title: Genome-wide association with select biomarker traits in the Framingham Heart Study.
abstract: BACKGROUND
  Systemic biomarkers provide insights into disease pathogenesis, diagnosis, and risk stratification. Many systemic biomarker concentrations are heritable phenotypes. Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations.
  
  
  METHODS
  We examined the association of Affymetrix 100K GeneChip single nucleotide polymorphisms (SNPs) to 22 systemic biomarker concentrations in 4 biological domains: inflammation/oxidative stress; natriuretic peptides; liver function; and vitamins. Related members of the Framingham Offspring cohort (n = 1012; mean age 59 +/- 10 years, 51% women) had both phenotype and genotype data (minimum-maximum per phenotype n = 507-1008). We used Generalized Estimating Equations (GEE), Family Based Association Tests (FBAT) and variance components linkage to relate SNPs to multivariable-adjusted biomarker residuals. Autosomal SNPs (n = 70,987) meeting the following criteria were studied: minor allele frequency > or = 10%, call rate > or = 80% and Hardy-Weinberg equilibrium p > or = 0.001.
  
  
  RESULTS
  With GEE, 58 SNPs had p < 10(-6): the top SNPs were rs2494250 (p = 1.00*10(-14)) and rs4128725 (p = 3.68*10(-12)) for monocyte chemoattractant protein-1 (MCP1), and rs2794520 (p = 2.83*10(-8)) and rs2808629 (p = 3.19*10(-8)) for C-reactive protein (CRP) averaged from 3 examinations (over about 20 years). With FBAT, 11 SNPs had p < 10(-6): the top SNPs were the same for MCP1 (rs4128725, p = 3.28*10(-8), and rs2494250, p = 3.55*10(-8)), and also included B-type natriuretic peptide (rs437021, p = 1.01*10(-6)) and Vitamin K percent undercarboxylated osteocalcin (rs2052028, p = 1.07*10(-6)). The peak LOD (logarithm of the odds) scores were for MCP1 (4.38, chromosome 1) and CRP (3.28, chromosome 1; previously described) concentrations; of note the 1.5 support interval included the MCP1 and CRP SNPs reported above (GEE model). Previous candidate SNP associations with circulating CRP concentrations were replicated at p < 0.05; the SNPs rs2794520 and rs2808629 are in linkage disequilibrium with previously reported SNPs. GEE, FBAT and linkage results are posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.
  
  
  CONCLUSIONS
  The Framingham GWAS represents a resource to describe potentially novel genetic influences on systemic biomarker variability. The newly described associations will need to be replicated in other studies.
authors: The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA. emelia@bu.edu
authors: Emelia J
authors: EJ
authors: Benjamin
authors: Josée
authors: J
authors: Dupuis
authors: Martin G
authors: MG
authors: Larson
authors: Kathryn L
authors: KL
authors: Lunetta
authors: Sarah L
authors: SL
authors: Booth
authors: Diddahally R
authors: DR
authors: Govindaraju
authors: Sekar
authors: S
authors: Kathiresan
authors: John F
authors: JF
authors: Keaney
authors: Michelle J
authors: MJ
authors: Keyes
authors: Jing-Ping
authors: JP
authors: Lin
authors: James B
authors: JB
authors: Meigs
authors: Sander J
authors: SJ
authors: Robins
authors: Jian
authors: J
authors: Rong
authors: Renate
authors: R
authors: Schnabel
authors: Joseph A
authors: JA
authors: Vita
authors: Thomas J
authors: TJ
authors: Wang
authors: Peter W F
authors: PW
authors: Wilson
authors: Philip A
authors: PA
authors: Wolf
authors: Ramachandran S
authors: RS
authors: Vasan
mesh_terms: D000328:Adult; D015415:Biomarkers; D002318:Cardiovascular Diseases / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D015415:Biomarkers