Rev Endocr Metab Disord DOI 10.1007/s11154-014-9293-9
Genetics of metabolic syndrome Alena Stančáková & Markku Laakso
# Springer Science+Business Media New York 2014
Abstract Metabolic syndrome (MetS) is a cluster of metabolic traits associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. Central obesity and insulin resistance are thought to play key roles in the pathogenesis of the MetS. The MetS has a significant genetic component, and therefore linkage analysis, candidate gene approach, and genome-wide association (GWA) studies have been applied in the search of gene variants for the MetS. A few variants have been identified, located mostly in or near genes regulating lipid metabolism. GWA studies for the individual components of the MetS have reported several loci having pleiotropic effects on multiple MetS-related traits. Genetic studies have provided so far only limited evidence for a common genetic background of the MetS. Epigenetic factors (DNA methylation and histone modification) are likely to play important roles in the pathogenesis of the MetS, and they might mediate the effects of environmental exposures on the risk of the MetS. Further research is needed to clarify the role of genetic variation and epigenetic mechanisms in the development of the MetS. Keywords Genetics . Metabolic syndrome . Obesity . Insulin resistance . Lipids . Genome-wide association study Abbreviations BMI BP
Body mass index Blood pressure
A. Stančáková Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland M. Laakso (*) Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland e-mail: [email protected]
EGIR GWA HDL IDF LDL MetS NCEP ATP III SNP TG WC WHO WHR
European Group for the Study of Insulin Resistance Genome-wide association High density lipoprotein International Diabetes Federation Low density lipoprotein Metabolic syndrome National Cholesterol Education Program Adult Treatment Panel III Single nucleotide polymorphism Triglycerides Waist circumference World Health Organization Waist-to-hip ratio
1 Definition of metabolic syndrome Metabolic syndrome (MetS) is defined as a cluster of several risk factors associated with cardiovascular disease and type 2 diabetes mellitus, which occur together more often than by chance alone. Several definitions of the MetS are available (Table 1). The first formal definition published in 1998 by the World Health Organization (WHO) emphasized insulin resistance as the major underlying risk factor of the MetS, and required insulin resistance and 2 additional risk factors, including obesity, hypertension, high triglyceride (TG) level, reduced high-density lipoprotein (HDL) cholesterol level, or microalbuminuria, for the diagnosis of the MetS [1]. Similarly, a definition by the European Group for the Study of Insulin Resistance (EGIR) in 1999 required the presence of insulin resistance plus any two other metabolic traits such as central obesity, dyslipidemia, hypertension, and elevated fasting glucose [2]. In contrast, a definition by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)
Urinary albumin excretion ratio≥20 μg/ min or albumin/creatinine ratio≥30 mg/g
< 1.03 mmol/L (40 mg/dL) in men
Population-specific definitions ≥ 1.7 mmol/L (150 mg/dL)
≥ 5.6 mmol/l (100 mg/dL)
≥ 130/85 mmHg
> 88 cm ( 35 in.) in women ≥ 1.7 mmol/L (150 mg/dL) < 1.03 mmol/L (40 mg/dL) in men < 1.29 mmol/L (50 mg/dL) in women
< 1.0 mmol/L (40 mg/dL) in men < 1.3 mmol/L (50 mg/dL) in women • Elevated blood pressure (or antihypertensive drug treatment Systolic≥130 and/or in a patient with a history of hypertension) diastolic≥85 mmHg • Elevated fasting glucose (or drug treatment of elevated glucose) ≥ 5.6 mmol/l (100 mg/dL)
IDF 2009 (presence of 3 of 5 criteria is required) • Elevated waist circumference • Elevated triglycerides (or drug treatment for elevated triglycerides) • Reduced HDL cholesterol (or drug treatment for reduced HDL cholesterol)
• Elevated fasting glucose (or use of medication for hyperglyemia)
≥ 6.1 mmol/l (110 mg/dL)
• Elevated triglycerides • Reduced HDL cholesterol
• Elevated blood pressure (or antihypertensive drug treatment)
Population- and country-specific definitions > 1.7 mmol/L (150 mg/dL)
≥ 6.1 mmol/L
AHA/NHLBI updated NCEP ATP III 2004 (presence of 3 of 5 criteria is required) • Elevated waist circumference > 102 cm (40 in.) in men
• Elevated fasting glucose
≥ 130/85 mmHg
> 88 cm ( 35 in.) in women ≥ 1.7 mmol/L (150 mg/dL) < 1.03 mmol/L (40 mg/dL) in men < 1.29 mmol/L (50 mg/dL) in women
< 1.29 mmol/L (50 mg/dL) in women • Elevated blood pressure (or antihypertensive drug Systolic≥130 and/or treatment in a patient with a history of diastolic≥85 mmHg hypertension) • Elevated fasting glucose (or previously ≥ 5.6 mmol/l (100 mg/dL) diagnosed type 2 diabetes)
IDF 2005 • Elevated waist circumference plus any two of the following: • Elevated triglycerides (or drug treatment for elevated triglycerides) • Reduced HDL cholesterol (or drug treatment for reduced HDL cholesterol)
• Elevated blood pressure (or antihypertensive drug treatment) • Elevated fasting glucose
• Elevated triglycerides • Reduced HDL cholesterol
NCEP ATP III 2001 (presence of 3 of 5 criteria is required) • Central obesity (elevated waist circumference) > 102 cm (40 in.) in men
• Microalbuminuria
WHO 1998 EGIR 1999 • Diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance • Insulin resistance defined as the top 25 % of the fasting insulin values among nondiabetic individuals plus any two of the following: plus any two of the following: • Central obesity waist/hip ratio>0.90 (male), > 0.85 • Central obesity (elevated waist circumference) ≥ 94 cm or 37 in. (male) (female) or body mass index>30 kg/m2 ≥ 80 cm or 31.5 in. (female) • Elevated triglycerides ≥ 1.7 mmol/L • Dyslipidemia (or drug treatment for dyslipidemia) TG≥2.0 mmol/L and/or • Reduced HDL cholesterol < 0.9 mmol/L (male), < 1.0 mmol/L HDL-C90 loci have been associated with hypertension or BP. In spite of a relatively large number of discovered susceptibility variants, their effect sizes are quite small and they explain only small portions of heritability of the respective traits, e.g.
Genetics of metabolic syndrome Alena Stančáková & Markku Laakso
# Springer Science+Business Media New York 2014
Abstract Metabolic syndrome (MetS) is a cluster of metabolic traits associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. Central obesity and insulin resistance are thought to play key roles in the pathogenesis of the MetS. The MetS has a significant genetic component, and therefore linkage analysis, candidate gene approach, and genome-wide association (GWA) studies have been applied in the search of gene variants for the MetS. A few variants have been identified, located mostly in or near genes regulating lipid metabolism. GWA studies for the individual components of the MetS have reported several loci having pleiotropic effects on multiple MetS-related traits. Genetic studies have provided so far only limited evidence for a common genetic background of the MetS. Epigenetic factors (DNA methylation and histone modification) are likely to play important roles in the pathogenesis of the MetS, and they might mediate the effects of environmental exposures on the risk of the MetS. Further research is needed to clarify the role of genetic variation and epigenetic mechanisms in the development of the MetS. Keywords Genetics . Metabolic syndrome . Obesity . Insulin resistance . Lipids . Genome-wide association study Abbreviations BMI BP
Body mass index Blood pressure
A. Stančáková Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland M. Laakso (*) Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland e-mail: [email protected]
EGIR GWA HDL IDF LDL MetS NCEP ATP III SNP TG WC WHO WHR
European Group for the Study of Insulin Resistance Genome-wide association High density lipoprotein International Diabetes Federation Low density lipoprotein Metabolic syndrome National Cholesterol Education Program Adult Treatment Panel III Single nucleotide polymorphism Triglycerides Waist circumference World Health Organization Waist-to-hip ratio
1 Definition of metabolic syndrome Metabolic syndrome (MetS) is defined as a cluster of several risk factors associated with cardiovascular disease and type 2 diabetes mellitus, which occur together more often than by chance alone. Several definitions of the MetS are available (Table 1). The first formal definition published in 1998 by the World Health Organization (WHO) emphasized insulin resistance as the major underlying risk factor of the MetS, and required insulin resistance and 2 additional risk factors, including obesity, hypertension, high triglyceride (TG) level, reduced high-density lipoprotein (HDL) cholesterol level, or microalbuminuria, for the diagnosis of the MetS [1]. Similarly, a definition by the European Group for the Study of Insulin Resistance (EGIR) in 1999 required the presence of insulin resistance plus any two other metabolic traits such as central obesity, dyslipidemia, hypertension, and elevated fasting glucose [2]. In contrast, a definition by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)
Urinary albumin excretion ratio≥20 μg/ min or albumin/creatinine ratio≥30 mg/g
< 1.03 mmol/L (40 mg/dL) in men
Population-specific definitions ≥ 1.7 mmol/L (150 mg/dL)
≥ 5.6 mmol/l (100 mg/dL)
≥ 130/85 mmHg
> 88 cm ( 35 in.) in women ≥ 1.7 mmol/L (150 mg/dL) < 1.03 mmol/L (40 mg/dL) in men < 1.29 mmol/L (50 mg/dL) in women
< 1.0 mmol/L (40 mg/dL) in men < 1.3 mmol/L (50 mg/dL) in women • Elevated blood pressure (or antihypertensive drug treatment Systolic≥130 and/or in a patient with a history of hypertension) diastolic≥85 mmHg • Elevated fasting glucose (or drug treatment of elevated glucose) ≥ 5.6 mmol/l (100 mg/dL)
IDF 2009 (presence of 3 of 5 criteria is required) • Elevated waist circumference • Elevated triglycerides (or drug treatment for elevated triglycerides) • Reduced HDL cholesterol (or drug treatment for reduced HDL cholesterol)
• Elevated fasting glucose (or use of medication for hyperglyemia)
≥ 6.1 mmol/l (110 mg/dL)
• Elevated triglycerides • Reduced HDL cholesterol
• Elevated blood pressure (or antihypertensive drug treatment)
Population- and country-specific definitions > 1.7 mmol/L (150 mg/dL)
≥ 6.1 mmol/L
AHA/NHLBI updated NCEP ATP III 2004 (presence of 3 of 5 criteria is required) • Elevated waist circumference > 102 cm (40 in.) in men
• Elevated fasting glucose
≥ 130/85 mmHg
> 88 cm ( 35 in.) in women ≥ 1.7 mmol/L (150 mg/dL) < 1.03 mmol/L (40 mg/dL) in men < 1.29 mmol/L (50 mg/dL) in women
< 1.29 mmol/L (50 mg/dL) in women • Elevated blood pressure (or antihypertensive drug Systolic≥130 and/or treatment in a patient with a history of diastolic≥85 mmHg hypertension) • Elevated fasting glucose (or previously ≥ 5.6 mmol/l (100 mg/dL) diagnosed type 2 diabetes)
IDF 2005 • Elevated waist circumference plus any two of the following: • Elevated triglycerides (or drug treatment for elevated triglycerides) • Reduced HDL cholesterol (or drug treatment for reduced HDL cholesterol)
• Elevated blood pressure (or antihypertensive drug treatment) • Elevated fasting glucose
• Elevated triglycerides • Reduced HDL cholesterol
NCEP ATP III 2001 (presence of 3 of 5 criteria is required) • Central obesity (elevated waist circumference) > 102 cm (40 in.) in men
• Microalbuminuria
WHO 1998 EGIR 1999 • Diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance • Insulin resistance defined as the top 25 % of the fasting insulin values among nondiabetic individuals plus any two of the following: plus any two of the following: • Central obesity waist/hip ratio>0.90 (male), > 0.85 • Central obesity (elevated waist circumference) ≥ 94 cm or 37 in. (male) (female) or body mass index>30 kg/m2 ≥ 80 cm or 31.5 in. (female) • Elevated triglycerides ≥ 1.7 mmol/L • Dyslipidemia (or drug treatment for dyslipidemia) TG≥2.0 mmol/L and/or • Reduced HDL cholesterol < 0.9 mmol/L (male), < 1.0 mmol/L HDL-C90 loci have been associated with hypertension or BP. In spite of a relatively large number of discovered susceptibility variants, their effect sizes are quite small and they explain only small portions of heritability of the respective traits, e.g.
