Genetic Association Study Of Fat Distribution With Diabetes

Obesity is an important and modifiable risk factor for type 2 diabetes.The link to type 2 diabetes is attributed not only to the amount of body fat but also its distribution.We aimed to investigate how those variants,which were identified to be associated with body mass index(BMI),waist and waist-to-hip ratio(WHR)by genome-wide association studies(GWASs),are linked to fat distribution and compare the the causal effect of different fat distribution on type 2 diabetes among Chinese Han individuals.Firstly,we genotyped 56 validated variants of BMI,waist and WHR in 2958 subjects from Chinese community-based populations and examined the association with visceral fat area(VFA)and subcutaneous fat area(SFA)imaged by magnetic resonance imaging(MRI).We found rs671 in ALDH2 exhibited the significant associations with VFA and the VFA-SFA ratio in all subjects(P=9.64×10-5 and 6.54×10-4,respectively),and the effects were restricted to drinkers(P=1.45×10-4 and 4.65×10-3,respectively),indicating that alcohol consumption may mediate the impact of the ALDH2 locus on visceral fat.rs17782313 near MC4R for VFA and rs4846567 near LYPLAL1 for SFA were found in females only(P=2.93×10-4 and 0.0015,respectively).Secondly,we constructed two genetic risk scores(GRSs)based on 32 established loci for BMI(a surrogate of overall obesity)and 11 WHR(a surrogate of central obesity)to assess the causal effects of BMI and WHR on several glycaemic-related traits in 2884 community-based individuals with the framework of Mendelian randomization(MR)approach.The MR analysis by two-stage least squares estimator(2SLS)demonstrated a causal relationship between BMI and Stumvoll first-phase insulin secretion(β=0.113,P=0.001)in contrast with a causal relationship between WHR and Gutt index(representing the insulin sensitivity)(β=-0.056,P=0.013).Besides,we compared the causal relationship of BMI and WHR with the risk of glucose deterioration and glycaemic traits using two different genetic instruments based on 30 BMI loci and six WHR loci by using MR method in three prospective cohorts(n=6476).We found that each one-SD genetically instrumented higher WHR was causally associated with a 65.7%higher risk of glucose deterioration(95%CI=1.069～2.569,P=0.024),whereas no significant association of BMI with glucose deterioration was observed.We also found that BMI had a causal effect on homeostasis model assessment of cell function(HOMA-B)(β=0.143,P=0.001),while WHR had causal effect on Gutt index(β=-0.379,P=0.022).In conclusion,our data implied that variants of MC4R and LYPLAL1 modulated body fat distribution with sexual dimorphism and that alcohol consumption may mediate the impact of the ALDH2 locus on visceral fat in a Chinese population;and we implied the potential causal relationship between central obesity and hyperglycaemia,which may be driven by aggravated insulin resistance,in contrast with the potential causal relationship between overall obesity and insulin secretion.