Analysis of metabolic syndrome components in >15 000 african americans identifies pleiotropic variants: results from the population architecture using genomics and epidemiology study.
Analysis of metabolic syndrome components in >15 000 african americans identifies pleiotropic variants: results from the population architecture using genomics and epidemiology study.
- 2014
BACKGROUND: Metabolic syndrome (MetS) refers to the clustering of cardiometabolic risk factors, including dyslipidemia, central adiposity, hypertension, and hyperglycemia, in individuals. Identification of pleiotropic genetic factors associated with MetS traits may shed light on key pathways or mediators underlying MetS. CONCLUSIONS: We highlight a method to increase power in large-scale genomic association analyses and report a novel variant associated with all MetS components in African Americans. We also identify pleiotropic associations that may be clinically useful in patient risk profiling and for informing translational research of potential gene targets and medications.Copyright � 2014 American Heart Association, Inc. METHODS AND RESULTS: Using the Metabochip array in 15 148 African Americans from the Population Architecture using Genomics and Epidemiology (PAGE) study, we identify susceptibility loci and investigate pleiotropy among genetic variants using a subset-based meta-analysis method, ASsociation-analysis-based-on-subSETs (ASSET). Unlike conventional models that lack power when associations for MetS components are null or have opposite effects, Association-analysis-based-on-subsets uses 1-sided tests to detect positive and negative associations for components separately and combines tests accounting for correlations among components. With Association-analysis-based-on-subsets, we identify 27 single nucleotide polymorphisms in 1 glucose and 4 lipids loci (TCF7L2, LPL, APOA5, CETP, and APOC1/APOE/TOMM40) significantly associated with MetS components overall, all P<2.5e-7, the Bonferroni adjusted P value. Three loci replicate in a Hispanic population, n=5172. A novel African American-specific variant, rs12721054/APOC1, and rs10096633/LPL are associated with >3 MetS components. We find additional evidence of pleiotropy for APOE, TOMM40, TCF7L2, and CETP variants, many with opposing effects (eg, the same rs7901695/TCF7L2 allele is associated with increased odds of high glucose and decreased odds of central adiposity).
English
1942-3268
*African Americans/ge [Genetics]
*Genomics
*Metabolic Syndrome X/ge [Genetics]
Aged
Alleles
Apolipoprotein C-I/ge [Genetics]
Apolipoproteins A/ge [Genetics]
Blood Glucose/an [Analysis]
Cholesterol Ester Transfer Proteins/ge [Genetics]
Cholesterol, HDL/bl [Blood]
Female
Genetic Loci
Genetic Pleiotropy
Genetic Predisposition to Disease
Genetic Variation
Genotype
Hispanic Americans/ge [Genetics]
Humans
Lipoprotein Lipase/ge [Genetics]
Male
Metabolic Syndrome X/ep [Epidemiology]
Middle Aged
Odds Ratio
Phenotype
Polymorphism, Single Nucleotide
Transcription Factor 7-Like 2 Protein/ge [Genetics]
MedStar Health Research Institute
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
BACKGROUND: Metabolic syndrome (MetS) refers to the clustering of cardiometabolic risk factors, including dyslipidemia, central adiposity, hypertension, and hyperglycemia, in individuals. Identification of pleiotropic genetic factors associated with MetS traits may shed light on key pathways or mediators underlying MetS. CONCLUSIONS: We highlight a method to increase power in large-scale genomic association analyses and report a novel variant associated with all MetS components in African Americans. We also identify pleiotropic associations that may be clinically useful in patient risk profiling and for informing translational research of potential gene targets and medications.Copyright � 2014 American Heart Association, Inc. METHODS AND RESULTS: Using the Metabochip array in 15 148 African Americans from the Population Architecture using Genomics and Epidemiology (PAGE) study, we identify susceptibility loci and investigate pleiotropy among genetic variants using a subset-based meta-analysis method, ASsociation-analysis-based-on-subSETs (ASSET). Unlike conventional models that lack power when associations for MetS components are null or have opposite effects, Association-analysis-based-on-subsets uses 1-sided tests to detect positive and negative associations for components separately and combines tests accounting for correlations among components. With Association-analysis-based-on-subsets, we identify 27 single nucleotide polymorphisms in 1 glucose and 4 lipids loci (TCF7L2, LPL, APOA5, CETP, and APOC1/APOE/TOMM40) significantly associated with MetS components overall, all P<2.5e-7, the Bonferroni adjusted P value. Three loci replicate in a Hispanic population, n=5172. A novel African American-specific variant, rs12721054/APOC1, and rs10096633/LPL are associated with >3 MetS components. We find additional evidence of pleiotropy for APOE, TOMM40, TCF7L2, and CETP variants, many with opposing effects (eg, the same rs7901695/TCF7L2 allele is associated with increased odds of high glucose and decreased odds of central adiposity).
English
1942-3268
*African Americans/ge [Genetics]
*Genomics
*Metabolic Syndrome X/ge [Genetics]
Aged
Alleles
Apolipoprotein C-I/ge [Genetics]
Apolipoproteins A/ge [Genetics]
Blood Glucose/an [Analysis]
Cholesterol Ester Transfer Proteins/ge [Genetics]
Cholesterol, HDL/bl [Blood]
Female
Genetic Loci
Genetic Pleiotropy
Genetic Predisposition to Disease
Genetic Variation
Genotype
Hispanic Americans/ge [Genetics]
Humans
Lipoprotein Lipase/ge [Genetics]
Male
Metabolic Syndrome X/ep [Epidemiology]
Middle Aged
Odds Ratio
Phenotype
Polymorphism, Single Nucleotide
Transcription Factor 7-Like 2 Protein/ge [Genetics]
MedStar Health Research Institute
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't