Association of Allelic Variation in Genes Mediating Aspects of Energy Homeostasis with Weight Gain during Administration of Antipsychotic Drugs (CATIE Study)

Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
Frontiers in Genetics 09/2011; 2(56). DOI: 10.3389/fgene.2011.00056
Source: PubMed


Antipsychotic drugs are widely used in treating schizophrenia, bipolar disorder, and other psychiatric disorders. Many of these drugs, despite their therapeutic advantages, substantially increase body weight. We assessed the association of alleles of 31 genes implicated in body weight regulation with weight gain among patients being treated with specific antipsychotic medications in the clinical antipsychotic trials in intervention effectiveness study, we found that rs2237988 in Potassium Channel Inwardly Rectifying Subfamily J Member 11 (KCNJ11), rs13269119 in Solute carrier family 30 member 8 (SLC30A8), and rs9922047 in fat mass and obesity associated (FTO) were associated with percent weight gain. We also observed the significant interaction of rs11643744 by treatment effect on the weight gain.

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Available from: Jeffrey A Lieberman
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    • "Pharmacogenetic studies have mainly focused on the Pro12Ala variant and have reported mixed results with higher risk for metabolic syndrome or weight gain in Ala-carriers (Fernandez et al., 2012; Herken et al., 2009), higher risk for obesity only in females (Chen et al., 2011) or no association of the variant with weight gain (Staeker et al., 2012; Tiwari et al., 2011; Ujike et al., 2008). Other PPARγ variants, such as the C161T (rs3856806) polymorphism have not been investigated extensively for their role in antipsychotic-induced weight gain and have, except for one study (Chen et al., 2011), not delivered positive association findings (Kang et al., 2011; Tiwari et al., 2011). One of the genes activated by PPARγ is ADIPOQ, encoding adiponectin, which is exclusively expressed in adipose tissue. "
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    ABSTRACT: Antipsychotics frequently cause changes in glucose metabolism followed by development of weight gain and/or diabetes. Recent findings from our group indicated an influence of glucose-related genes on this serious side effect. With this study, we aimed to extend previous research and performed a comprehensive study on the peroxisome proliferator-activated receptor gamma (PPARG) and the adiponectin (ADIPOQ) genes. In 216 schizophrenic patients receiving antipsychotics for up to 14 weeks, we investigated single-nucleotide polymorphisms in or near PPARG (N=24) and ADIPOQ (N=18). Statistical analysis was done using ANCOVA in SPSS. Haplotype analysis was performed in UNPHASED 3.1.4 and Haploview 4.2. None of the PPARG or ADIPOQ variants showed significant association with antipsychotic-induced weight gain in our combined sample or in a refined subsample of patients of European ancestry treated with clozapine or olanzapine after correction for multiple testing. Similarly, no haplotype association could withstand multiple test correction. Although we could not find a significant influence of ADIPOQ and PPARG on antipsychotic-induced weight gain, our comprehensive examination of these two genes contributes to understanding the biology of this serious side effect. More research on glucose metabolism genes is warranted to elucidate their role in metabolic changes during antipsychotic treatment.
    Full-text · Article · May 2014 · Psychiatry Research
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    • "The important and independent Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial of the relative effects of several antipsychotic drugs35) is a valuable sample source for pharmacogenetic studies. A recent study of this cohort also identified an association of weight gain with a SNP in FTO, as well as with two other significant genes.36) "
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    ABSTRACT: Treatment with several antipsychotic drugs can result in weight gain, which may lead to further morbidity such as type 2 diabetes and cardiovascular disease via the development of metabolic syndrome. These important and problematic metabolic consequences of antipsychotic drug treatment probably reflect a pharmacological disruption of the mechanisms involved in control of food intake and body weight. The extent of weight gain following antipsychotic drug treatment shows substantial variability between individuals, due in part to genetic factors. Common functional polymorphisms in many candidate genes implicated in the control of body weight and various aspects of energy and lipid metabolism have been investigated for association with weight gain in subjects receiving antipsychotic drug treatment, and with metabolic pathology in chronic schizophrenia. Perhaps the strongest and most replicated findings are the associations with promoter polymorphisms in the 5-HT2C receptor and leptin genes, although many other possible genetic risk factors, including polymorphisms in the fat mass and obesity associated (FTO) gene and genes for the alpha2A adrenoceptor and melanocortin4 receptor, have been reported. Genome-wide association studies (GWAS) have also addressed antipsychotic-induced weight gain and other indicators of metabolic disturbances. However there is as yet little consistency between these studies or between GWAS and classical candidate gene approaches. Identifying common genetic factors associated with drug-induced weight gain and its metabolic consequences may provide opportunities for personalized medicine in the predictive assessment of metabolic risk as well as indicating underlying physiological mechanisms.
    Full-text · Article · Aug 2012 · Clinical Psychopharmacology and Neuroscience
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    ABSTRACT: Weight gain, leading to further morbidity and poor treatment adherence, is a common consequence of treatment with antipsychotic drugs. A recent study showed that a polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene is associated with antipsychotic-induced weight gain. The authors determined whether this association held true for weight gain after clozapine treatment. Thirty-two Chinese Han patients with first-episode schizophrenia were genotyped for the -759C/T polymorphism and had weight changes monitored after 6 weeks of clozapine treatment. The authors found that the 10 patients with the -759T variant allele showed significantly less weight gain than those without this allele. The effect was strongest in the male patients and not apparent in the female patients. These findings identify an important genetic factor associated with clozapine-induced weight increases in schizophrenia.
    No preview · Article · May 2003 · American Journal of Psychiatry
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