Favourable Adiposity’ Genes Provide Evidence that some People Are Fat on The Outside but Thin on The Inside - European Medical Journal
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Favourable Adiposity’ Genes Provide Evidence that some People Are Fat on The Outside but Thin on The Inside

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2 Mins
Authors:
*Hanieh Yaghootkar, Yingjie Ji, Jessica Tyrrell, Samuel E. Jones, Robin Beaumont, Marcus A. Tuke, Katherine S. Ruth, Rachel M. Freathy, Andrew R. Wood, Anna Murray, Michael N. Weedon, Timothy M. Frayling
Disclosure:

This research has been conducted using the UK Biobank Resource and was carried out under UK Biobank project numbers 9072 and 9055. Hanieh Yaghootkar is an RD Lawrence Fellow funded by Diabetes UK. This work was supported by EFSD/ Novo Nordisk. Andrew R. Wood and Timothy M. Frayling are supported by the European Research Council grant 323195:GLUCOSEGENESFP7-IDEAS-ERC. Rachel M. Freathy is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant 104150/Z/14/Z). Robin Beaumont is funded by the Wellcome Trust and Royal Society grant 104150/Z/14/Z. Jessica Tyrrell is funded by the European Regional Development Fund and a Diabetes Research and Wellness Foundation Fellowship. Samuel E. Jones is funded by the Medical Research Council (grant: MR/M005070/1). Marcus A. Tuke, Michael N. Weedon, and Anna Murray are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF) (323195). The other authors have declared no conflicts of interest. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Citation
EMJ Diabet. ;5[1]:78-80. Abstract Review No. AR6.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

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Higher BMI is associated with an adverse metabolic effect and a higher risk of Type 2 diabetes mellitus (T2DM), heart disease, and hypertension. However, there are some obese individuals who will not develop T2DM throughout their lives. Age, sex, ethnicity, and physical activity are factors that make two people of the same BMI have different risks of T2DM. Another important factor is genetics; recent genetic studies have identified seven genetic variants associated with ‘favourable adiposity’, which refers to alleles associated with higher body fat percentage but lower risk of T2DM, hypertension, and heart disease.1-4 Examples of these variants are in PPARG and IRS1. We aimed to identify more of these genetic variants and use genetics to understand the underlying mechanism of favourable adiposity.

We designed a three-step study to identify genetic variants associated with ‘favourable adiposity’. First, we used data from the UK Biobank, a single cohort of 500,000 men and women. These individuals were sourced from different study centres within the UK and were aged between 40 and 69 years at baseline. We identified genetic variants associated with adiposity (as measured by body fat percentage using a Tanita analyser). Secondly, we tested genetic variants associated with adiposity against a multivariate metabolic outcome using data from published genome-wide association studies (GWAS). We identified favourable adiposity variants as those with a favourable effect on metabolic biomarkers; alleles associated with higher adiposity are associated with higher high density lipoprotein cholesterol (n=99,900),5 higher adiponectin (n=29,400),6 higher sex hormone binding globulin (n=21,800),7 lower triglycerides (n=96,600),5 lower fasting insulin (n=51,800),8 and lower alanine transaminase (n=55,500).9 We used data from the UK Biobank to find the impact of favourable adiposity on metabolic diseases and used the published GWAS of subcutaneous and visceral fat distribution, as measured by computed tomography (CT) or magnetic resonance imaging (MRI),10 to understand the underlying mechanism.

We identified 15 genetic variants associated with ‘favourable adiposity’, including seven known variants in or near PPARG, LYPLAL1, GRB14, IRS1, PEPD, FAM13A, and ANKRD55. Carrying additional ‘favourable adiposity’ alleles was associated with a higher BMI (n=382,902), but a lower risk of T2DM (12,333 cases versus 370,112 controls), a lower risk of hypertension (79,586 cases versus 307,602 controls), and a lower risk of heart disease (32,105 cases versus 275,037 controls). These effects were similar when we removed the seven known ‘favourable adiposity’ variants from the analysis. Carrying more ‘favourable adiposity’ alleles was associated with a favourable body shape in women (associated with a lower waist but a higher hip circumference). However, in men, ‘favourable adiposity’ alleles were associated with fat all over the body (associated with a higher hip and waist circumference). ‘Favourable adiposity’ alleles were associated with higher levels of subcutaneous adipose tissue and a lower visceral-to-subcutaneous adipose tissue ratio in both men and women. The p-values in all the analyses were <1×10-10.

Our genetic study suggests that the underlying mechanism is through better ability to store fat in a suitable location within the body (subcutaneous adipose tissue).

References
Yaghootkar H et al. Genetic evidence for a link between favorable adiposity and lower risk of type 2 diabetes, hypertension, and heart disease. Diabetes. 2016;65(8):2448-60. Yaghootkar H et al. Genetic evidence for a normal-weight “metabolically obese” phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes. Diabetes. 2014;63(12):4369-77. Scott RA et al. Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity. Diabetes. 2014;63(12):4378-87. Kilpeläinen TO et al. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nat Genet. 2011;43(8):753-60. Teslovich TM et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466(7307):707-13. Dastani Z et al. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic meta-analysis of 45,891 individuals. PLoS Genet. 2012;8(3):e1002607. Coviello AD et al. A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. PLoS Genet. 2012;8(7):e1002805. Manning AK et al. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat Genet. 2012;44(6):659-69. Chambers JC et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet. 2011;43(11):1131-8. Chu AY et al. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation. Nat Genet. 2017;49(1):125-30.