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The association of genetic polymorphisms in CYP1A2, UGT1A4, and ABCB1 with autonomic nervous system dysfunction in schizophrenia patients treated with olanzapine.

ABSTRACT: BACKGROUND:Use of the antipsychotic drug olanzapine by patients with schizophrenia is associated with autonomic nervous system (ANS) dysfunction. It is presumed that there are interindividual differences in ANS dysfunction that correspond to pharmacogenetics. In this study, we investigated whether genetic polymorphisms in ABCB1, CYP1A2, and UGT1A4 are associated with this observed ANS dysfunction. METHODS:A total of 91 schizophrenia patients treated with olanzapine monotherapy participated in this study. A power spectral analysis of heart rate variability was used to assess ANS activity. The TaqMan system was used to genotype seven single nucleotide polymorphisms (SNPs) in CYP1A2 (rs2069514 and rs762551), UGT1A4 (rs2011425), and ABCB1 (rs1045642, rs1128503, rs2032582, rs2235048). RESULTS:Sympathetic nervous activity was significantly higher in individuals with the UGT1A4 rs2011425 G allele than in those with the UGT1A4 rs2011425 non-G allele (sympathetic activity, p?=?.001). Furthermore, sympathetic nervous activity was also significantly associated with UGT1A4 rs2011425 genotype as revealed by multiple regression analysis (sympathetic activity, p?=?.008). CONCLUSIONS:We suggest that the UGT1A4 rs2011425 polymorphism affects olanzapine tolerability because it is associated with the observed side effects of olanzapine in schizophrenia patients, namely sympathetic dysfunction.

SUBMITTER: Hattori S

PROVIDER: S-EPMC7027321 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The association of genetic polymorphisms in CYP1A2, UGT1A4, and ABCB1 with autonomic nervous system dysfunction in schizophrenia patients treated with olanzapine.

Hattori Saki S Suda Akira A Miyauchi Masatoshi M Shiraishi Yohko Y Saeki Takashi T Fukushima Tadashi T Fujibayashi Mami M Tsujita Natsuki N Ishii Chie C Ishii Norio N Moritani Tosiho T Saigusa Yusuke Y Kishida Ikuko I

BMC psychiatry 20200218 1

<h4>Background</h4>Use of the antipsychotic drug olanzapine by patients with schizophrenia is associated with autonomic nervous system (ANS) dysfunction. It is presumed that there are interindividual differences in ANS dysfunction that correspond to pharmacogenetics. In this study, we investigated whether genetic polymorphisms in ABCB1, CYP1A2, and UGT1A4 are associated with this observed ANS dysfunction.<h4>Methods</h4>A total of 91 schizophrenia patients treated with olanzapine monotherapy par ...[more]

PMID: 32070304

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Project description:ObjectiveTo assess the distribution of autonomic nervous system (ANS) dysfunction in overweight and obese children.MethodsParasympathetic and sympathetic ANS function was assessed in children and adolescents with no evidence of impaired glucose metabolism by analysis of heart rate variability (low frequency power ln(LF), high frequency power, ln(HF); ln(LF/HF) ratio, ratio of longest RR interval during expiration to shortest interval during inspiration (E/I ratio), root mean square of successive differences (RMSSD); sympathetic skin response (SSR); and quantitative pupillography (pupil diameter in darkness, light reflex amplitude, latency, constriction velocity, re-dilation velocity). The relationship of each ANS variable to the standard deviation score of body mass index (BMI-SDS) was assessed in a linear model considering age, gender and pubertal stage as co-variates and employing an F-statistic to compare the fit of nested models. Group comparisons between normal weight and obese children as well as an analysis of dependence on insulin resistance (as indexed by the Homeostasis Model Assessment of Insulin Resistance, HOMA-IR) were performed for parameters shown to correlate with BMI-SDS. Statistical significance was set at 5%.ResultsMeasurements were performed in 149 individuals (mean age 12.0 y; 90 obese 45 boys; 59 normal weight, 34 boys). E/I ratio (p = 0.003), ln(HF) (p = 0.03), pupil diameter in darkness (p = 0.01) were negatively correlated with BMI-SDS, whereas ln(LF/HF) was positively correlated (p = 0.05). Early re-dilation velocity was in trend negatively correlated to BMI-SDS (p = 0.08). None of the parameters that depended significantly on BMI-SDS was found to be significantly correlated with HOMA-IR.ConclusionThese findings demonstrate extended ANS dysfunction in obese children and adolescents, affecting several organ systems. Both parasympathetic activity and sympathetic activity are reduced. The conspicuous pattern of ANS dysfunction raises the possibility that obesity may give rise to dysfunction of the peripheral autonomic nerves resembling that observed in normal-weight diabetic children and adolescents.

Project description:Alterations in autonomic nervous function are common in hemodialysis (HD) patients. Sympathetic as well as parasympathetic activation may be associated with immune and inflammatory responses. We intended to confirm a role of autonomous dysregulation for inflammation in HD patients.30 HD patients (including 15 diabetics) and 15 healthy controls were studied for heart rate variability (HRV) using 5 min ECG recordings. Heart rate variability was estimated by time-domain parameters (the standard deviation of the RR intervals (SDNN) and the percentage of pairs of adjacent RR intervals differing by >50 ms (pNN50)) and frequency-domain-analysis (high- and low-frequency variation of RR intervals, HF and LF). Inflammation was detected as serum C-reactive Protein (CRP), IL-6 and circulating monocyte subpopulation numbers. Immune cells were characterized by ACh receptor expression.Patients differed from controls in terms of age (68.0 [14.8] yrs vs. 58.0 [13.0] yrs, p?<?0.001; Median [IQR]) and sex. However, HRV parameters were different in controls and HD patients (SDNN controls 34.0 [14.0] ms, HD patients 15.5 [14.8] ms, p?<?0.01). This finding was not restricted to patients with diabetes mellitus (diab), although diabetes is an important cause of autonomous dysfunction (SDNN, diab 13.0 [14.0] ms, non-diab 18.0 [15.3] ms, p?=?0.8). LF and HF were reduced by the same magnitude to 1/3 of those in controls. Patients suffered from chronic inflammation (CRP 9.4 [12.9] mg/l, controls 1.6 [2.4] mg/l, p?<?0.001) and expanded proinflammatory monocyte subpopulations (CD14++/CD16+ cells: patients 41 [27]/?l, controls 24 [18]/?l, p?<?0.01). ECG parameters did not correlate with inflammation in patients, but monocyte ACh receptor expression was enhanced, indicating potentially elevated responsiveness of this cell type to parasympathetic regulation.HD patients have strongly impaired HRV. Chronic inflammation is not related to autonomous dysfunction, although monocytes express the ACh receptor at enhanced density making them potentially more sensitive to parasympathetic effects.This study was listed with ClinicalTrials.gov ( NCT00878033 ).

Project description:Objective: Re-hospitalization after sepsis can lead to impaired quality of life. Predictors of re-hospitalization could help identify sepsis survivors who may benefit from targeted interventions. Our goal was to determine whether low heart rate variability (HRV), a measure of autonomic nervous system dysfunction, is associated with re-hospitalization in pediatric septic shock survivors. Materials and Methods: This was a retrospective, observational cohort study of patients admitted between 6/2012 and 10/2020 at a single institution. Patients admitted to the pediatric intensive care unit with septic shock who had continuous heart rate data available from the bedside monitors and survived their hospitalization were included. HRV was measured using age-normalized z-scores of the integer HRV (HRVi), which is the standard deviation of the heart rate sampled every 1 s over 5 consecutive minutes. The 24-h median HRVi was assessed on two different days: the last 24 h of PICU admission ("last HRVi") and the 24-h period with the lowest median HRVi ("lowest HRVi"). The change between the lowest and last HRVi was termed "delta HRVi." The primary outcome was re-hospitalization within 1 year of discharge, including both emergency department encounters and hospital readmission, with sensitivity analyses at 30 and 90 days. Kruskal-Wallis, logistic regression, and Poisson regression evaluated the association between HRVi and re-hospitalizations and adjusted for potential confounders. Results: Of the 463 patients who met inclusion criteria, 306 (66%) were re-hospitalized, including 270 readmissions (58%). The last HRVi was significantly lower among re-hospitalized patients compared to those who were not (p = 0.02). There was no difference in the lowest HRVi, but patients who were re-hospitalized showed a smaller recovery in their delta HRVi compared to those who were not re-hospitalized (p = 0.02). This association remained significant after adjusting for potential confounders. In the sensitivity analysis, a smaller recovery in delta HRVi was consistently associated with a higher likelihood of re-hospitalization. Conclusion: In pediatric septic shock survivors, a smaller recovery in HRV during the index admission is significantly associated with re-hospitalization. This continuous physiologic measure could potentially be used as a predictor of patients at risk for re-hospitalization and lower health-related quality of life.

Dataset Information

The association of genetic polymorphisms in CYP1A2, UGT1A4, and ABCB1 with autonomic nervous system dysfunction in schizophrenia patients treated with olanzapine.

Publications

The association of genetic polymorphisms in CYP1A2, UGT1A4, and ABCB1 with autonomic nervous system dysfunction in schizophrenia patients treated with olanzapine.

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