engleski

Genetic Risk Factors for Metabolic Syndrome

Metabolic syndrome (MetS) is defined as clustering of different conditions that increase the risk of developing cardiovascular disease and diabetes. According to definition used, components of MetS are insulin resistance, hypertension, dyslipidemia, obesity, microalbuminuria and glucose concentration. Pathogenesis of each of these components is multifactorial and cumulative action between large number of genes and environment is required for its development. Heritability, as a measure of assessing genetic components in the disease, has not yet been determined for the MetS, although the heritability for its components is substantial and well recognized. Family and twin studies estimated heritability for hypertension to be from 20-60%. Genetic contribution in type 2 diabetes ranges from 37% in dizygotic to 50% in monozygotic twin pairs. Insulin resistance also strongly clusters within families, thus 45% of first relatives with insulin resistance are also insulin resistant. Genetic background can explain 40% of variation in body fat and 70% in abdominal obesity. Approaches on identifying genes involved in metabolic syndrome development include animal models on the levels of the basic research, genome scan models and candidate gene approach. Genome scan models include search of entire genome in order to localize loci associated with studied phenotype. As a result, chromosomal regions associated with disease are identified, but nothing is known about biological function of genes involved. Several genetic loci have been identified in association with metabolic syndrome: 1p36.13, 3p25, 10p11.2, 19q13.4. After location in genome is identified, a search of candidate genes localized in the identified region begins. The most commonly used way to study candidate genes of polygenic traits is genetic association study. However, this approach has some serious shortcomings that can influence the result. Depending on the definition used, different components and cut-off values are used in the recruitment criteria. As a result, MetS study population is very heterogeneous which frequently leads to failure to replicate results in independent studies. An important source of difficulties in these studies is small gene effect of single gene in polygenic traits. Due to that, a very large number of participants are needed to detect an influence of genetic variants. A meta-analysis is a useful tool to asses the results of genetic-association studies. Based on the thrifty genotype hypothesis, genes involved in energy storage could be predisposing to MetS. This large group of candidate genes involves genes associated with different phenotypes: obesity (leptin, leptin receptor, melanocortin receptor) ; free fatty acid metabolism (adiponectin, β -adrenergic receptor, lipases) ; insulin sensitivity (PPARγ , insulin receptor substrates) ; lipid metabolism (ApoE, Apo ApoA5, ApoC3) ; hypertension (ACE) and inflammation (TNFα , CRP, IL-6). These genes and their polymorphic variants have been extensively studied in association with both, metabolic syndrome in general and individual components of metabolic syndrome. PPARγ controls expression of many genes involved in lipid and glucose metabolism. It is localized on chromosome 3p25, a locus that has been identified in several diabetes and metabolic syndrome genome scans. Pro12Ala polymorphic variant has been associated with BMI, insulin sensitivity, HDL cholesterol, type 2 diabetes, hypertension, triglycerides and glucose concentration. Adiponectine is secreted by adipocytes, regulates homeostasis, glucose and lipid metabolism and is inversely correlated with BMI and body fat. Several polymorphic variants (-11, 377C G, 276G T) have been associated with plasma levels of adiponectin and/or metabolic syndrome and associated phenotypes. β -adrenergic receptors are involved in lipid metabolism via catecholamine-induced lipolysis. β 3AR is a candidate gene for obesity, and its Trp64Arg variant has been associated with hyperinsulinemia, obesity and hypertension. Interleukin 6 (Il-6) is a proinflammatory cytokine secreted from leukocytes and adipocytes. Polymorphic variants in IL-6 gene (-579G A, 572G C, -174G C) have been associated with metabolic syndrome and this finding has been independently replicated. Besides candidate genes for metabolic syndrome development, some genes have been identified to have a protective role in MetS development. One of such genes is ghrelin, a protein that regulates energy balance, insulin signalling and plasma glucose. R51Q variant has been associated with significant risk reduction in MetS development.

genetic polymorphism; metabolic syndrome

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