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

Abstract

Aims/hypothesis 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. Methods Genetic variants were studied in a large prospective study of 16,143 non-diabetic individuals (mean followup time 23 years) from the Malmö 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. Results 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). Conclusions/interpretation Polymorphisms in susceptibility genes for type 2 diabetes (TCF7L2, WFS1, IGF2BP2) and obesity (FTO) predispose to the metabolic syndrome by Diabetologia

Genetic Associations with Metabolic Syndrome and Its Quantitative Traits by Race/Ethnicity in the United States

“…Sjö gren et al examined whether 17 variants associated with T2D and 10 variants associated with at least two components of metabolic syndrome (including FTO rs9939609, GCKR rs1260326, and ENPP1 rs1044498) predicted incident metabolic syndrome in the longitudinal Malmö Preventive Project with more than 16,000 participants. 35 Of these 27 variants, only rs7903146 in TCF7L2 predicted metabolic syndrome after correction for multiple testing, although rs9939609 in FTO had an odds ratio for metabolic syndrome of 1.02-1.14 (P = 0.0065), mediated predominantly through its effects in BMI.…”

The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation

“…Other central or contributory mechanisms that have been considered include: chronic activation of the immune system; disorders of the hypothalamic-pituitary-adrenal axis; altered glucocorticoid hormone action; chronic stress; and the contributions of cytokines, hormones and other molecules produced by adipocytes [10,12]. Prenatal and early-life influences might play a role [13], as may multiple gene combinations [14], possibly explaining why current definitions encompass heterogeneous phenotypes in different ethnic groups.…”

Association of the rs9939609 gene variant in FTO with insulin resistance, carciovascular risk factor and serum adipokine levels in obese patients

“…One of these genetic variants (rs9939609), located within the first FTO intron, has been related to an increased risk for both obesity and type 2 diabetes mellitus (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Although the association of the FTO gene with obesity is observed across many different ethnic populations (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), there are several controversies. Some showed an association of the FTO gene with obesity (15)(16), and some failed to replicate the result (17).…”