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

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.