The Relationships of Obesity-Related Genetic Variants With Metabolic Profiles and Response to Metformin in Clozapine-Treated Patients With Schizophrenia.
Obesity-related genetic variants, including TMEM18 (rs6548238), SH2B1 (rs7498665), and GNPDA2 (rs10938397), have been shown to be associated with obesity in the general population. Our study aimed to test whether these genetic variants are associated with metabolic profiles and metformin treatment response in clozapine-treated schizophrenic patients. We recruited 107 clozapine-treated patients who were genotyped and measured their metabolic profiles. Fifty-five subjects, who had at least 1 metabolic abnormality in a range of measures, were subsequently randomized to a 24-week trial of metformin (n = 28) or placebo (n = 27). We examined the associations between TMEM18, SH2B1, GNPDA2 genetic variants and metabolic profiles at baseline in all patients and metabolic changes in the trial groups. We found a significant association between SH2B1 and blood pressure at baseline in all patients. In the metformin group, TMEM18 minor allele carriers had a greater reduction in insulin levels (P = 0.04). A significantly higher proportion of TMEM18 and GNPDA2 minor allele carriers (60% and 40%) lost more than 7% of their body weight after metformin treatment as compared with their homozygous counterparts (21.7% and 15.4%, P = 0.02 and 0.004, respectively).There were trends toward favorable metabolic changes in minor allele carrier groups. In the placebo group, no association between genetic variants and changes in metabolic profiles was found. In conclusion, the study results suggest that these genes might be associated with metabolic abnormalities and response to metformin in clozapine-treated patients with schizophrenia.
From the *Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital; †Graduate Institute of Medical Science, School of Medicine, ‡Department of Psychiatry, Wan Fang Hospital, and §Department of Psychiatry, School of Medicine, Taipei Medical University; ∥Department of Public Health and Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University; and ¶Research Center for Genes, Environment and Human Health, National Taiwan University, Taipei, Taiwan.
Po-Yu
PY
Chen
Mong-Liang
ML
Lu
Ming-Chyi
MC
Huang
Chung-Feng
CF
Kao
Po-Hsiu
PH
Kuo
Chih-Chiang
CC
Chiu
Shih-Ku
SK
Lin
Chun-Hsin
CH
Chen
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D019747:Aldose-Ketose Isomerases / Q000235:genetics; D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use; D003024:Clozapine / Q000009:adverse effects* / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008659:Metabolic Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009765:Obesity / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy*
D048868:Adaptor Proteins, Signal Transducing; D014150:Antipsychotic Agents; D008565:Membrane Proteins; C518910:SH2B1 protein, human; C530715:TMEM18 protein, human; D008687:Metformin; C020582:glucosamine-6-phosphate isomerase; D019747:Aldose-Ketose Isomerases; D003024:Clozapine