Genetic analysis of the estrogen-related receptor α and studies of association with obesity and type 2 diabetes

Larsen, Lesli H.; Rose, Christian Schack; Sparsø, Thomas; Overgaard, Jesper; Torekov, Signe S.; Grarup, Niels; Jensen, D. P.; Albrechtsen, Anders; Andersen, Gitte; Ek, Jakob; Glümer, Charlotte; Borch‐Johnsen, Knut; Jørgensen, Torben; Hansen, Torben; Pedersen, Oluf

doi:10.1038/sj.ijo.0803408

Cited by 21 publications

(13 citation statements)

References 19 publications

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“…However, in the present study, no association between the phenotypes of T2D, such as BMI, was found. Our data also showed that there were three common variants (rs731703, rs650008, rs11600990) in ESRRA in Han Chinese populations, while only one common variant rs11600990 was found in Danish populations [28]. The analysis of rs11600990 in the two populations is consistent.…”

Section: Discussionsupporting

confidence: 76%

Association of Polymorphisms in Mitofusin-2 Gene with Type 2 Diabetes in Han Chinese

Zhu

et al. 2012

Journal of Biomedicine and Biotechnology

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MFN2 and ESRRA are candidate genes involved in the pathogenesis of T2D. Five tag-SNPs in MFN2 gene and three in ESRRA gene were selected and genotyped with TaqMan or PCR-RFLP method in stage 1 populations (555 patients with T2D and 649 control subjects) and stage 2 populations (546 patients with T2D versus 419 control subjects) in Han Chinese. And combining our published data, we estimated the interactions between genetic variants in the MFN2, ESRRA, and PGC-1α genes on the T2D risk using MDR. rs873458 (G > A) and rs2878677 (C > T) in MFN2 gene were significantly associated with T2D (P = 0.005 and 0.01) in stage 1 populations, and the association of other SNPs with T2D was not found. In stage 2 populations, we further confirmed the association between rs2878677 and T2D (P = 0.01). Combining the two stage populations, the data supported more significant effect of rs873458 and rs2878677 on T2D risk (P = 0.003 and 0.0001). A-C-G-T-C and G-T-C-T-C in MFN2 had significant association with T2D (P = 0.007 and 0.009). The present study also provided the evidence that MFN2 had interactions with PGC-1α (P < 0.0001) or ESRRA (P < 0.0001). This study suggested a role of MFN2 polymorphism in the risk of T2D; however, further studies are needed.

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Section: Discussionsupporting

confidence: 76%

Association of Polymorphisms in Mitofusin-2 Gene with Type 2 Diabetes in Han Chinese

Zhu

et al. 2012

Journal of Biomedicine and Biotechnology

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“…(2) Gene-gene and gene-environment interactions could not be addressed in this meta-analysis. Actually, obesity is a complex trait, and many genes are related to obesity [61], such as MC4R [50,62,63], MAF [50], and NPC1 [50]. On the other hand, lifestyle factors, including diet and physical inactivity, are important contributors to weight gain and obesity [64-66] (3) It may be unreliable to use Begg's and Egger's test as the criteria for publication bias.…”

Section: Discussionmentioning

confidence: 99%

FTO gene polymorphisms and obesity risk: a meta-analysis

Peng

Zhu

et al. 2011

BMC Med

176

146

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BackgroundThe pathogenesis of obesity is reportedly related to variations in the fat mass and an obesity-associated gene (FTO); however, as the number of reports increases, particularly with respect to varying ethnicities, there is a need to determine more precisely the effect sizes in each ethnic group. In addition, some reports have claimed ethnic-specific associations with alternative SNPs, and to that end there has been a degree of confusion.MethodsWe searched PubMed, MEDLINE, Web of Science, EMBASE, and BIOSIS Preview to identify studies investigating the associations between the five polymorphisms and obesity risk. Individual study odds ratios (OR) and their 95% confidence intervals (CI) were estimated using per-allele comparison. Summary ORs were estimated using a random effects model.ResultsWe identified 59 eligible case-control studies in 27 articles, investigating 41,734 obesity cases and 69,837 healthy controls. Significant associations were detected between obesity risk and the five polymorphisms: rs9939609 (OR: 1.31, 95% CI: 1.26 to 1.36), rs1421085 (OR: 1.43, 95% CI: 1.33 to 1.53), rs8050136 (OR: 1.25, 95% CI: 1.13 to 1.38), rs17817449 (OR: 1.54, 95% CI: 1.41 to 1.68), and rs1121980 (OR: 1.34, 95% CI: 1.10 to 1.62). Begg's and Egger's tests provided no evidence of publication bias for the polymorphisms except rs1121980. There is evidence of higher heterogeneity, with I2 test values ranging from 38.1% to 84.5%.ConclusionsThis meta-analysis suggests that FTO may represent a low-penetrance susceptible gene for obesity risk. Individual studies with large sample size are needed to further evaluate the associations between the polymorphisms and obesity risk in various ethnic populations.

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“…Furthermore, genetic and functional analysis and biochemistry studies have demonstrated that ERRα plays a critical role in regulating many important physiological functions (Giguère, 2008), including energy metabolism (Villena & Kralli, 2008) by controlling the transcriptional functions or protein expression of key components involved in tricarboxylic acid metabolism (Pedram, Razandi, Blumberg, & Levin, 2015), oxidative phosphorylation (Eichner & Giguère, 2011) and glycolysis (Jhuang et al, 2015). Therefore, ERRα might be treated as a potential therapeutic target to find small molecule agonists for the treatment of metabolic disorders such as type 2 diabetes and obesity (Larsen et al, 2007). However, very few ERRα agonists have been found likely due to the tiny ligand binding pocket (Kallen et al, 2004).…”

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confidence: 99%

Computational insights into the interaction mechanisms of estrogen‐related receptor alpha with endogenous ligand cholesterol

Cai

Teng

et al. 2019

Chem Biol Drug Des

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Estrogen‐related receptor alpha (ERRα) has attracted increasing concerns. ERRα, orphan nuclear receptor, plays important roles in energy metabolism. Therefore, small molecule agonists of ERRα could be a potential therapeutic strategy in the treatment of metabolic diseases such as diabetes. Recently, Wei et al. identified cholesterol as the endogenous agonist of ERRα. However, the detailed molecular mechanism of cholesterol bound with ERRα remains ambiguous. Thus, in this study molecular docking and molecular dynamics (MD) simulations were performed to characterize how cholesterol affects the behavior of ERRα. Based on the results, we found that a proven residue Phe232 and others including Leu228, Glu235, Arg276, and Phe399 were key residues to ligand binding. A hydrogen‐bonding interaction between cholesterol and Glu235 ensured the orientation of the ligand in the binding pocket, while hydrophobic interactions between cholesterol and the above‐mentioned residues promoted the stability of ERRα‐cholesterol complex. In the presence of the proliferator‐activated receptor γ coactivator 1α (PGC‐1α), the cholesterol‐ERRα interaction became more stable. Interestingly, we observed that cholesterol facilitated the binding of ERRα with its coactivator PGC‐1α via stabilizing the conformation of helix 12 and the interaction surface of ERRα/PGC‐1α. Overall, these findings would be valuable for the future rational design of novel ERRα agonists.

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Genetic analysis of the estrogen-related receptor α and studies of association with obesity and type 2 diabetes

Cited by 21 publications

References 19 publications

Association of Polymorphisms in Mitofusin-2 Gene with Type 2 Diabetes in Han Chinese

Association of Polymorphisms in Mitofusin-2 Gene with Type 2 Diabetes in Han Chinese

FTO gene polymorphisms and obesity risk: a meta-analysis

Computational insights into the interaction mechanisms of estrogen‐related receptor alpha with endogenous ligand cholesterol

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