Association of TMEM18 variants with BMI and waist circumference in children and correlation of mRNA expression in the PFC with body weight in rats

Abstract

Genome-wide association studies have shown a strong association of single-nucleotide polymorphisms (SNPs) in the near vicinity of the TMEM18 gene. The effects of the TMEM18-associated variants are more readily observed in children. TMEM18 encodes a 3TM protein, which locates to the nuclear membrane. The functional context of TMEM18 and the effects of its associated variants are as of yet undetermined. To further explore the effects of near-TMEM18 variants, we have genotyped two TMEM18-associated SNPs, rs6548238 and rs4854344, in a cohort of 2352 Greek children (Healthy Growth Study). Included in this study are data on anthropomorphic traits body weight, BMI z-score and waist circumference. Also included are dietary energy and macronutrient intake as measured via 24-h recall interviews. Major alleles of rs6548238 and rs4854344 were significantly associated with an increased risk of obesity (odds ratio¼1.489 (1.161-1.910) and 1.494 (1.165-1.917), respectively), and positively correlated to body weight (P¼0.017, P¼0.010) and waist circumference (P¼0.003, P¼0.003). An association to energy and macronutrient intake was not observed in this cohort. We also correlated food intake and body weight in a food choice model in rats to Tmem18 expression in central regions involved in feeding behavior. We observed a strong positive correlation between TMEM18 expression and body weight in the prefrontal cortex (PFC) (r¼0.5694, P¼0.0003) indicating a potential role for TMEM18 in higher functions related to feeding involving the PFC. Keywords: obesity; TMEM18; FTO INTRODUCTION Genome-wide association (GWA) studies have led to the identification of several loci in the human genome containing genetic variants conferring an increased risk of developing overweight and obesity. 1-2 One such gene to be associated with a higher BMI, the fat mass and obesity-associated gene (FTO) was identified by Frayling et al in 2007. 3 FTO has since been shown to be involved in regulation of feeding behavior via homeostatic hypothalamic pathways, 4-6 and its obesityassociated variants to confer gain-of-function by increasing gene transcription. 7 The most recent meta analyses of GWA studies on obesity, which included genetic information from 249 796 individuals, identified variants at a total of 32 genetic loci affecting the development of BMI. 2 Single-nucleotide polymorphisms (SNPs) in the FTO gene, followed by SNPs in the proximity of TMEM18 and MC4R, have consistently given the strongest associations to obesity in large-scale GWA studies. TMEM18-associated SNPs were first found to be associated with a higher BMI in 2009 by the GIANT consortium, 1 and this was confirmed in the same year by an independent group. 8 Results from child cohorts have shown stronger effects of near-TMEM18 SNPs to obesity, compared with adults. Zhao et al 9 found near-TMEM18 SNPs to confer the strongest effect on pediatric BMI out of 25 studied obesity-associated variants in a cohort of 6078

Validation of obesity susceptibility loci identified by genome‐wide association studies in early childhood in South Brazilian children

“…The associations reported herein were directionally consistent with results from GWAS: TMEM18 rs6548238 C‐allele , BDNF rs6265 G‐allele , rs10767664 A‐allele and NEGR1 rs2815752 A‐allele . Regarding BDNF , Zegers et al screened the coding region of the gene and did not find mutations associated with overweight or obesity in children and adolescents .…”

The role and possible mechanism of lncRNA AC092159.2 in modulating adipocyte differentiation

“…Moreover, the methylation levels of TMEM18 promoter were possibly associated with parameters of obesity and fat distribution (Rohde et al 2014). Similar to our study, mRNA expression of TMEM18 was reported to be well correlated with body weight in rats (Rask-Andersen et al 2012) and knockdown of TMEM18 resulted in an obvious reduction in triacylglycerol accumulation and adipocyte differentiation in HPA-v (Bernhard et al 2013). However, Rachel et al reported that loss of Tmem18 in male mice led to an increase in body weight, which was aggravated by high-fat diet and influenced by increased food intake.…”

Association of FTO gene with obesity in Polish schoolchildren

“…This result is much higher than the data for the European population (Frayling et al 2007) as well as for Polish children (OR at age 4-18 years=1.97, 95% CI 1.29-3.00, p=0.002) (Luczynski et al 2012). It seems that it may be related to the age of the studied subjects, as analyses, carried out in various populations, demonstrate that many of the genetic variant know to be associated with BMI have stronger role during childhood and adolescence than during adulthood (e.g., Hardy et al 2010;Graff et al 2012;Rask-Andersen et al 2012). According to the authors, during adulthood, the obesogenic environment may have a relatively higher influence on body weight than the genetic factors.…”