ADRA1A gene is associated with BMI in chronic schizophrenia patients exposed to antipsychotics

Yun-Ru Liu, El-Wui Loh, Tsuo-Hung Lan, Shuo-Fei Chen, Yen-Hsin Yu, Yung-Han Chang, Chun-Jung Huang, Tsung-Ming Hu, Keh-Ming Lin, Yu-Tung Yao, Hsien-Jane Chiu

研究成果: 雜誌貢獻文章

22 引文 (Scopus)

摘要

Noradrenaline and adrenaline are neurotransmitters of the sympathetic nervous system that interact with various adrenergic receptor (ADR) subtypes, and this regulates the basal metabolic rate, thermogenesis and efficiency of energy utilization. We examined a possible role of the gene coding for ADRA1A receptor in weight gain in schizophrenia subjects exposed to antipsychotics. A total of 401 schizophrenia in-patients treated with antipsychotics for 2 years were recruited and a final 394 DNA samples were genotyped. Their body mass indexes (BMIs) were recorded for 12 months and parameterized to be correlated in regression. Among the 58 single-nucleotide polymorphisms (SNPs) genotyped, 44 valid SNPs, which had minor allele frequency 0.03, were analyzed in statistics. Linear regression model with age, gender, diabetes, use of typical antipsychotics and use of atypical antipsychotics as covariates, with or without gender interaction, showed evidence of associations between the ADRA1A gene and BMI. Most of the SNPs associated with BMI are located in the promoter and intron regions, and being female appeared to enhance the gene effect. Our study suggests that the ADRA1A gene is involved in weight gain among schizophrenia patients treated with antipsychotics. Further molecular dissection of the ADRA1A gene warrants better understanding on weight gain mechanisms in schizophrenia. © 2010 Nature Publishing Group All rights reserved.
原文英語
頁(從 - 到)30-39
頁數10
期刊Pharmacogenomics Journal
10
發行號1
DOIs
出版狀態已發佈 - 2010
對外發佈Yes

指紋

Antipsychotic Agents
Schizophrenia
Body Mass Index
Weight Gain
Single Nucleotide Polymorphism
Genes
Linear Models
Basal Metabolism
Thermogenesis
Sympathetic Nervous System
Genetic Promoter Regions
Gene Frequency
Introns
Adrenergic Receptors
Epinephrine
Neurotransmitter Agents
Dissection
Norepinephrine
DNA

引用此文

ADRA1A gene is associated with BMI in chronic schizophrenia patients exposed to antipsychotics. / Liu, Yun-Ru; Loh, El-Wui; Lan, Tsuo-Hung; Chen, Shuo-Fei; Yu, Yen-Hsin; Chang, Yung-Han; Huang, Chun-Jung; Hu, Tsung-Ming; Lin, Keh-Ming; Yao, Yu-Tung; Chiu, Hsien-Jane.

於: Pharmacogenomics Journal, 卷 10, 編號 1, 2010, p. 30-39.

研究成果: 雜誌貢獻文章

Liu, Y-R, Loh, E-W, Lan, T-H, Chen, S-F, Yu, Y-H, Chang, Y-H, Huang, C-J, Hu, T-M, Lin, K-M, Yao, Y-T & Chiu, H-J 2010, 'ADRA1A gene is associated with BMI in chronic schizophrenia patients exposed to antipsychotics', Pharmacogenomics Journal, 卷 10, 編號 1, 頁 30-39. https://doi.org/10.1038/tpj.2009.55
Liu, Yun-Ru ; Loh, El-Wui ; Lan, Tsuo-Hung ; Chen, Shuo-Fei ; Yu, Yen-Hsin ; Chang, Yung-Han ; Huang, Chun-Jung ; Hu, Tsung-Ming ; Lin, Keh-Ming ; Yao, Yu-Tung ; Chiu, Hsien-Jane. / ADRA1A gene is associated with BMI in chronic schizophrenia patients exposed to antipsychotics. 於: Pharmacogenomics Journal. 2010 ; 卷 10, 編號 1. 頁 30-39.
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title = "ADRA1A gene is associated with BMI in chronic schizophrenia patients exposed to antipsychotics",
abstract = "Noradrenaline and adrenaline are neurotransmitters of the sympathetic nervous system that interact with various adrenergic receptor (ADR) subtypes, and this regulates the basal metabolic rate, thermogenesis and efficiency of energy utilization. We examined a possible role of the gene coding for ADRA1A receptor in weight gain in schizophrenia subjects exposed to antipsychotics. A total of 401 schizophrenia in-patients treated with antipsychotics for 2 years were recruited and a final 394 DNA samples were genotyped. Their body mass indexes (BMIs) were recorded for 12 months and parameterized to be correlated in regression. Among the 58 single-nucleotide polymorphisms (SNPs) genotyped, 44 valid SNPs, which had minor allele frequency 0.03, were analyzed in statistics. Linear regression model with age, gender, diabetes, use of typical antipsychotics and use of atypical antipsychotics as covariates, with or without gender interaction, showed evidence of associations between the ADRA1A gene and BMI. Most of the SNPs associated with BMI are located in the promoter and intron regions, and being female appeared to enhance the gene effect. Our study suggests that the ADRA1A gene is involved in weight gain among schizophrenia patients treated with antipsychotics. Further molecular dissection of the ADRA1A gene warrants better understanding on weight gain mechanisms in schizophrenia. {\circledC} 2010 Nature Publishing Group All rights reserved.",
keywords = "ADR, ADRA1A gene, Antipsychotics, BMI, Obesity, Schizophrenia, alpha 1A adrenergic receptor, atypical antipsychotic agent, neuroleptic agent, adult, article, body mass, controlled study, diabetes mellitus, DNA determination, female, gene frequency, gene interaction, genetic association, genotype, human, intron, major clinical study, male, pharmacogenetics, priority journal, promoter region, schizophrenia, side effect, single nucleotide polymorphism, weight gain, Adult, Aged, Aged, 80 and over, Antipsychotic Agents, Base Sequence, Body Mass Index, Female, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Receptors, Adrenergic, alpha-1, Weight Gain",
author = "Yun-Ru Liu and El-Wui Loh and Tsuo-Hung Lan and Shuo-Fei Chen and Yen-Hsin Yu and Yung-Han Chang and Chun-Jung Huang and Tsung-Ming Hu and Keh-Ming Lin and Yu-Tung Yao and Hsien-Jane Chiu",
note = "被引用次數:14 Export Date: 29 March 2016 CODEN: PJHOA 通訊地址: Chiu, H.-J.; Department of Health, Jianan Mental Hospital, 80, Lane 870, Jhung-Shan Road, Rende Township, Tainan 717, Taiwan; 電子郵件: chiu8@mail2000.com.tw 化學物質/CAS: Antipsychotic Agents; Receptors, Adrenergic, alpha-1; adrenergic receptor alpha(1a) 參考文獻: Aronne, L.J., Epidemiology, morbidity, and treatment of overweight and obesity (2001) J Clin Psychiatry, 62 (SUPPL. 23), pp. 13-22; Hsiao, C.C., Ree, S.C., Chiang, Y.L., Yeh, S.S., Chen, C.K., Obesity in schizophrenic outpatients receiving antipsychotics in Taiwan (2004) Psychiatry Clin Neurosci, 58, pp. 403-409; Newcomer, J.W., Metabolic considerations in the use of antipsychotic medications: A review of recent evidence (2007) J Clin Psychiatry, 68 (SUPPL. 1), pp. 20-27; Reinholz, J., Skopp, O., Breitenstein, C., Bohr, I., Winterhoff, H., Knecht, S., Compensatory weight gain due to dopaminergic hypofunction: New evidence and own incidental observations (2008) Nutr Metab (Lond), 5, p. 35; Leibowitz, S.F., Alexander, J.T., Hypothalamic serotonin in control of eating behavior, meal size, and body weight (1998) Biol Psychiatry, 44, pp. 851-864; Templeman, L.A., Reynolds, G.P., Arranz, B., San, L., Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first episode psychosis (2005) Pharmacogenet Genomics, 15, pp. 195-200; Correll, C.U., Malhotra, A.K., Pharmacogenetics of antipsychotic-induced weight gain (2004) Psychopharmacology (Berl), 174, pp. 477-489; M{\"u}ller, D.J., Muglia, P., Fortune, T., Kennedy, J.L., Pharmacogenetics of antipsychotic-induced weight gain (2004) Pharmacol Res, 49, pp. 309-329; Chagnon, Y.C., Susceptibility genes for the side effect of antipsychotics on body weight and obesity (2006) Curr Drug Targets, 7, pp. 1681-1695; Bray, G.A., Obesity, a disorder of nutrient partitioning: The MONA LISA hypothesis (1991) J Nutr, 121, pp. 1146-1162; Fain, J.N., Garcija-Sainz, J.A., Adrenergic regulation of adipocyte metabolism (1983) J Lipid Res, 24, pp. 945-966; Knowler, W.C., Pettitt, D.J., Saad, M.F., Charles, M.A., Nelson, R.G., Howard, B.V., Obesity in the Pima Indians: Its magnitude and relationship with diabetes (1991) Am J Clin Nutr, 53, pp. 1543S-1551S; Snitker, S., Tataranni, P.A., Ravussin, E., Respiratory quotient is inversely associated with muscle sympathetic nerve activity (1998) J Clin Endocrinol Metab, 83, pp. 3977-3979; Bai, Y.M., Lin, C.C., Chen, J.Y., Lin, C.Y., Su, T.P., Chou, P., Association of initial antipsychotic response to clozapine and long-term weight gain (2006) Am J Psychiatry, 163, pp. 1276-1279; Procyshyn, R.M., Wasan, K.M., Thornton, A.E., Barr, A.M., Chen, E.Y., Pomarol-Clotet, E., Changes in serum lipids, independent of weight, are associated with changes in symptoms during long-term clozapine treatment (2007) J Psychiatry Neurosci, 32, pp. 331-338; Nonogaki, K., New insights into sympathetic regulation of glucose and fat metabolism (2000) Diabetologia, 43, pp. 533-549; Piascik, M.T., Perez, D.M., Alpha1-adrenergic receptors: New insights and directions (2001) J Pharmacol Exp Ther, 298, pp. 403-410; Phares, D.A., Halverstadt, A.A., Shuldiner, A.R., Ferrell, R.E., Douglass, L.W., Ryan, A.S., Association between body fat response to exercise training and multilocus ADR genotypes (2004) Obes Res, 12, pp. 807-815; Dionne, I.J., Turner, A.N., Tchernof, A., Pollin, T.I., Avrithi, D., Gray, D., Identification of an interactive effect of beta3-and alpha2b-adreno- ceptor gene polymorphisms on fat mass in Caucasian women (2001) Diabetes, 50, pp. 91-95; Linne, Y., Dahlman, I., Hoffstedt, J., Beta1-adrenoceptor gene polymorphism predicts long-term changes in body weight (2005) Int J Obes Relat Metab Disord, 29, pp. 458-462; Dionne, I.J., Garant, M.J., Nolan, A.A., Pollin, T.I., Lewis, D.G., Shuldiner, A.R., Association between obesity and a polymorphism in the beta(1)-adrenoceptor gene (Gly389Arg ADRB1) in Caucasian women (2002) Int J Obes Relat Metab Disord, 26, pp. 633-639; Lin, R.C.Y., Ericsson, J.O., Benjafield, A.V., Morris, B.J., Association of beta2-adrenoceptor Gln27Glu variant with body weight but not hypertension (2001) Am J Hypertens, 14, pp. 1201-1204; Pereira, A.C., Floriano, M.S., Mota, G.F., Cunha, R.S., Herkenhoff, F.L., Mill, J.G., Beta2 adrenoceptor functional gene variants, obesity, and blood pressure level interactions in the general population (2003) Hypertension, 42, pp. 685-692; Ehrenborg, E., Skogsberg, J., Ruotolo, G., Large, V., Eriksson, P., Arner, P., The Q/E27 polymorphism in the beta2-adrenoceptor gene is associated with increased body weight and dyslipoproteinaemia involving trigly-ceride-rich lipoproteins (2000) J Intern Med, 247, pp. 651-656; Martinez, J.A., Corbalan, M.S., Sanchez-Villegas, A., Forga, L., Marti, A., Martinez-Gonzalez, M.A., Obesity risk is associated with carbohydrate intake in women carrying the Gln27Glu beta2-adrenoceptor polymorphism (2003) J Nutr, 133, pp. 2549-2554; MacHo-Azcarate, T., Marti, A., Calabuig, J., Martinez, J.A., Basal fat oxidation and after a peak oxygen consumption test in obese women with a beta2 adrenoceptor gene polymorphism (2003) J Nutr Biochem, 14, pp. 275-279; Meirhaeghe, A., Helbecque, N., Cottel, D., Amouyel, P., Impact of polymorphisms of the human beta2-adrenoceptor gene on obesity in a French population (2000) Int J Obes Relat Metab Disord, 24, pp. 382-387; 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year = "2010",
doi = "10.1038/tpj.2009.55",
language = "English",
volume = "10",
pages = "30--39",
journal = "Pharmacogenomics Journal",
issn = "1470-269X",
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}

TY - JOUR

T1 - ADRA1A gene is associated with BMI in chronic schizophrenia patients exposed to antipsychotics

AU - Liu, Yun-Ru

AU - Loh, El-Wui

AU - Lan, Tsuo-Hung

AU - Chen, Shuo-Fei

AU - Yu, Yen-Hsin

AU - Chang, Yung-Han

AU - Huang, Chun-Jung

AU - Hu, Tsung-Ming

AU - Lin, Keh-Ming

AU - Yao, Yu-Tung

AU - Chiu, Hsien-Jane

N1 - 被引用次數:14 Export Date: 29 March 2016 CODEN: PJHOA 通訊地址: Chiu, H.-J.; Department of Health, Jianan Mental Hospital, 80, Lane 870, Jhung-Shan Road, Rende Township, Tainan 717, Taiwan; 電子郵件: chiu8@mail2000.com.tw 化學物質/CAS: Antipsychotic Agents; Receptors, Adrenergic, alpha-1; adrenergic receptor alpha(1a) 參考文獻: Aronne, L.J., Epidemiology, morbidity, and treatment of overweight and obesity (2001) J Clin Psychiatry, 62 (SUPPL. 23), pp. 13-22; Hsiao, C.C., Ree, S.C., Chiang, Y.L., Yeh, S.S., Chen, C.K., Obesity in schizophrenic outpatients receiving antipsychotics in Taiwan (2004) Psychiatry Clin Neurosci, 58, pp. 403-409; Newcomer, J.W., Metabolic considerations in the use of antipsychotic medications: A review of recent evidence (2007) J Clin Psychiatry, 68 (SUPPL. 1), pp. 20-27; Reinholz, J., Skopp, O., Breitenstein, C., Bohr, I., Winterhoff, H., Knecht, S., Compensatory weight gain due to dopaminergic hypofunction: New evidence and own incidental observations (2008) Nutr Metab (Lond), 5, p. 35; Leibowitz, S.F., Alexander, J.T., Hypothalamic serotonin in control of eating behavior, meal size, and body weight (1998) Biol Psychiatry, 44, pp. 851-864; Templeman, L.A., Reynolds, G.P., Arranz, B., San, L., Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first episode psychosis (2005) Pharmacogenet Genomics, 15, pp. 195-200; Correll, C.U., Malhotra, A.K., Pharmacogenetics of antipsychotic-induced weight gain (2004) Psychopharmacology (Berl), 174, pp. 477-489; Müller, D.J., Muglia, P., Fortune, T., Kennedy, J.L., Pharmacogenetics of antipsychotic-induced weight gain (2004) Pharmacol Res, 49, pp. 309-329; Chagnon, Y.C., Susceptibility genes for the side effect of antipsychotics on body weight and obesity (2006) Curr Drug Targets, 7, pp. 1681-1695; Bray, G.A., Obesity, a disorder of nutrient partitioning: The MONA LISA hypothesis (1991) J Nutr, 121, pp. 1146-1162; Fain, J.N., Garcija-Sainz, J.A., Adrenergic regulation of adipocyte metabolism (1983) J Lipid Res, 24, pp. 945-966; Knowler, W.C., Pettitt, D.J., Saad, M.F., Charles, M.A., Nelson, R.G., Howard, B.V., Obesity in the Pima Indians: Its magnitude and relationship with diabetes (1991) Am J Clin Nutr, 53, pp. 1543S-1551S; Snitker, S., Tataranni, P.A., Ravussin, E., Respiratory quotient is inversely associated with muscle sympathetic nerve activity (1998) J Clin Endocrinol Metab, 83, pp. 3977-3979; Bai, Y.M., Lin, C.C., Chen, J.Y., Lin, C.Y., Su, T.P., Chou, P., Association of initial antipsychotic response to clozapine and long-term weight gain (2006) Am J Psychiatry, 163, pp. 1276-1279; Procyshyn, R.M., Wasan, K.M., Thornton, A.E., Barr, A.M., Chen, E.Y., Pomarol-Clotet, E., Changes in serum lipids, independent of weight, are associated with changes in symptoms during long-term clozapine treatment (2007) J Psychiatry Neurosci, 32, pp. 331-338; Nonogaki, K., New insights into sympathetic regulation of glucose and fat metabolism (2000) Diabetologia, 43, pp. 533-549; Piascik, M.T., Perez, D.M., Alpha1-adrenergic receptors: New insights and directions (2001) J Pharmacol Exp Ther, 298, pp. 403-410; Phares, D.A., Halverstadt, A.A., Shuldiner, A.R., Ferrell, R.E., Douglass, L.W., Ryan, A.S., Association between body fat response to exercise training and multilocus ADR genotypes (2004) Obes Res, 12, pp. 807-815; Dionne, I.J., Turner, A.N., Tchernof, A., Pollin, T.I., Avrithi, D., Gray, D., Identification of an interactive effect of beta3-and alpha2b-adreno- ceptor gene polymorphisms on fat mass in Caucasian women (2001) Diabetes, 50, pp. 91-95; Linne, Y., Dahlman, I., Hoffstedt, J., Beta1-adrenoceptor gene polymorphism predicts long-term changes in body weight (2005) Int J Obes Relat Metab Disord, 29, pp. 458-462; Dionne, I.J., Garant, M.J., Nolan, A.A., Pollin, T.I., Lewis, D.G., Shuldiner, A.R., Association between obesity and a polymorphism in the beta(1)-adrenoceptor gene (Gly389Arg ADRB1) in Caucasian women (2002) Int J Obes Relat Metab Disord, 26, pp. 633-639; Lin, R.C.Y., Ericsson, J.O., Benjafield, A.V., Morris, B.J., Association of beta2-adrenoceptor Gln27Glu variant with body weight but not hypertension (2001) Am J Hypertens, 14, pp. 1201-1204; Pereira, A.C., Floriano, M.S., Mota, G.F., Cunha, R.S., Herkenhoff, F.L., Mill, J.G., Beta2 adrenoceptor functional gene variants, obesity, and blood pressure level interactions in the general population (2003) Hypertension, 42, pp. 685-692; Ehrenborg, E., Skogsberg, J., Ruotolo, G., Large, V., Eriksson, P., Arner, P., The Q/E27 polymorphism in the beta2-adrenoceptor gene is associated with increased body weight and dyslipoproteinaemia involving trigly-ceride-rich lipoproteins (2000) J Intern Med, 247, pp. 651-656; Martinez, J.A., Corbalan, M.S., Sanchez-Villegas, A., Forga, L., Marti, A., Martinez-Gonzalez, M.A., Obesity risk is associated with carbohydrate intake in women carrying the Gln27Glu beta2-adrenoceptor polymorphism (2003) J Nutr, 133, pp. 2549-2554; MacHo-Azcarate, T., Marti, A., Calabuig, J., Martinez, J.A., Basal fat oxidation and after a peak oxygen consumption test in obese women with a beta2 adrenoceptor gene polymorphism (2003) J Nutr Biochem, 14, pp. 275-279; Meirhaeghe, A., Helbecque, N., Cottel, D., Amouyel, P., Impact of polymorphisms of the human beta2-adrenoceptor gene on obesity in a French population (2000) Int J Obes Relat Metab Disord, 24, pp. 382-387; 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PY - 2010

Y1 - 2010

N2 - Noradrenaline and adrenaline are neurotransmitters of the sympathetic nervous system that interact with various adrenergic receptor (ADR) subtypes, and this regulates the basal metabolic rate, thermogenesis and efficiency of energy utilization. We examined a possible role of the gene coding for ADRA1A receptor in weight gain in schizophrenia subjects exposed to antipsychotics. A total of 401 schizophrenia in-patients treated with antipsychotics for 2 years were recruited and a final 394 DNA samples were genotyped. Their body mass indexes (BMIs) were recorded for 12 months and parameterized to be correlated in regression. Among the 58 single-nucleotide polymorphisms (SNPs) genotyped, 44 valid SNPs, which had minor allele frequency 0.03, were analyzed in statistics. Linear regression model with age, gender, diabetes, use of typical antipsychotics and use of atypical antipsychotics as covariates, with or without gender interaction, showed evidence of associations between the ADRA1A gene and BMI. Most of the SNPs associated with BMI are located in the promoter and intron regions, and being female appeared to enhance the gene effect. Our study suggests that the ADRA1A gene is involved in weight gain among schizophrenia patients treated with antipsychotics. Further molecular dissection of the ADRA1A gene warrants better understanding on weight gain mechanisms in schizophrenia. © 2010 Nature Publishing Group All rights reserved.

AB - Noradrenaline and adrenaline are neurotransmitters of the sympathetic nervous system that interact with various adrenergic receptor (ADR) subtypes, and this regulates the basal metabolic rate, thermogenesis and efficiency of energy utilization. We examined a possible role of the gene coding for ADRA1A receptor in weight gain in schizophrenia subjects exposed to antipsychotics. A total of 401 schizophrenia in-patients treated with antipsychotics for 2 years were recruited and a final 394 DNA samples were genotyped. Their body mass indexes (BMIs) were recorded for 12 months and parameterized to be correlated in regression. Among the 58 single-nucleotide polymorphisms (SNPs) genotyped, 44 valid SNPs, which had minor allele frequency 0.03, were analyzed in statistics. Linear regression model with age, gender, diabetes, use of typical antipsychotics and use of atypical antipsychotics as covariates, with or without gender interaction, showed evidence of associations between the ADRA1A gene and BMI. Most of the SNPs associated with BMI are located in the promoter and intron regions, and being female appeared to enhance the gene effect. Our study suggests that the ADRA1A gene is involved in weight gain among schizophrenia patients treated with antipsychotics. Further molecular dissection of the ADRA1A gene warrants better understanding on weight gain mechanisms in schizophrenia. © 2010 Nature Publishing Group All rights reserved.

KW - ADR

KW - ADRA1A gene

KW - Antipsychotics

KW - BMI

KW - Obesity

KW - Schizophrenia

KW - alpha 1A adrenergic receptor

KW - atypical antipsychotic agent

KW - neuroleptic agent

KW - adult

KW - article

KW - body mass

KW - controlled study

KW - diabetes mellitus

KW - DNA determination

KW - female

KW - gene frequency

KW - gene interaction

KW - genetic association

KW - genotype

KW - human

KW - intron

KW - major clinical study

KW - male

KW - pharmacogenetics

KW - priority journal

KW - promoter region

KW - schizophrenia

KW - side effect

KW - single nucleotide polymorphism

KW - weight gain

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antipsychotic Agents

KW - Base Sequence

KW - Body Mass Index

KW - Female

KW - Humans

KW - Linkage Disequilibrium

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Receptors, Adrenergic, alpha-1

KW - Weight Gain

UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-75549092068&partnerID=40&md5=54f2a987ec5de3f9dbfdc1322f758fd7

UR - https://www.scopus.com/results/citedbyresults.uri?sort=plf-f&cite=2-s2.0-75549092068&src=s&imp=t&sid=ebdd0811fe5e96e4b5afac9055139f5c&sot=cite&sdt=a&sl=0&origin=recordpage&editSaveSearch=&txGid=d924ec2f08638a976169fe5a12a84bc3

U2 - 10.1038/tpj.2009.55

DO - 10.1038/tpj.2009.55

M3 - Article

VL - 10

SP - 30

EP - 39

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

SN - 1470-269X

IS - 1

ER -