The role of genetic variation across IL-1β, IL-2, IL-6, and BDNF in antipsychotic-induced weight gain

Abstract

Objectives. Antipsychotics with high weight gain-inducing propensities influence the expression of immune and neurotrophin genes, which have been independently related to obesity indices. Thus, we investigated whether variants in the genes encoding interleukin (IL)-1β, IL-2, and IL-6 and brain-derived neurotrophic factor (BDNF) Val66Met are associated with antipsychotic-induced weight gain (AIWG). Methods. Nineteen polymorphisms were genotyped using Taqman^® assays in 188 schizophrenia patients on antipsychotic treatment for up to 14 weeks. Mean weight change (%) from baseline was compared across genotypic groups using analysis of covariance (ANCOVA). Epistatic effects between cytokine polymorphisms and BDNF Val66Met were tested using Model-Based Multifactor Dimensionality Reduction. Results. In European patients, IL-1β rs16944*GA (P = 0.013, P_corrected = 0.182), IL-1β rs1143634*G (P = 0.001, P_corrected = 0.014), and BDNF Val66Met (Val/Val, P = 0.004, P_corrected = 0.056) were associated with greater AIWG, as were IL-1β rs4849127*A (P = 0.049, P_corrected = 0.784), and IL-1β rs16944*GA (P = 0.012, P_corrected = 0.192) in African Americans. BDNF Val66Met interacted with both IL-1β rs13032029 (Val/Met+ TT, P_Perm = 0.029), and IL-6 rs2069837 (Val/Val+ AA, P_Perm = 0.021) in Europeans, in addition to IL-1β rs16944 (Val/Val+ GA, P_Perm = 0.006) in African Americans. Conclusions. SNPs across IL-1β and BDNF Val66Met may influence AIWG. Replication of these findings in larger, independent samples is warranted.

Key words::

• IL-1 β
• BDNF
• cytokine
• genetics
• antipsychotic-induced weight gain

Acknowledgements

The authors would like to thank the participants of this study. We have no acknowledgements of assistance to disclose. TMF is a recipient of a Canadian Institutes of Health Research (CIHR) 2012 Frederick Banting and Charles Best Masters Award. AKT is a recipient of a NARSAD 2010 Young Investigator Award. JLK is a recipient of a CIHR operating grant. SHK has received grant/research support from: Lundbeck, Ontario Brain Institute, CIHR, St. Jude Medical, Bristol-Myers Squibb and Clera Inc. DJM has received the following: CIHR operating grant (Genetics of Antipsychotics Induced Metabolic Syndrome, MOP 89853), Brain & Behaviour Research Foundation NARSAD Independent Investigator Award, CIHR Michael Smith New Investigator Salary Prize for Research in Schizophrenia, Early Researcher Award from the Ontario Ministry of Research and Innovation, and a New Investigator Fellowship from the Ontario Mental Health Foundation (OMHF). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of these organizations.

Statement of Interest

We confirm this manuscript describes original work that has not been published elsewhere and is not under consideration by another journal. JAL reports having received research funding or is a member of the advisory board of Allon, Alkermes Bioline, GlaxoSmithKline Intracellular Therapies, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Psychogenics, F. Hoffmann-La Roche LTD, Sepracor (Sunovion) and Targacept. JAL receives no direct financial compensation or salary support for participation in these research, consulting, or advisory board activities. HYM has received grants or is/was a consultant to: Abbott Labs, ACADIA, Alkemes, Bristol Myers Squibb, DaiNippon Sumitomo, Eli Lilly, EnVivo, Janssen, Otsuka, Pfizer, Roche, Sunovion, and BiolineRx. HYM is a shareholder of ACADIA and Glaxo Smith Kline. JLK has been a consultant to GSK, Sanofi-Aventis, and Dainippon-Sumitomo. SHK has received speaking fees from and/or is a member of an advisory board for: Eli Lilly, Lundbeck, Lundbeck Institute, Pfizer, Bristol Myers Squibb, Servier and Forest. BIG has received honoraria from Purdue Pharma, and travel support from BMS.