Association of HTR2C, But Not LEP or INSIG2, Genes with Antipsychotic-Induced Weight Gain in a German Sample

Abstract

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. Aim: 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). Patients & 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 χ² 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. Conclusion: 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 D₂ receptor antagonism.

KEYWORDS::

• bodyweight gain
• HTR2C
• INSIG2
• leptin
• pharmacogenetics

Acknowledgements

The authors are grateful to all patients who agreed to participate in the study. The authors thank Emilie Bectas for DNA preparation.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.