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Topiramate's reduction of body mass index in heavy drinkers: lack of moderation by a GRIK1 polymorphism.

ABSTRACT: Topiramate, which interacts with multiple neurotransmitter and enzyme systems, is approved by the Food and Drug Administration to treat seizure disorder, prevent migraine, and (in combination with phentermine) reduce weight. Topiramate has also been shown in multiple studies to reduce heavy drinking. The authors found that topiramate 200 mg/day significantly reduced heavy drinking in heavy drinkers with a treatment goal of reduced drinking (Kranzler et al., 2014). Further, in the European American (EA) subsample (n = 122), a single nucleotide polymorphism (rs2832407) in GRIK1, which encodes the GluK1 subunit of the kainate receptor, moderated the effect on heavy drinking days. Here the authors examined the effects of topiramate on body mass index (BMI) and the moderating effect of rs2832407 in the EA subsample from Kranzler et al. (2014). Across the 12 weeks of treatment, BMI was reduced by 1.2 kg/m2 (p < .001) in the topiramate group but was unchanged in the placebo group. There was no evidence of moderation by rs2832407 of topiramate's effects on BMI. Controlling for changes in drinking and other potential confounders did not alter the findings. These results suggest that the effect of topiramate on drinking behavior, in which the GluK1-containing kainate receptor appears to play a key role, can be dissociated from its effect on weight, the specific mechanism of which remains to be determined.

SUBMITTER: Kranzler HR

PROVIDER: S-EPMC4180772 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Topiramate's reduction of body mass index in heavy drinkers: lack of moderation by a GRIK1 polymorphism.

Kranzler Henry R HR Feinn Richard R Gelernter Joel J Pond Timothy T Covault Jonathan J

Experimental and clinical psychopharmacology 20140630 5

Topiramate, which interacts with multiple neurotransmitter and enzyme systems, is approved by the Food and Drug Administration to treat seizure disorder, prevent migraine, and (in combination with phentermine) reduce weight. Topiramate has also been shown in multiple studies to reduce heavy drinking. The authors found that topiramate 200 mg/day significantly reduced heavy drinking in heavy drinkers with a treatment goal of reduced drinking (Kranzler et al., 2014). Further, in the European Americ ...[more]

PMID: 24978347

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Project description:ImportanceBody mass index (BMI) is used to diagnose obesity in adolescents worldwide, despite evidence that weight does not scale with height squared in adolescents. To account for this, health care providers diagnose obesity using BMI percentiles for each age (BMI z scores), but this does not ensure that BMI is accurate in adolescents.ObjectiveTo compare the accuracy of BMI vs other body fat indices of the form body mass divided by heightn in estimating body fat levels in adolescents.Design, setting, and participantsCross-sectional data from the 1999 to 2006 US National Health and Nutrition Examination Survey were analyzed between September 2015 and December 2016.Main outcomes and measuresDual-energy x-ray absorptiometry and anthropometric data were used to determine changes in body fat levels, body proportions, and the scaling relationships among body mass, height, and percent body fat. To assess the merits of each adiposity index, 3 criteria were used: stability with age, accuracy in estimating percent body fat, and accuracy in classifying adolescents as overweight vs normal weight.ResultsParticipants included 2285 non-Hispanic white participants aged 8 to 29 years. Percent body fat varied with both age and height during adolescence, invalidating the standard weight-to-height regression as the way of finding the optimal body fat index. Because the correct regression model (percent body fat is proportional to mass divided by heightn) suggested that percent body fat scales to height with an exponent closer to 3, we therefore focused on the tri-ponderal mass index (TMI; mass divided by height cubed) as an alternative to BMI z scores. For ages 8 to 17 years, TMI yielded greater stability with age and estimated percent body fat better than BMI (R2?=?0.64 vs 0.38 in boys and R2?=?0.72 vs 0.66 in girls). Moreover, TMI misclassified adolescents as overweight vs normal weight less often than BMI z scores (TMI, 8.4%; 95% CI, 7.3%-9.5% vs BMI, 19.4%; 95% CI, 17.8%-20.0%; P?<?.001) and performed equally as well as updated BMI percentiles derived from the same data set (TMI, 8.4%; 95% CI, 7.3%-9.5% vs BMI, 8.0%; 95% CI, 6.9%-9.1%; P?=?.62).Conclusions and relevanceThe tri-ponderal mass index estimates body fat levels more accurately than BMI in non-Hispanic white adolescents aged 8 to 17 years. Moreover, TMI diagnoses adolescents as overweight more accurately than BMI z scores and equally as well as updated BMI percentiles but is much simpler to use than either because it does not involve complicated percentiles. Taken together, it is worth considering replacing BMI z scores with TMI to estimate body fat levels in adolescents.

Project description:Background: Alcohol-associated liver disease (ALD) is the most common disorder of prolonged drinking. Mechanisms underlying cirrhosis in such patients remain unclear. MicroRNAs play regulatory role in several diseases, are affected by alcohol and may be important players in alcohol use disorders, such as cirrhosis. Methods: We investigated serum samples from heavy chronic alcohol users (80 g/day (male) and 50 g/day (female) for ≥10 years) that were available from our previously reported GenomALC study. A subset of GenomALC drinkers with liver cirrhosis (cases, n = 24) and those without significant liver disease (drinking controls, n = 23) were included. Global microRNA profiling was performed using high-throughput real-time quantitative PCR to identify the microRNA signatures associated with cirrhosis. Ingenuity Pathway Analysis (IPA) software was utilized to identify target mRNAs of significantly altered microRNAs, and molecular pathways were analysed. Identified microRNAs were analysed for correlation with traditional liver disease biomarkers and risk gene variants previously reported from GenomALC genome-wide association study. Results: The expression of 21 microRNAs was significantly downregulated in cases compared to drinking controls (p < 0.05, ∆∆Ct > 1.5-fold). Seven microRNAs (miR-16, miR-19a, miR-27a, miR-29b, miR-101, miR-130a, and miR-191) had a highly significant correlation (p < 0.001) with INR, bilirubin and MELD score. Three microRNAs (miR-27a, miR-130a and miR-191) significantly predicted cases with AUC-ROC 0.8, 0.78 and 0.85, respectively (p < 0.020); however, INR performed best (0.97, p < 0.001). A different set of six microRNAs (miR-19a, miR-26a, miR-101, miR-151-3p, miR-221, and miR-301) showed positive correlation (ranging from 0.32 to 0.51, p < 0.05) with rs10433937:HSD17B13 gene variant, associated with the risk of cirrhosis. IPA analysis revealed mRNA targets of the significantly altered microRNAs associated with cell death/necrosis, fibrosis and increased steatosis, particularly triglyceride metabolism. Conclusions: MicroRNA signatures in drinkers distinguished those with liver cirrhosis from drinkers without liver disease. We identified mRNA targets in liver functions that were enriched for disease pathogenesis pathways.

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Topiramate's reduction of body mass index in heavy drinkers: lack of moderation by a GRIK1 polymorphism.

Publications

Topiramate's reduction of body mass index in heavy drinkers: lack of moderation by a GRIK1 polymorphism.

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