The role of common and rare MC4R variants and FTO polymorphisms in extreme form of obesity

Rovīte, Vita; Petrovska, Ramona; Vaivade, Iveta; Kalniņa, Ineta; Fridmanis, Dāvids; Zaharenko, Linda; Pečulis, Raitis; Pīrāgs, Valdis; Schiöth, Helgi B.; Kloviņš, Jānis

doi:10.1007/s11033-013-2994-4

Cited by 17 publications

(14 citation statements)

References 42 publications

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“…Analysis of the investigations of model animals shows that a MC4R block in mice leads to the development of the hyperphagia and hyperin sulinemia phenotype. Some investigators showed that SNPs of the MC4R gene are associated with quantita tive characteristics determining metabolic disorders and changes of anthropometric characteristics, as well as changes in feeding behavior [17].…”

Section: Introductionmentioning

confidence: 99%

Association of polymorphic variants of FTO and MC4R genes with obesity in a Tatar population

et al. 2014

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Obesity is a chronic relapsing disease that leads to numerous ailments and requires lifelong treat ment. Genetic predisposition is one of the mostly discussed aspects of obesity development, and genome wide association studies have provided evidence that several variants of the FTO and MC4R genes are signif icantly associated with obesity. In this study the association of FTO (rs9939609, rs7202116, and rs9930506) and MC4R (rs12970134 and rs17782313) genes' SNPs with obesity in Tatar women has been analyzed. In the investigation 340 women with obesity (Body Mass Index (BMI) ≥ 30 kg/m 2 ) and 330 women from a control group (BMI up to 24.9 kg/m 2 ) took part. The FTO rs9939609 (p = 0.0002) and rs9930506 (p = 0.0005) SNPs were shown to be associated with obesity risk following an additive model, while the MC4R rs12970134 (p = 0.0076) and rs1778231 (p = 0.021) SNPs were associated by a recessive model. We also showed an association of quantitative parameters (age, weight, and BMI) with two the FTO rs9939609 and rs9930506 SNPs and the association of age and the MC4R rs12970134 SNP. Our study demonstrates the role of genetic variability in FTO and MC4R genes in obesity development in Tatar women from Russia.

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Section: Introductionmentioning

confidence: 99%

Association of polymorphic variants of FTO and MC4R genes with obesity in a Tatar population

et al. 2014

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“…Variations in the coding regions of melanocortin receptors have been associated with a number of medically important diseases and traits that result from dysregulated energy metabolism. For example, inactivating mutations of the melanocortin-2 receptor (MC2R) or melanocortin receptor accessory protein (MRAP) are known to cause familial glucocorticoid deficiency (3,4), and mutations in melanocortin-4 receptor (MC4R) are responsible for 1% to 5% of early-onset human obesity (5)(6)(7)(8)(9)(10). Like MC4R, melanocortin-3 receptor (MC3R) has been found to play a role in energy balance.…”

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confidence: 99%

Melanocortin 3 Receptor Has a 5′ Exon That Directs Translation of Apically Localized Protein From the Second In-Frame ATG

Park

Sharma

Cutting

2014

Molecular Endocrinology

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Melanocortin-3 receptor (MC3R) is a canonical MSH receptor that plays an essential role in energy homeostasis. Variants in MC3R have been implicated in obesity in humans and mice. However, interpretation of the functional consequences of these variants is challenging because the translational start site of MC3R is unclear. Using 5' rapid amplification of cDNA ends, we discovered a novel upstream exon that extends the length of the 5' untranslated region (UTR) in MC3R without changing the open-reading frame. The full-length 5' UTR directs utilization of an evolutionarily conserved second in-frame ATG as the primary translation start site. MC3R synthesized from the second ATG is localized to apical membranes of polarized Madin-Darby canine kidney cells, consistent with its function as a cell surface mediator of melanocortin signaling. Expression of MC3R causes relocalization of melanocortin receptor accessory protein 2, an accessory factor for melanocortin-2 receptor, to the apical membrane, coincident with the location of MC3R. In contrast, protein synthesized from MC3R cDNAs lacking the 5' UTR displayed diffuse cytosolic distribution and has no effect on the distribution of melanocortin receptor accessory protein 2. Our findings demonstrate that a previously unannotated 5' exon directs translation of MC3R protein that localizes to apical membranes of polarized cells. Together, our work provides insight on the structure of human MC3R and reveals a new pathway for regulation of energy metabolism.

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“…Breakdown analysis by the BMI categories (14) was then conducted. However, no significant associations were found under the stringent Bonferroni's correction (Table III).…”

Section: Resultsmentioning

confidence: 99%

“…Meta-analysis plot for the association between fat mass and obesity-associated gene rs11642015 and obesity. data from two previous publications (10,14). A meta-analysis suggested that the association between FTO rs11642015 and obesity under the additive model was not significant with high heterogeneity (OR, 1.15; 95% CI, 0.92-1.44; P= 0.21; P heterogeneity = 0.03; I 2 =70.6%; Fig.…”

Section: Or (95% Ci) or (95% Ci) Fto --------------------------------mentioning

confidence: 91%

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Fat mass and obesity-associated gene rs11642015 polymorphism is significantly associated with prediabetes and type 2 diabetes subsequent to adjustment for body mass index

et al. 2014

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The association of the fat mass and obesity-associated gene () rs11642015 polymorphism with prediabetes, type 2 diabetes and obesity in certain populations has not been previously reported. A population-based study was conducted that included 490 type 2 diabetic, 471 prediabetic and 575 normal subjects. The main outcomes of the study were prediabetes, type 2 diabetes and obesity. Binary logistic regression was performed to estimate the association of rs11642015 with the risk of prediabetes, type 2 diabetes and obesity following adjustment for the corresponding confounders. A meta-analysis was also conducted to evaluate the association between rs11642015 and obesity. rs11642015 was significantly associated with prediabetes in the whole sample under the additive model [odds ratio (OR), 1.50; 95% confidence interval (CI), 1.17-1.93; P=0.002], particularly in females. The polymorphism remained consistently significant following adjustment for age and body mass index (BMI), showing an increased prediabetes risk with an additive effect (OR, 1.55; 95% CI, 1.19-2.01; P=0.001). In addition, a significant association was found for rs11642015 with prediabetes and type 2 diabetes under the dominant model. However, under the stringent Bonferroni's correction there was no evidence of positive associations for rs11642015 with obesity in the whole sample, females or males. Findings of the meta-analysis showed that rs11642015 was not predisposed to obesity. In conclusion, the T allele of rs11642015 is positively associated with an increased risk of prediabetes, even after adjustment for age and BMI, particularly in females. Subjects carrying the CT + TT genotype are predisposed to prediabetes and type 2 diabetes. Therefore, results of the population-based study and follow-up meta-analysis suggested that rs11642015 is not significantly associated with susceptibility to obesity.

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The role of common and rare MC4R variants and FTO polymorphisms in extreme form of obesity

Cited by 17 publications

References 42 publications

Association of polymorphic variants of FTO and MC4R genes with obesity in a Tatar population

Association of polymorphic variants of FTO and MC4R genes with obesity in a Tatar population

Melanocortin 3 Receptor Has a 5′ Exon That Directs Translation of Apically Localized Protein From the Second In-Frame ATG

Fat mass and obesity-associated gene rs11642015 polymorphism is significantly associated with prediabetes and type 2 diabetes subsequent to adjustment for body mass index

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