Testing the role of genetic variation of the MC4R gene in Chinese population in antipsychotic-induced metabolic disturbance
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摘要
Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4 R in Chinese population by genotyping two SNPs(rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index(BMI), waist circumference(WC), glucose, triglyceride, high-density lipoprotein(HDL), and low-density lipoprotein(LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status(drug-na?ve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-na?ve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.
Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4 R in Chinese population by genotyping two SNPs(rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index(BMI), waist circumference(WC), glucose, triglyceride, high-density lipoprotein(HDL), and low-density lipoprotein(LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status(drug-na?ve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-na?ve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.
Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4 R in Chinese population by genotyping two SNPs(rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index(BMI), waist circumference(WC), glucose, triglyceride, high-density lipoprotein(HDL), and low-density lipoprotein(LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status(drug-na?ve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-na?ve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.
引文
Bender,R.,and Lange,S.(2001).Adjusting for multiple testing-when and how?J Clin Epidemiol 54,343-349.
Chagnon,Y.C.,Bureau,A.,Gendron,D.,Bouchard,R.H.,Mérette,C.,Roy,M.A.,and Maziade,M.(2007).Possible association of the pro-melaninconcentrating hormone gene with a greater body mass index as a side effect of the antipsychotic olanzapine.Am J Med Genet 144B,1063-1069.
Chambers,J.C.,Elliott,P.,Zabaneh,D.,Zhang,W.,Li,Y.,Froguel,P.,Balding,D.,Scott,J.,and Kooner,J.S.(2008).Common genetic variation near MC4R is associated with waist circumference and insulin resistance.Nat Genet 40,716-718.
Chiliza,B.,Asmal,L.,Oosthuizen,P.,van Niekerk,E.,Erasmus,R.,Kidd,M.,Malhotra,A.,and Emsley,R.(2015).Changes in body mass and metabolic profiles in patients with first-episode schizophrenia treated for 12 months with a first-generation antipsychotic.Eur Psychiatr 30,277-283.
Chowdhury,N.I.,Tiwari,A.K.,Souza,R.P.,Zai,C.C.,Shaikh,S.A.,Chen,S.,Liu,F.,Lieberman,J.A.,Meltzer,H.Y.,Malhotra,A.K.,et al.(2013).Genetic association study between antipsychotic-induced weight gain and the melanocortin-4 receptor gene.Pharmacogenomics J 13,272-279.
Comings,D.E.,and MacMurray,J.P.(2000).Molecular heterosis:a review.Mol Genet Metab 71,19-31.
Czerwensky,F.,Leucht,S.,and Steimer,W.(2013a).Association of the common MC4R rs17782313 polymorphism with antipsychotic-related weight gain.J Clin Psychopharmacol 33,74-79.
Czerwensky,F.,Leucht,S.,and Steimer,W.(2013b).MC4R rs489693:a clinical risk factor for second generation antipsychotic-related weight gain?Int J Neuropsychopharmacol 16,2103-2109.
Gebhardt,S.,Theisen,F.M.,Haberhausen,M.,Heinzel-Gutenbrunner,M.,Wehmeier,P.M.,Krieg,J.C.,Kühnau,W.,Schmidtke,J.,Remschmidt,H.,and Hebebrand,J.(2010).Body weight gain induced by atypical antipsychotics:an extension of the monocygotic twin and sib pair study.J Clin Pharm Ther 35,207-211.
Hartling,L.,Abou-Setta,A.M.,Dursun,S.,Mousavi,S.S.,Pasichnyk,D.,and Newton,A.S.(2012).Antipsychotics in adults with schizophrenia:comparative effectiveness of first-generation versus second-generation medications.Ann Intern Med 157,498-511.
Lett,T.A.P.,Wallace,T.J.M.,Chowdhury,N.I.,Tiwari,A.K.,Kennedy,J.L.,and Müller,D.J.(2012).Pharmacogenetics of antipsychotic-induced weight gain:review and clinical implications.Mol Psychiatry 17,242-266.
List,J.F.,and Habener,J.F.(2003).Defective melanocortin 4 receptors in hyperphagia and morbid obesity.N Engl J Med 348,1160-1163.
Loos,R.J.F.,Lindgren,C.M.,Li,S.,Wheeler,E.,Zhao,J.H.,Prokopenko,I.,Inouye,M.,Freathy,R.M.,Attwood,A.P.,Beckmann,J.S.,et al.(2008).Common variants near MC4R are associated with fat mass,weight and risk of obesity.Nat Genet 40,768-775.
Malhotra,A.K.,Correll,C.U.,Chowdhury,N.I.,Müller,D.J.,Gregersen,P.K.,Lee,A.T.,Tiwari,A.K.,Kane,J.M.,Fleischhacker,W.W.,Kahn,R.S.,et al.(2012).Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain.Arch Gen Psychiatry 69,904-912.
Monteleone,P.,Milano,W.,Petrella,C.,Canestrelli,B.,and Maj,M.(2010).Endocannabinoid Pro129Thr FAAH functional polymorphism but not 1359G/A CNR1 polymorphism is associated with antipsychoticinduced weight gain.J Clin Psychopharmacol 30,441-445.
Reynolds,G.P.(2012).Pharmacogenetic aspects of antipsychotic druginduced weight gain-a critical review.Clin Psychopharmacol Neurosci10,71-77.
Reynolds,G.P.,Hill,M.J.,and Kirk,S.L.(2006).The 5-HT2C receptor and antipsychoticinduced weight gain-mechanisms and genetics.JPsychopharmacol 20,15-18.
Templeman,L.A.,Reynolds,G.P.,Arranz,B.,and San,L.(2005).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.Pharmacogenet Genomics 15,195-200.
Theisen,F.M.,Gebhardt,S.,Haberhausen,M.,Heinzel-Gutenbrunner,M.,Wehmeier,P.M.,Krieg,J.C.,Khnau,W.,Schmidtke,J.,Remschmidt,H.,and Hebebrand,J.(2005).Clozapine-induced weight gain:a study in monozygotic twins and same-sex sib pairs.Psychiatric Genet 15,285-289.
Tiwari,A.K.,Zai,C.C.,Likhodi,O.,Lisker,A.,Singh,D.,Souza,R.P.,Batra,P.,Zaidi,S.H.E.,Chen,S.,Liu,F.,et al.(2010).A common polymorphism in the cannabinoid receptor 1(CNR1)gene is associated with antipsychotic-induced weight gain in Schizophrenia.Neuropsychopharmacology 35,1315-1324.
Xu,B.,Goulding,E.H.,Zang,K.,Cepoi,D.,Cone,R.D.,Jones,K.R.,Tecott,L.H.,and Reichardt,L.F.(2003).Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor.Nat Neurosci 6,736-742.
Xu,Y.,Jones,J.E.,Lauzon,D.A.,Anderson,J.G.,Balthasar,N.,Heisler,L.K.,Zinn,A.R.,Lowell,B.B.,and Elmquist,J.K.(2010).A serotonin and melanocortin circuit mediates D-fenfluramine anorexia.J Neurosci30,14630-14634.
Yoon,C.K.(2008).Weight gain and first-generation antipsychotics.J Clin Psychopharmacol 28,574-576.
Yu,H.,Wang,L.,Lv,L.,Ma,C.,Du,B.,Lu,T.,Jin,C.,Yan,H.,Yang,Y.,Li,W.,et al.(2016).Genome-wide association study suggested the PTPRD polymorphisms were associated with weight gain effects of atypical antipsychotic medications.Schizophr Bull 42,814-823.
Zhang,J.P.,Lencz,T.,Zhang,R.X.,Nitta,M.,Maayan,L.,John,M.,Robinson,D.G.,Fleischhacker,W.W.,Kahn,R.S.,Ophoff,R.A.,et al.(2016).Pharmacogenetic associations of antipsychotic drug-related weight gain:a systematic review and meta-analysis.Schizophr Bull 42,1418-1437.
Zhang,X.Y.,Tan,Y.L.,Zhou,D.F.,Haile,C.N.,Cao,L.Y.,Xu,Q.,Shen,Y.,Kosten,T.A.,and Kosten,T.R.(2007).Association of clozapineinduced weight gain with a polymorphism in the leptin promoter region in patients with chronic schizophrenia in a Chinese population.J Clin Psychopharmacol 27,246-251.
Zhang,X.Y.,Zhou,D.F.,Wu,G.Y.,Cao,L.Y.,Tan,Y.L.,Haile,C.N.,Li,J.,Lu,L.,Kosten,T.A.,and Kosten,T.R.(2008).BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia.Neuropsychopharmacology 33,2200-2205.
Zhang,Z.J.,Yao,Z.J.,Mou,X.D.,Chen,J.F.,Zhu,R.X.,Liu,W.,Zhang,X.R.,Sun,J.,and Hou,G.(2003).Association of-2548G/A functional polymorphism in the promoter region of leptin gene with antipsychotic agent-induced weight gain(in Chinese).Zhonghua Yi Xue Za Zhi 83,2119-2123.
Zobel,D.P.,Andreasen,C.H.,Grarup,N.,Eiberg,H.,S?rensen,T.I.A.,Sandbaek,A.,Lauritzen,T.,Borch-Johnsen,K.,J?rgensen,T.,Pedersen,O.,et al.(2009).Variants near MC4R are associated with obesity and influence obesity-related quantitative traits in a population of middle-aged people:studies of 14,940 Danes.Diabetes 58,757-764.
Chagnon,Y.C.,Bureau,A.,Gendron,D.,Bouchard,R.H.,Mérette,C.,Roy,M.A.,and Maziade,M.(2007).Possible association of the pro-melaninconcentrating hormone gene with a greater body mass index as a side effect of the antipsychotic olanzapine.Am J Med Genet 144B,1063-1069.
Chambers,J.C.,Elliott,P.,Zabaneh,D.,Zhang,W.,Li,Y.,Froguel,P.,Balding,D.,Scott,J.,and Kooner,J.S.(2008).Common genetic variation near MC4R is associated with waist circumference and insulin resistance.Nat Genet 40,716-718.
Chiliza,B.,Asmal,L.,Oosthuizen,P.,van Niekerk,E.,Erasmus,R.,Kidd,M.,Malhotra,A.,and Emsley,R.(2015).Changes in body mass and metabolic profiles in patients with first-episode schizophrenia treated for 12 months with a first-generation antipsychotic.Eur Psychiatr 30,277-283.
Chowdhury,N.I.,Tiwari,A.K.,Souza,R.P.,Zai,C.C.,Shaikh,S.A.,Chen,S.,Liu,F.,Lieberman,J.A.,Meltzer,H.Y.,Malhotra,A.K.,et al.(2013).Genetic association study between antipsychotic-induced weight gain and the melanocortin-4 receptor gene.Pharmacogenomics J 13,272-279.
Comings,D.E.,and MacMurray,J.P.(2000).Molecular heterosis:a review.Mol Genet Metab 71,19-31.
Czerwensky,F.,Leucht,S.,and Steimer,W.(2013a).Association of the common MC4R rs17782313 polymorphism with antipsychotic-related weight gain.J Clin Psychopharmacol 33,74-79.
Czerwensky,F.,Leucht,S.,and Steimer,W.(2013b).MC4R rs489693:a clinical risk factor for second generation antipsychotic-related weight gain?Int J Neuropsychopharmacol 16,2103-2109.
Gebhardt,S.,Theisen,F.M.,Haberhausen,M.,Heinzel-Gutenbrunner,M.,Wehmeier,P.M.,Krieg,J.C.,Kühnau,W.,Schmidtke,J.,Remschmidt,H.,and Hebebrand,J.(2010).Body weight gain induced by atypical antipsychotics:an extension of the monocygotic twin and sib pair study.J Clin Pharm Ther 35,207-211.
Hartling,L.,Abou-Setta,A.M.,Dursun,S.,Mousavi,S.S.,Pasichnyk,D.,and Newton,A.S.(2012).Antipsychotics in adults with schizophrenia:comparative effectiveness of first-generation versus second-generation medications.Ann Intern Med 157,498-511.
Lett,T.A.P.,Wallace,T.J.M.,Chowdhury,N.I.,Tiwari,A.K.,Kennedy,J.L.,and Müller,D.J.(2012).Pharmacogenetics of antipsychotic-induced weight gain:review and clinical implications.Mol Psychiatry 17,242-266.
List,J.F.,and Habener,J.F.(2003).Defective melanocortin 4 receptors in hyperphagia and morbid obesity.N Engl J Med 348,1160-1163.
Loos,R.J.F.,Lindgren,C.M.,Li,S.,Wheeler,E.,Zhao,J.H.,Prokopenko,I.,Inouye,M.,Freathy,R.M.,Attwood,A.P.,Beckmann,J.S.,et al.(2008).Common variants near MC4R are associated with fat mass,weight and risk of obesity.Nat Genet 40,768-775.
Malhotra,A.K.,Correll,C.U.,Chowdhury,N.I.,Müller,D.J.,Gregersen,P.K.,Lee,A.T.,Tiwari,A.K.,Kane,J.M.,Fleischhacker,W.W.,Kahn,R.S.,et al.(2012).Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain.Arch Gen Psychiatry 69,904-912.
Monteleone,P.,Milano,W.,Petrella,C.,Canestrelli,B.,and Maj,M.(2010).Endocannabinoid Pro129Thr FAAH functional polymorphism but not 1359G/A CNR1 polymorphism is associated with antipsychoticinduced weight gain.J Clin Psychopharmacol 30,441-445.
Reynolds,G.P.(2012).Pharmacogenetic aspects of antipsychotic druginduced weight gain-a critical review.Clin Psychopharmacol Neurosci10,71-77.
Reynolds,G.P.,Hill,M.J.,and Kirk,S.L.(2006).The 5-HT2C receptor and antipsychoticinduced weight gain-mechanisms and genetics.JPsychopharmacol 20,15-18.
Templeman,L.A.,Reynolds,G.P.,Arranz,B.,and San,L.(2005).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.Pharmacogenet Genomics 15,195-200.
Theisen,F.M.,Gebhardt,S.,Haberhausen,M.,Heinzel-Gutenbrunner,M.,Wehmeier,P.M.,Krieg,J.C.,Khnau,W.,Schmidtke,J.,Remschmidt,H.,and Hebebrand,J.(2005).Clozapine-induced weight gain:a study in monozygotic twins and same-sex sib pairs.Psychiatric Genet 15,285-289.
Tiwari,A.K.,Zai,C.C.,Likhodi,O.,Lisker,A.,Singh,D.,Souza,R.P.,Batra,P.,Zaidi,S.H.E.,Chen,S.,Liu,F.,et al.(2010).A common polymorphism in the cannabinoid receptor 1(CNR1)gene is associated with antipsychotic-induced weight gain in Schizophrenia.Neuropsychopharmacology 35,1315-1324.
Xu,B.,Goulding,E.H.,Zang,K.,Cepoi,D.,Cone,R.D.,Jones,K.R.,Tecott,L.H.,and Reichardt,L.F.(2003).Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor.Nat Neurosci 6,736-742.
Xu,Y.,Jones,J.E.,Lauzon,D.A.,Anderson,J.G.,Balthasar,N.,Heisler,L.K.,Zinn,A.R.,Lowell,B.B.,and Elmquist,J.K.(2010).A serotonin and melanocortin circuit mediates D-fenfluramine anorexia.J Neurosci30,14630-14634.
Yoon,C.K.(2008).Weight gain and first-generation antipsychotics.J Clin Psychopharmacol 28,574-576.
Yu,H.,Wang,L.,Lv,L.,Ma,C.,Du,B.,Lu,T.,Jin,C.,Yan,H.,Yang,Y.,Li,W.,et al.(2016).Genome-wide association study suggested the PTPRD polymorphisms were associated with weight gain effects of atypical antipsychotic medications.Schizophr Bull 42,814-823.
Zhang,J.P.,Lencz,T.,Zhang,R.X.,Nitta,M.,Maayan,L.,John,M.,Robinson,D.G.,Fleischhacker,W.W.,Kahn,R.S.,Ophoff,R.A.,et al.(2016).Pharmacogenetic associations of antipsychotic drug-related weight gain:a systematic review and meta-analysis.Schizophr Bull 42,1418-1437.
Zhang,X.Y.,Tan,Y.L.,Zhou,D.F.,Haile,C.N.,Cao,L.Y.,Xu,Q.,Shen,Y.,Kosten,T.A.,and Kosten,T.R.(2007).Association of clozapineinduced weight gain with a polymorphism in the leptin promoter region in patients with chronic schizophrenia in a Chinese population.J Clin Psychopharmacol 27,246-251.
Zhang,X.Y.,Zhou,D.F.,Wu,G.Y.,Cao,L.Y.,Tan,Y.L.,Haile,C.N.,Li,J.,Lu,L.,Kosten,T.A.,and Kosten,T.R.(2008).BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia.Neuropsychopharmacology 33,2200-2205.
Zhang,Z.J.,Yao,Z.J.,Mou,X.D.,Chen,J.F.,Zhu,R.X.,Liu,W.,Zhang,X.R.,Sun,J.,and Hou,G.(2003).Association of-2548G/A functional polymorphism in the promoter region of leptin gene with antipsychotic agent-induced weight gain(in Chinese).Zhonghua Yi Xue Za Zhi 83,2119-2123.
Zobel,D.P.,Andreasen,C.H.,Grarup,N.,Eiberg,H.,S?rensen,T.I.A.,Sandbaek,A.,Lauritzen,T.,Borch-Johnsen,K.,J?rgensen,T.,Pedersen,O.,et al.(2009).Variants near MC4R are associated with obesity and influence obesity-related quantitative traits in a population of middle-aged people:studies of 14,940 Danes.Diabetes 58,757-764.