1Schizophr. Res. 2010 Aug 121: 213-7
PMID20591628
TitlePolymorphisms of the LEP- and LEPR genes, metabolic profile after prolonged clozapine administration and response to the antidiabetic metformin.
AbstractThe role of leptin in atypical antipsychotic-induced metabolic dysfunction was explored by assessing the anthropometric and metabolic profile and the response to metformin (MET) of clozapine- (CLZ) treated schizophrenia patients according to their single nucleotide polymorphisms (SNPs) in the leptin promoter (LEP2548/GA) and leptin receptor (LEPR Q223R) genes.
Phase 1. Body mass index (BMI), waist circumference, serum glucose, HbA1C, lipids, leptin, cortisol, insulin resistance index (HOMA-IR), metabolic syndrome and the frequencies of SNPs were assessed in 56 CLZ-treated patients (78.6% males). Phase 2. Fifty two phase 1 subjects were randomly assigned to MET XR (n=23) (1000 mg/day) or placebo (n=29) for 14 weeks. Changes in anthropometric and biochemical variables were compared between the SNPs.
Phase 1. The QQ group displayed the lowest triglyceride levels (p<0.05). No other significant difference was observed. Phase 2. Change in anthropometric variables did not differ between the genotypes in any treatment group. After MET, glucose levels significantly increased in the GG group (p<0.05), whereas the HOMA-IR and the low density cholesterol significantly decreased in the QQ- but not in the (QR+RR) group (p<0.05). No differences were observed after placebo.
BW response to CLZ was not related to LEP- and LEPR-SNPs. The GG and (QR+RR) genotypes showed an unexpectedly opposite and blunted response to MET administration respectively.
SCZ Keywordsschizophrenia, schizophrenic
2Schizophr. Res. 2011 Feb 125: 187-93
PMID21050724
TitleClock genes and body composition in patients with schizophrenia under treatment with antipsychotic drugs.
AbstractIn the healthy population, several pathways are known to exert an effect on basal metabolic factors. Previous studies have found associations between single nucleotide polymorphisms in clock genes or downstream hormone receptors such as the leptin receptor (LEPR) or glucocorticoid receptor (NR3C1) and obesity in the healthy population, but this association remains to be examined in patients with schizophrenia treated with antipsychotics.
To assess anthropomorphic parameters in patients taking second-generation antipsychotics (SGA) as a function of nine polymorphisms in three core genes of the clock pathway, and two genes of downstream hormone receptors.
Clinical parameters were evaluated in 261 patients with schizophrenia spectrum disorder. Polymorphisms in LEPR, MC3R, NR3C1, PER2 and SDC3 were genotyped. In order to control for multiple testing, permutation tests were used to generate corrected empirical p-values using the Max(T) procedure in PLINK.
A significant effect of the rs6196 polymorphism in the NR3C1 on weight (?=-4.18; SE=2.02; p=0.018), BMI (?=-1.88; SE=0.64; p=0.004), waist (?=-5.77; SE=1.75; p=0.001) and waist/hip ratio (?=-0.03; SE=0.012; p=0.009) was found. Permutation tests confirmed the findings for BMI (p=0.037) and waist (p=0.024). Carriers of the G allele consistently displayed better parameters than patients with the wild type allele. A weak effect of rs4949184 in SDC3 on BMI was found, but this did not sustain permutation testing (?=-1.27; SE=0.58; p=0.030, p=0.270 after permutations).
Variations in genes implicated in circadian regulation or its related downstream pathways may be important in the regulation of antropomorphic parameters in patients with schizophrenia during long-term treatment with SGA.
SCZ Keywordsschizophrenia, schizophrenic
3J Clin Psychopharmacol 2011 Dec 31: 705-11
PMID22020349
TitlePolymorphisms of INSIG2, MC4R, and LEP are associated with obesity- and metabolic-related traits in schizophrenic patients.
Abstractschizophrenic patients have a high prevalence of metabolic adversities. Previous studies have suggested some candidate genes for obesity- and metabolic-related traits, including the insulin-induced gene (INSIG2), melanocortin 4 receptor gene (MC4R), and leptin and leptin receptor genes (LEP and LEPR). We aimed to investigate the associations between these genes and metabolic disturbances in patients with schizophrenia in Taiwan.
Patients with a diagnosis of schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were recruited from 36 community psychiatric rehabilitation centers or hospitals in Taipei. A total of 650 subjects were enrolled, and 577 were included in the genetic analyses. The anthropometric (body mass index, waist circumference [WC], and blood pressure) and biochemical measurements (fasting plasma glucose, insulin, triglyceride, high-density lipoprotein cholesterol, and Homeostasis Model of Assessment - Insulin Resistance index [HOMA-IR]) were assessed. Seven loci in the 4 genes were genotyped using standard TaqMan assays. Genetic association analyses were conducted for binary and quantitative measurements of the previously mentioned traits. Obese patients with schizophrenia exhibited more metabolic disturbances than nonobese patients.
Our data showed that INSIG2 was significantly associated with fasting plasma glucose (for rs17587100, P < 0.0001), MC4R was associated with WC (for rs2229616, P = 0.005), and LEP was associated with body mass index and WC (for rs7799039, P < 0.01). In addition, these loci showed suggestive associations with traits including high-density lipoprotein cholesterol and triglyceride, metabolic syndrome, insulin level, and HOMA-IR index (P = 0.05). In addition to the effect from antipsychotic medications and an unhealthy lifestyle, genetic factors also contribute to the high prevalence of obesity and metabolic disturbances in patients with schizophrenia, especially genes involved in metabolic-related pathways.
SCZ Keywordsschizophrenia, schizophrenic
4J Clin Psychopharmacol 2011 Dec 31: 705-11
PMID22020349
TitlePolymorphisms of INSIG2, MC4R, and LEP are associated with obesity- and metabolic-related traits in schizophrenic patients.
Abstractschizophrenic patients have a high prevalence of metabolic adversities. Previous studies have suggested some candidate genes for obesity- and metabolic-related traits, including the insulin-induced gene (INSIG2), melanocortin 4 receptor gene (MC4R), and leptin and leptin receptor genes (LEP and LEPR). We aimed to investigate the associations between these genes and metabolic disturbances in patients with schizophrenia in Taiwan.
Patients with a diagnosis of schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were recruited from 36 community psychiatric rehabilitation centers or hospitals in Taipei. A total of 650 subjects were enrolled, and 577 were included in the genetic analyses. The anthropometric (body mass index, waist circumference [WC], and blood pressure) and biochemical measurements (fasting plasma glucose, insulin, triglyceride, high-density lipoprotein cholesterol, and Homeostasis Model of Assessment - Insulin Resistance index [HOMA-IR]) were assessed. Seven loci in the 4 genes were genotyped using standard TaqMan assays. Genetic association analyses were conducted for binary and quantitative measurements of the previously mentioned traits. Obese patients with schizophrenia exhibited more metabolic disturbances than nonobese patients.
Our data showed that INSIG2 was significantly associated with fasting plasma glucose (for rs17587100, P < 0.0001), MC4R was associated with WC (for rs2229616, P = 0.005), and LEP was associated with body mass index and WC (for rs7799039, P < 0.01). In addition, these loci showed suggestive associations with traits including high-density lipoprotein cholesterol and triglyceride, metabolic syndrome, insulin level, and HOMA-IR index (P = 0.05). In addition to the effect from antipsychotic medications and an unhealthy lifestyle, genetic factors also contribute to the high prevalence of obesity and metabolic disturbances in patients with schizophrenia, especially genes involved in metabolic-related pathways.
SCZ Keywordsschizophrenia, schizophrenic
5Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Aug 38: 134-41
PMID22426215
TitleAssociation study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain.
AbstractAntipsychotic-induced weight gain (AIWG) is a serious side-effect of antipsychotic medication leading to metabolic syndrome and increased cardiovascular morbidity. Unfortunately, there are still no valid predictors to assess an individual's risk to gain weight. Previous studies have indicated an impact of genetic variation in the genes encoding leptin, LEP, and leptin receptor, LEPR, on AIWG, but results have not been conclusive. Thus, we investigated polymorphisms in both genes for an association with AIWG.
A total of 181 schizophrenic and schizoaffective patients treated with various antipsychotics were included. In a small subset of patients, leptin plasma levels were additionally obtained. Five polymorphisms in LEP and LEPR (LEP: rs7799039 (-2548G/A polymorphism), rs10954173, rs3828942; LEPR: rs1327120, rs1137101 (Q223R polymorphism) were genotyped using TaqMan assays. Statistical association with % weight change from baseline weight was performed using ANCOVA with baseline weight as covariate.
ANCOVA showed a non-significant trend for genotype association of the rs7799039 marker (p=.068). No significant association of the other LEP and LEPR SNPs with AIWG was detected. However, we found a significant association between a haplotype of LEP rs7799039G-rs10954173G-rs3828942G (p=.035) and AIWG. The rs7799039 G-allele (p=.042) and G-allele of rs3828942 (p=.032) were associated with higher weight gain.
Our study supports the hypothesis of an impact of LEP gene variation on AIWG. Limitations of our study include heterogeneous samples, short treatment duration and multiple comparisons. Our findings were compared to previous studies in detail in order to provide the readers with a more conclusive picture. However, further studies are warranted including more gene variants and interaction analyses with other genes of the leptin-melanocortin pathway.
SCZ Keywordsschizophrenia, schizophrenic
6Pharmacogenomics 2014 Mar 15: 477-85
PMID24624915
TitleAssociation of FTO, LEPR and MTHFR gene polymorphisms with metabolic syndrome in schizophrenia patients receiving antipsychotics.
AbstractThe occurrence of metabolic syndrome (MS) in schizophrenia patients receiving long-term antipsychotics (APs) contributes to their high mortality rate. We aimed to determine whether genetic polymorphisms of identified candidate genes are associated with MS in our study population.
We recruited 206 schizophrenia patients receiving AP treatment for at least a year. Cross-sectional measurements of weight, height, blood pressure, waist and hip circumference, and other lipid profiles were recorded. Patient DNA was genotyped for 16 candidate gene polymorphisms.
Of these patients, 59.7% were found to have MS while 40.3% did not. All metabolic parameters were significantly different between the two groups. Only three of the 16 polymorphisms studied showed significant association with MS; rs9939609 of the FTO gene confers risk for MS (odds ratio [OR]: 1.73, 95% CI: 1.07-2.78, p = 0.026), while rs1137101 of the LEPR gene (OR: 0.47, 95% CI: 0.28-0.80, p = 0.005) and rs1801133 of the MTHFR gene (OR: 0.59, 95% CI: 0.35-0.99, p = 0.049) are protective against MS.
Polymorphisms of the FTO, LEPR and MTHFR genes may play a role in MS in Malaysian schizophrenia patients receiving long-term treatment with APs.
SCZ Keywordsschizophrenia, schizophrenic
7Psychiatry Res 2015 Jul 228: 177-8
PMID25841316
TitleEffects of LEP, LEPR, ADIPOQ, MC4R and FTO polymorphisms on dyslipidemia in Korean patients with schizophrenia who are taking clozapine.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic
8Schizophr. Res. 2016 Jan 170: 1-17
PMID26621002
TitleA systematic review of genetic variants associated with metabolic syndrome in patients with schizophrenia.
AbstractMetabolic syndrome (MetS) is a cluster of factors that increases the risk of cardiovascular disease (CVD), one of the leading causes of mortality in patients with schizophrenia. Incidence rates of MetS are significantly higher in patients with schizophrenia compared to the general population. Several factors contribute to this high comorbidity. This systematic review focuses on genetic factors and interrogates data from association studies of genes implicated in the development of MetS in patients with schizophrenia. We aimed to identify variants that potentially contribute to the high comorbidity between these disorders. PubMed, Web of Science and Scopus databases were accessed and a systematic review of published studies was conducted. Several genes showed strong evidence for an association with MetS in patients with schizophrenia, including the fat mass and obesity associated gene (FTO), leptin and leptin receptor genes (LEP, LEPR), methylenetetrahydrofolate reductase (MTHFR) gene and the serotonin receptor 2C gene (HTR2C). Genetic association studies in complex disorders are convoluted by the multifactorial nature of these disorders, further complicating investigations of comorbidity. Recommendations for future studies include assessment of larger samples, inclusion of healthy controls, longitudinal rather than cross-sectional study designs, detailed capturing of data on confounding variables for both disorders and verification of significant findings in other populations. In future, big genomic datasets may allow for the calculation of polygenic risk scores in risk prediction of MetS in patients with schizophrenia. This could ultimately facilitate early, precise, and patient-specific pharmacological and non-pharmacological interventions to minimise CVD associated morbidity and mortality.
SCZ Keywordsschizophrenia, schizophrenic