Carrying more favourable adiposity gene7c factors is associated with higher adiposity but lower ectopic fat and lower risk of type 2 diabetes.
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1 Carrying more favourable adiposity gene7c factors is associated with higher adiposity but lower ectopic fat and lower risk of type 2 diabetes. Hanieh Yaghootkar 15 March 2018 Diabetes UK - London
2 Who has type 2 diabetes? Mr. LeO Age: 62 Non-smoker Ac7vity: 3/10 Ethnicity: White Bri7sh BMI: 28 Mr. Right Age: 62 Non-smoker Ac7vity: 3/10 Ethnicity: White Bri7sh BMI: 26
3 Who has type 2 diabetes? Mr. LeO Age: 62 Non-smoker Ac7vity: 3/10 Ethnicity: White Bri7sh BMI: 28 Mr. Right Age: 62 Non-smoker Ac7vity: 3/10 Ethnicity: White Bri7sh BMI: 26 Normal lipid levels No Insulin resistance No Type 2 diabetes No Heart disease No Hypertension Dyslipidemia Insulin resistance Type 2 diabetes Heart disease Hypertension
4 Are gene7c factors involved in difference between Mr LeO and Mr Right?
5 There are known gene7c variants associated with opposite effects on adiposity and type 2 diabetes. Polygenic lipodystrophy Unfavourable adiposity Favourable adiposity FTO variant PPARG variant Body fat % Body fat % T/T A/T A/A Pro/Pro Pro/Ala Ala/Ala Type 2 diabetes Odds raio Type 2 diabetes Odds raio T/T A/T A/A Pro/Pro Pro/Ala Ala/Ala Data from UK Biobank
6 Favourable adiposity variants were associated with higher BMI BUT bexer insulin sensi7vity, lower risk of type 2 diabetes, heart disease and hypertension.
7 Sec7on 1 Can we find more variants associated with favourable adiposity to understand the underlying mechanism?
8 We aimed to iden7fy gene7c factors that increase body fat percentage with favourable metabolic effect. Step 1: Find geneic variants associated with body fat percentage. Step 2: IdenIfy geneic variants where the allele associated with higher adiposity is associated with favourable metabolic profile. Adverse metabolic effect Favourable metabolic effect Body fat%; Lu et al. Nature communica5ons (2016) Adiponec7n; Dastani et al. PLoS Genet (2012) SHBG; Coviello et al. PLoS Genet (2012) HDL-C; Teslovich et al. Nature (2010) Triglycerides; Teslovich et al. Nature (2010) Fas7ng insulin; Manning et al. Nature gene5cs (2012) Alanine transaminase; Chambers et al. Nature gene5cs (2011)
9 We characterized 14 gene7c variants associated with favourable adiposity. Nega7ve correla7on Posi7ve correla7on [DNAH10] VEGFA [] C6orf223 AEBP2 [] PDE3A LYPLAL1 [] SLC30A10 [FAM13A] [PEPD] CITED2 [] NYAP2 [] IRS1 GRB14 [] COBLL1 [PPARG] ANKRD55 [] MAP3K1 [MAFF] KLF14 [] MKLN1 TRIB1 [] [PPP1R2 [FTO] [ACMSD Favourable metabolic effect Body fat% AdiponecIn SHBG HDL-C Triglycerides FasIng insulin Alanine transaminase (ALT)
10 Sec7on 2 What is the impact of favourable adiposity on cardiometabolic diseases?
11 Favourable adiposity variants together were associated with higher adiposity but lower risk of type 2 diabetes, heart disease and hypertension. Effects Per 5+ alleles Body fat percentage (%) 6x x10-43 Type 2 diabetes (Odds ratio) Heart disease (Odds ratio) Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) x x x x x x x x10-12
12 Sec7on 3 What is the underlying mechanism of favourable adiposity?
13 The effect is NOT due to a favourable body shape in men. Data from UK Biobank Men 175,776 Women 207,126 Waist circumference Hip circumference Waist circumference Hip circumference
14 We inves7gated the associa7ons between the favourable adiposity variants and MRI/CT scan measures of abdominal adipose 7ssue. Visceral and subcutaneous fat (N = 27,766) Liver fat (N = 9,210) UK Biobank (N = 5045) UK Biobank (N = 5045) The Netherlands Epidemiology of Obesity Study (NEO) (N = 2236) The Netherlands Epidemiology of Obesity Study (NEO) (N = 1821) Tübingen Family Study for Type-2 Diabetes (TÜF) (N = 833) Tübingen Family Study for Type-2 Diabetes (TÜF) (N = 911) DIRECT (N = 1320) DIRECT (N = 1433) Published GWAS* (N = 18332) *Chu A. et al. MulIethnic genome-wide meta-analysis of ectopic fat depots idenifies loci associated with adipocyte development and differeniaion. Nature Gene5cs, 2016
15 The gene7c score of 14 favourable adiposity variants was associated with higher subcutaneous fat but lower liver fat. Subcutaneous fat (litre) VATSAT ra7o (ra7o) Liver fat (%)
16 Individual favourable adiposity variants have opposite effects on subcutaneous fat compared with liver fat and risk of type 2 diabetes. Effect on subcutaneous fat Effect on liver fat Effect on Type 2 diabetes FAM13A KLF14 LYPLAL1 GRB14 IRS1 MAFF AEBP2 PDE3A DNAH10 VEGFA TRIB1 CITED2 ANKRD55 PEPD PPARG AEBP2 PDE3A LYPLAL1 ANKRD55 FAM13A VEGFA PEPD MAFF KLF14 CITED2 DNAH10 IRS1 TRIB1 GRB14 PPARG AEBP2 PDE3A TRIB1 CITED2 VEGFA FAM13A ANKRD55 PEPDMAFF DNAH10 LYPLAL1 KLF14 IRS1 GRB14 PPARG Effect on body fat % Effect on body fat % Effect on body fat %
17 Summary There are 14 variants associated with favourable adiposity. The favourable adiposity geneic score is associated with higher adiposity but lower risk of type 2 diabetes, heart disease and hypertension. The mechanism seems to be through beaer ability to store fat in a safe place abdominal subcutaneous fat and less liver fat.
18 The favourable adiposity alleles provide evidence for adipose 7ssue expandability hypothesis. Mr. LeO + PosiIve energy balance Favourable adiposity gene7c factors - Mr. Right Subcutaneous obesity Healthy adipose Issue Visceral obesity DysfuncIonal adipose Issue No ectopic fat Lipid overflow-ectopic fat Low liver fat Low epicardial fat Low muscle fat High liver fat High epicardial fat High muscle fat Favourable higher BMI Unfavourable higher BMI Low risk of type 2 diabetes and heart disease High risk of type 2 diabetes and heart disease Adopted from Despres, Circula5on. 2012
19 Acknowledgements The GeneIcs of Complex Traits team at Exeter: Analysis of MRI image data of abdominal & liver fat: UK Biobank: Jimmy Bell, Alex Blakemore and Andrianos Yiorkas Robin Beaumont Tim Frayling Rachel Freathy James Harrison Yingjie Ji Sam Jones Anna Murray DIRECT study: Francesca Frau, Karla V. Allebrandt, Ewan Pearson NEO study: Dennis Mook-Kanamori, Renée de Mutsert, Kate Ruth Seth Sharp William Thompson Marcus Tuke Jessica Tyrrell Mike Weedon Andy Wood TÜF study: Norbert Stefan, Harald Staiger
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