate (BHR), blood pressure (BP), and spectral indices of HRV such as total power (TP), normalized low frequency power (LFnu), normalized high frequency power (HFnu), ratio of low frequency power to high frequency power (LF-HF ratio), mean heart rate (mean RR), square root of the mean squared differences of successive normal to normal intervals (RMSSD), 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 (n = 32), prehypertensives (n = 28), and hypertensives (n = 31). Sympathovagal balance was analyzed and correlated with BMI, BHR, and BP in all the groups. It was observed that autonomic imbalance in prehypertensives was due to proportionate increased sympathetic activity and vagal inhibition, whereas in hypertensives, vagal withdrawal was more prominent than sympathetic overactivity. The LF-HF ratio, the sensitive indicator of sympathovagal balance, was significantly correlated with BMI, BHR, and BP. It was concluded that vagal inhibition plays an important role in the critical alteration of sympathovagal balance in the development of clinical hypertension in prehypertensive subjects.