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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*
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: [email protected]

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.

Type
Research Article
Copyright
Copyright © 2009 John Wiley & Sons A/S

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