The search for putative unifying genetic factors for components of the metabolic syndrome

The metabolic syndrome is a cluster of factors contributing to increased risk of cardiovascular disease and type 2 diabetes but unifying mechanisms have not been identified. Our aim was to study whether common variations in 17 genes previously associated with type 2 diabetes or components of the metabolic syndrome and variants in nine genes with inconsistent association with at least two components of the metabolic syndrome would also predict future development of components of the metabolic syndrome, individually or in combination. Genetic variants were studied in a large prospective study of 16,143 non-diabetic individuals (mean follow-up time 23 years) from the Malmo Preventive Project. In this study, development of at least three of obesity (BMI >= 30 kg/m(2)), dyslipidaemia (triacylglycerol >= 1.7 mmol/l and/or lipid-lowering treatment), hypertension (blood pressure >= 140/90 mmHg and/or antihypertensive medication) and hyperglycaemia (fasting plasma glucose >= 5.6 mmol/l and/or known diabetes) was defined as development of the metabolic syndrome. The risk of developing at least three components of the metabolic syndrome or the individual components was calculated by logistic regression adjusted for age at baseline, follow-up time and sex. Polymorphisms in TCF7L2 (rs7903146, OR 1.10, 95% CI 1.04-1.17, p=0.00097), FTO (rs9939609, OR 1.08, 95% CI 1.02-1.14, p=0.0065), WFS1 (rs10010131, OR 1.07, 95% CI 1.02-1.13, p=0.0078) and IGF2BP2 (rs4402960, OR 1.07, 95% CI 1.01-1.13, p=0.021) predicted the development of at least three components of the metabolic syndrome in both univariate and multivariate analysis; in the case of TCF7L2, WFS1 and IGF2BP this was due to their association with hyperglycaemia (p<0.00001, p=0.0033 and p=0.027, respectively) and for FTO it was due to its association with obesity (p=0.004). A polymorphism in the GCKR gene predicted dyslipidaemia (rs1260326, OR 1.15, 95% CI 1.09-1.22, p<0.00001) but not the metabolic syndrome. None of the studied polymorphisms was associated with more than two components of the metabolic syndrome. A composite genotype score of the 17 polymorphisms associated with type 2 diabetes predicted the development of at least three components of the metabolic syndrome (OR 1.04, p<0.00001) and the development of hyperglycaemia (OR 1.06, p<0.00001). Carriers of >= 19 risk alleles had 51 and 72% increased risk of developing at least three components of the metabolic syndrome and hyperglycaemia, respectively, compared with carriers of <= 12 risk alleles (p<0.00001 for both). Polymorphisms in susceptibility genes for type 2 diabetes (TCF7L2, WFS1, IGF2BP2) and obesity (FTO) predispose to the metabolic syndrome by increasing the risk of one specific component of the metabolic syndrome. The findings argue against a unifying genetic component for the metabolic syndrome.