Molecular Genetics of Metabolic Syndrome

Abstract

Abstract The clustering of metabolic traits (known as metabolic syndrome), including central obesity, abnormal glucose regulation, dyslipidemia and elevated blood pressure, was associated with increased risk of cardiovascular disease and type 2 diabetes. The close clustering and strong heritability of these metabolic traits suggest a common underlying genetic basis. Genetically modified mice models and identification of causative gene for human monogenic obesity/insulin resistance syndrome provided important insights into the pathogenesis of the metabolic syndrome. Recent genome‐wide association studies (GWAS) also identified several genes reproducibly associated with the metabolic syndrome or multiple metabolic traits, including genes involved in lipid metabolism ( CETP, APOA1/C3/A4/A5 cluster, LPL , LIPC and ABCB11 ), glucose sensing ( GCKR ), insulin signalling ( IRS1 ), beta‐cell function (TCF7L2) and appetite control ( FTO ). However, these variants explain only a small fraction of the observed heritability. Further pursuit for structural variants, rare sequence variants and epigenetic modification related to the metabolic syndrome may help to elucidate the unexplained heritability. Key Concepts: The estimated heritability of the metabolic syndrome and related metabolic traits (including obesity, dyslipidemia, abnormal glucose regulation and elevated blood pressure) is relatively high. Genetically modified knockout mice models and human monogenic obese/insulin resistant syndrome provide important molecular insights into the pathogenesis of the metabolic syndrome. Family linkage mapping for the metabolic syndrome is of limited success because of inconsistency among studies. Large‐scale genome‐wide association mapping identified many genetic loci associated with the metabolic syndrome and related traits. Important loci are located in genes involved in lipid metabolism ( CETP, APOA1/C3/A4/A5 cluster, LPL , LIPC and ABCB11 ), glucose sensing ( GCKR ), insulin signalling ( IRS1 ), beta‐cell function (TCF7L2) and appetite control ( FTO ). The genetic variants identified by genome‐wide association mapping explain only a minor fraction of the estimated heritability. Other potential contributors to the unexplained heritability are structural variants, rare sequence variants and epigenetic modification.