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Genetic determinants of common obesity and their value in prediction

MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Best Practice & Research: Clinical Endocrinology & Metabolism (Impact Factor: 4.91). 04/2012; 26(2):211-26. DOI: 10.1016/j.beem.2011.11.003
Source: PubMed

ABSTRACT Genome-wide association studies (GWAS) have revolutionised the discovery of genes for common traits and diseases, including obesity-related traits. In less then four years time, 52 genetic loci were identified to be unequivocally associated with obesity-related traits. This vast success raised hope and expectations that genetic information would become soon an integral part of personalised medicine. However, these loci have only small effects on obesity-susceptibility and explain just a fraction of the total variance. As such, their accuracy to predict obesity is poor and not competitive with the predictive ability of traditional risk factors. Nevertheless, some of these loci are being used in commercially available personal genome tests to estimate individuals' lifetime risk of obesity. While proponents believe that personal genome profiling could have beneficial effects on behaviour, early reports do not support this hypothesis. To conclude, the most valuable contribution of GWAS-identified loci lies in their contribution to elucidating new physiological pathways that underlie obesity-susceptibility.

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    • "Recent fruitful genomewide association studies (GWAS) have identified a large number of genetic variants contributing to obesity (Loos, 2012). However, a majority of these loci have only a small effect on obesity susceptibility and explain just a fraction of total variance (Loos, 2012). There is growing evidence suggesting that epigenetics, a plastic and heritable (during cell division) mechanism to record cues from external and internal environments (Petronis, 2010) may play an important role in obesity (Drong et al., 2012; Feinberg et al., 2010; Wang et al., 2010). "
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    ABSTRACT: Background: Previous genome-wide association studies (GWAS) have identified a large number of genetic variants for obesity and its related traits, representing a group of potential key genes in the etiology of obesity. Emerging evidence suggests that epigenetics may play an important role in obesity. It has not been explored whether the GWAS-identified loci contribute to obesity through epigenetics (e.g., DNA (deoxyribonucleic acid) methylation) in addition to genetics. Method: A multi-stage cross-sectional study was designed. We did a literature search and identified 117 genes discovered by GWAS for obesity and its related traits. Then we analyzed whether the methylation levels of these genes were also associated with obesity in two genome-wide methylation panels. We examined an initial panel of seven adolescent obese cases and seven age-matched lean controls, followed by a second panel of 48 adolescent obese cases and 48 age- and gender-matched lean controls. The validated CpG sites were further replicated in two independent replication panels of youth (46 vs. 46 and 230 cases vs. 413 controls, respectively) and a general population of youth, including 703 healthy subjects. Results: One CpG site in the lymphocyte antigen 86 (LY86) gene, which showed higher methylation in the obese in both the initial (p = .009) and second genome-wide DNA methylation panel (p = .008), was further validated in both replication panels (meta p = .00016). Moreover, in the general population of youth, the methylation levels of this region were significantly correlated with adiposity indices (p ≤ .02), insulin resistance (p = .001), and inflammatory markers (p < .001). Conclusion: By focusing on recent GWAS findings in genome-wide methylation profiles, we identified a solid association between LY86 gene DNA methylation and obesity.
    Twin Research and Human Genetics 04/2014; 17(3):1-9. DOI:10.1017/thg.2014.22 · 1.92 Impact Factor
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    • "The lack of diet-induced weight-loss intervention studies and GHRL gene polymorphisms limits the comparison with our study. Candidate gene and genome-wide linkage approaches are used for more than 15 years in the search for genes related to obesity (Loos, 2012). Such studies are useful for identifying the possible genes or related polymorphisms . "
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    ABSTRACT: The individual response to diet may be influenced by gene polymorphisms. This study hypothesized that ADRB2 (Gln27Glu, rs1042714 and Arg16Gly, rs1042713), ADRB3 (Trp64Arg, rs4994) and GHRL (Leu72Met, rs696217) polymorphisms moderate weight loss. The study was a seven weeks dietary weight loss intervention with Brazilian adult obese women (n = 109). The body mass index (BMI) was calculated and polymorphisms in these genes were assessed by real-time PCR assays. Two-way repeated-measures ANOVA (2 × 2) were used to analyze the intervention effect between polymorphisms and BMI over the period and after stratification for age and socioeconomic status (SES). The weight loss intervention resulted in decreased BMI over the seven-week period (p < 0.001), for high and low SES (p < 0.05) and mainly for participants with 30-49 y. The intervention did not result in a statistically significant difference in weight loss between polymorphism carriers and non-carriers, and although, the ADRB2, ADRB3 and GHRL polymorphisms did not moderate weight loss, the Gln27Glu polymorphism carriers showed a lower BMI compared to non-carriers in the low SES (p = 0.018) and the 30-39 y (p = 0.036) groups, suggesting a role for this polymorphism related to BMI control.
    Genetics and Molecular Biology 03/2014; 37(1):15-22. DOI:10.1590/S1415-47572014000100005 · 0.88 Impact Factor
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    • "We also found altered mRNA expression in response to exercise for some of the proposed candidate genes for T2D (Morris et al. 2012), with the largest difference in fold change observed for CDC123 (19% increase), whereas IGF2BP2 and HHEX both decreased by 16% (Table S2). Our results also include candidate genes for obesity (Loos 2012), for example the mRNA expression of TMEM18 increased by 25% and that of CADM2 decreased by 19% in response to exercise. "
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    ABSTRACT: Adipose tissue has an important function in total energy homeostasis and its dysregulation may contribute to life-style related diseases such as type 2 diabetes, cancer and cardiovascular diseases. The aim of this study was to investigate genome-wide mRNA expression in adipose tissue in healthy men before and after an exercise intervention to identify genes or pathways that mediate the beneficial effect of regular exercise. We also investigated the difference in adipose tissue mRNA expression between individuals with or without a family history of type 2 diabetes. The six months supervised exercise intervention was conducted in 47 healthy men (age 37.8±4.3 years, BMI 28.5±3.6 kg/m(2) ) with a previous low level of physical activity. RNA was analysed using GeneChip Human Gene 1.0 ST arrays (Affymetrix) before and after the exercise. We identified 2,560 significant transcripts differentially expressed before versus after exercise (FDR<0.1%), including genes encoding the respiratory chain, histone subunits, small nucleolar RNAs and ribosomal proteins. Additionally, pathways enriched in response to exercise include the ribosome, oxidative phosphorylation, proteasome and many metabolic pathways, whereas the WNT and MAPK signalling pathways were down-regulated (FDR<5%) after exercise. There were no significant differences in mRNA expression between individuals with or without a family history of type 2 diabetes. Exercise increased the expression of genes involved in oxidative phosphorylation, which is the opposite of what has been seen in adipose tissue from elderly or obese individuals with low physical fitness, and our study thereby demonstrates a mechanism for the beneficial effect of exercise. This article is protected by copyright. All rights reserved.
    Acta Physiologica 02/2014; DOI:10.1111/apha.12247 · 4.25 Impact Factor
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