Association of Genetic Variants With the Metabolic Syndrome in White Women
Background: Candidate genes associated with cardiovascular disease (CVD) represent potential risk factors for the metabolic syndrome (MetS).
Methods: The association between prevalent MetS and a panel of 62 polymorphisms within 42 candidate genes, previously implicated in the pathophysiology of CVD, were investigated in 20,806 white participants of the Women's Health Study. All were free of known CVD and diabetes at baseline. Logistic regression was performed to investigate the relationship between genotype and the MetS assuming an additive model. Stratified analyses by hormone therapy use were also performed. Correction for multiple testing was performed using false discovery rate for polymorphisms and false positive rate probability for stratified analysis, respectively.
Results: The prevalence of the MetS was 23%. In a marker-by-marker analysis, the ADRB2 rs180088 (OR 1.22, 95% CI 1.01-1.48) and PAI1 rs1799768 (OR 1.05, 95% CI 1.01-1.10) were associated with an increased MetS risk, whereas the C5 rs17611 (OR 0.95, 95% CI 0.91-1.00) and the CTLA4 rs5742909 (OR 0.91, 95% CI 0.84-0.99) were associated with a decreased risk. In postmenopausal women, an increased MetS risk was found for the ADRB2 rs180088 (OR 1.28, 95% CI 0.99-1.65), PAI1 rs1799768 (OR 1.07, 95% CI 1.01-1.14), SCNN1A rs5742912 (OR 1.22, 95% CI 1.01-1.47), and IL1A rs1800587 (OR 1.07, 95% CI 1.01-1.15), whereas the AGTR1 rs5186 (OR 0.93, 95% CI 0.87-0.99) was associated with decreased risk. However, none remained significant after false discovery rate correction. In a stratified analysis, one or more copies of the variant C allele of SCNN1A rs5742912 were associated with an increased MetS risk among the current users (OR 1.56, 95% CI 1.21-2.01, P interaction .007, false positive rate probability 0.13).
Conclusions: Effect modification of the SCNN1A rs5742912 on the MetS by hormone therapy use warrants further investigation.
The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors, which is associated with substantial risk of type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). Individuals with the MetS have a 6-fold increased risk of DM and a 2-fold increased risk of CVD, regardless of age, sex, and ethnicity. Although multiple definitions have been proposed, according to the adenosine triphosphate III definition, the MetS is characterized by ≥3 of the following: abdominal obesity, elevated triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, high blood pressure (BP), and elevated fasting glucose. The prevalence of MetS increases with aging, and some studies suggest that the prevalence of MetS is higher in middle-aged women than middle-aged men. The MetS may be also associated with greater cardiovascular risk in women than in men.
The etiology of MetS is complex, being determined by interplay of environmental and genetic factors. However, heritability is a substantial contributor to the MetS (r = 0.61). Because the MetS is a cluster of conditions each of which has been associated with risk of CVD, candidate genes previously implicated in the pathophysiology of CVD may represent potential candidates for the MetS. Genetic variants in pathways related to inflammation, thrombosis, homeostasis, neurohormonal activation, and endothelial dysfunction may represent potential risk factors for the MetS. Although previous studies have shown genetic associations for many of the components of the MetS, few genome wide linkage studies have examined the full MetS. Recent candidate gene association studies have studied polymorphisms in candidate genes for CVD in the context of the MetS and its components; however, no polymorphisms have been consistently replicated. Insufficient statistical power, population stratification, heterogeneity between populations, genetic variants with modest effects or even gene-environment influences may contribute to limited progress in identifying candidate genes associated with complex traits such as the MetS. In this context, association-based studies may be more powerful than linkage analyses for identification of the genes that contribute to variation in complex traits.
In the current study, we assessed a panel of 62 polymorphisms from 42 candidate genes previously implicated in CVD to determine their association with prevalent MetS in a large cohort of white women.
Abstract and Article Outline
Abstract
Background: Candidate genes associated with cardiovascular disease (CVD) represent potential risk factors for the metabolic syndrome (MetS).
Methods: The association between prevalent MetS and a panel of 62 polymorphisms within 42 candidate genes, previously implicated in the pathophysiology of CVD, were investigated in 20,806 white participants of the Women's Health Study. All were free of known CVD and diabetes at baseline. Logistic regression was performed to investigate the relationship between genotype and the MetS assuming an additive model. Stratified analyses by hormone therapy use were also performed. Correction for multiple testing was performed using false discovery rate for polymorphisms and false positive rate probability for stratified analysis, respectively.
Results: The prevalence of the MetS was 23%. In a marker-by-marker analysis, the ADRB2 rs180088 (OR 1.22, 95% CI 1.01-1.48) and PAI1 rs1799768 (OR 1.05, 95% CI 1.01-1.10) were associated with an increased MetS risk, whereas the C5 rs17611 (OR 0.95, 95% CI 0.91-1.00) and the CTLA4 rs5742909 (OR 0.91, 95% CI 0.84-0.99) were associated with a decreased risk. In postmenopausal women, an increased MetS risk was found for the ADRB2 rs180088 (OR 1.28, 95% CI 0.99-1.65), PAI1 rs1799768 (OR 1.07, 95% CI 1.01-1.14), SCNN1A rs5742912 (OR 1.22, 95% CI 1.01-1.47), and IL1A rs1800587 (OR 1.07, 95% CI 1.01-1.15), whereas the AGTR1 rs5186 (OR 0.93, 95% CI 0.87-0.99) was associated with decreased risk. However, none remained significant after false discovery rate correction. In a stratified analysis, one or more copies of the variant C allele of SCNN1A rs5742912 were associated with an increased MetS risk among the current users (OR 1.56, 95% CI 1.21-2.01, P interaction .007, false positive rate probability 0.13).
Conclusions: Effect modification of the SCNN1A rs5742912 on the MetS by hormone therapy use warrants further investigation.
Article Outline
The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors, which is associated with substantial risk of type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). Individuals with the MetS have a 6-fold increased risk of DM and a 2-fold increased risk of CVD, regardless of age, sex, and ethnicity. Although multiple definitions have been proposed, according to the adenosine triphosphate III definition, the MetS is characterized by ≥3 of the following: abdominal obesity, elevated triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, high blood pressure (BP), and elevated fasting glucose. The prevalence of MetS increases with aging, and some studies suggest that the prevalence of MetS is higher in middle-aged women than middle-aged men. The MetS may be also associated with greater cardiovascular risk in women than in men.
The etiology of MetS is complex, being determined by interplay of environmental and genetic factors. However, heritability is a substantial contributor to the MetS (r = 0.61). Because the MetS is a cluster of conditions each of which has been associated with risk of CVD, candidate genes previously implicated in the pathophysiology of CVD may represent potential candidates for the MetS. Genetic variants in pathways related to inflammation, thrombosis, homeostasis, neurohormonal activation, and endothelial dysfunction may represent potential risk factors for the MetS. Although previous studies have shown genetic associations for many of the components of the MetS, few genome wide linkage studies have examined the full MetS. Recent candidate gene association studies have studied polymorphisms in candidate genes for CVD in the context of the MetS and its components; however, no polymorphisms have been consistently replicated. Insufficient statistical power, population stratification, heterogeneity between populations, genetic variants with modest effects or even gene-environment influences may contribute to limited progress in identifying candidate genes associated with complex traits such as the MetS. In this context, association-based studies may be more powerful than linkage analyses for identification of the genes that contribute to variation in complex traits.
In the current study, we assessed a panel of 62 polymorphisms from 42 candidate genes previously implicated in CVD to determine their association with prevalent MetS in a large cohort of white women.
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