Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample.
BACKGROUND
Drug-induced bodyweight gain (BWG) is a serious concern in pharmacotherapy with second-generation antipsychotics. The interindividual variability is likely to be modulated by genetic factors. In the past, pharmacogenetic studies yielded conflicting results, and none of the identified genetic alterations exerts sufficient predictive value for this severe side effect of psychopharmacotherapy.


OBJECTIVE
We aimed to contribute to the replication and extension of prior association findings and investigated the genes encoding serotonin 2C receptor (HTR2C), insulin-induced gene 2 (INSIG2) and leptin (LEP).


METHODS
We investigated the association of HTR2C, LEP and INSIG2 SNPs with antipsychotic-induced BWG in 128 German schizophrenic patients. Genotyping was performed for nine SNPs (HTR2C: rs498207, rs3813928, rs6318 and rs3813929; INSIG2: rs17587100, rs10490624, rs17047764 and rs7566605; LEP: rs7799039). Association analysis included logistic regression analysis and Pearson s chi(2) tests.


RESULTS
We report a significant association of three HTR2C SNPs (rs498207, rs3813928 and rs3813929) and of the respective haplotype with antipsychotic-induced BWG. Regarding the X-chromosomal SNP rs498207, individuals with AA/A genotype gained more weight than those with GG/G genotype. The association observed with the SNP rs498207 was also significant after correcting for multiple testing (p = 0.0196). No association was found for INSIG2 and LEP SNPs.


CONCLUSIONS
The results contribute to the accumulating evidence for an association of the X-chromosomal HTR2C gene with antipsychotic-induced BWG. The proposed underlying mechanisms include decreased HTR2C gene expression with reduced 5-HT-modulated activation of hypothalamic proopiomelanocortin-neurons, and inverse 5-HT(2C) agonism in the presence of D(2) receptor antagonism.
Opgen-Rhein
Carolin
C
Department of Psychiatry & Psychotherapy, Charité University Medicine Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany. carolin.opgen-rhein@charite.de
Brandl
Eva Janina
EJ
Müller
Daniel J
DJ
Neuhaus
Andres H
AH
Tiwari
Arun K
AK
Sander
Thomas
T
Dettling
Michael
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D005260:Female; D050172:Genes, X-Linked; D005838:Genotype; D005858:Germany; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D020738:Leptin / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*; D012189:Retrospective Studies; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics; D015430:Weight Gain / Q000187:drug effects* / Q000235:genetics; D055815:Young Adult
D014150:Antipsychotic Agents; C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D008565:Membrane Proteins; D044405:Receptor, Serotonin, 5-HT2C