title: Analysis of metabolic syndrome components in >15 000 african americans identifies pleiotropic variants: results from the population architecture using genomics and epidemiology study.
abstract: 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.
  
  
  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).
  
  
  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.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Carty
authors.forename: Samsiddhi
authors.initials: S
authors.lastname: Bhattacharjee
authors.forename: Jeff
authors.initials: J
authors.lastname: Haessler
authors.forename: Iona
authors.initials: I
authors.lastname: Cheng
authors.forename: Lucia A
authors.initials: LA
authors.lastname: Hindorff
authors.forename: Vanita
authors.initials: V
authors.lastname: Aroda
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Hsu
authors.forename: Lynne
authors.initials: L
authors.lastname: Wilkens
authors.forename: Simin
authors.initials: S
authors.lastname: Liu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Selvin
authors.forename: Rebecca
authors.initials: R
authors.lastname: Jackson
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000483:Alleles; D000072040:Apolipoprotein A-V; D053302:Apolipoprotein C-I / Q000235:genetics; D001054:Apolipoproteins A / Q000235:genetics; D001786:Blood Glucose / Q000032:analysis; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D005260:Female; D056426:Genetic Loci; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D023281:Genomics; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D024821:Metabolic Syndrome / Q000453:epidemiology / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics
chemical_list: C437704:APOA5 protein, human; C505803:APOC1 protein, human; D000072040:Apolipoprotein A-V; D053302:Apolipoprotein C-I; D001054:Apolipoproteins A; D001786:Blood Glucose; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C548261:LPL protein, human; D008071:Lipoprotein Lipase
keywords: African continental ancestry group; Hispanic Americans; genetic pleiotropy; genetic variation; high-density lipoprotein cholesterol; hyperglycemia; metabolic syndrome