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Upstream genetic variant near INSIG2, influences response to carnitine supplementation in bipolar patients with valproate-induced weight gain

Published online by Cambridge University Press:  24 June 2014

K Doudney ,
JA Harley ,
JF Pearson ,
A Miller ,
A Aitchison ,
MA Kennedy ,
RJ Porter ,
JL Elmslie  and
PR Joyce
K Doudney*
Affiliation:
Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand
JA Harley
Affiliation:
Department of Psychological Medicine, University of Otago Christchurch, Christchurch, New Zealand
JF Pearson
Affiliation:
Department of Public Health and General Practice, University of Otago Christchurch, Christchurch, New Zealand
A Miller
Affiliation:
Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand
A Aitchison
Affiliation:
Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand
MA Kennedy
Affiliation:
Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand
RJ Porter
Affiliation:
Department of Psychological Medicine, University of Otago Christchurch, Christchurch, New Zealand
JL Elmslie
Affiliation:
Department of Psychological Medicine, University of Otago Christchurch, Christchurch, New Zealand
PR Joyce
Affiliation:
Department of Psychological Medicine, University of Otago Christchurch, Christchurch, New Zealand
*
Dr Kit Doudney, Department of Pathology, University of Otago Christchurch, PO Box 4345, Christchurch 8140, New Zealand. Tel: +64 3 378 6268; Fax: +64 3 364 0009; E-mail: kit.doudney@otago.ac.nz
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Abstract

Background:

The protein product of INSIG2 is involved in cholesterol and triglyceride metabolism and homeostasis. Variation at rs7566605 near the gene INSIG2 has been associated with increased BMI.

Objective:

To evaluate the effect of rs7566605/INSIG2 genotype on the ability of valproate-treated bipolar patients (BMI ≥ 25 kg/m2) to lose weight using carnitine supplementation during a 26-week lifestyle intervention study.

Design:

Forty-eight bipolar patients with clinically significant treatment emergent weight gain were genotyped at the rs7566605 SNP. Participants were randomised to l-carnitine (15 mg/kg/day) or placebo for 26 weeks in conjunction with a moderately energy restricted, low-fat diet. Weight and body fat percent were measured fortnightly. Waist circumference measurements and dual-energy X-ray absorptiometry were used to assess changes in body composition. Obesity-related biomarkers were measured at baseline and 26 weeks.

Results:

There was a significant interaction between rs7566605/INSIG2 genetic status and treatment with carnitine or placebo. Carnitine had no significant effect on body composition measures in G allele homozygous patients who lost between 0.97 and 2.23 kg of fat. However C allele carriers on average gained 2.28 kg when given a placebo. Carnitine supplementation in this group enabled average weight loss of 2.22 kg of fat (p = 0.01). Approximately half of this mass was in the vital truncal compartment (p = 0.002). Bioinformatic analysis detected that the SNP lies in a highly conserved 336 bp sequence which potentially affects INSIG2 gene expression.

Conclusions:

C-carriers at rs7566605, possibly regulating the homeostasis gene INSIG2, lost significantly less weight in this lifestyle intervention study. This effect was reversed by carnitine supplementation.

Keywords

carnitineINSIG2rs7566605valproateweight loss
Type
Research Article
Information
Acta Neuropsychiatrica , Volume 21 , Issue 3 , June 2009 , pp. 133 - 140
Copyright
Copyright © 2009 John Wiley & Sons A/S

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