PMID- 17903293
OWN - NLM
STAT- MEDLINE
DCOM- 20071107
LR  - 20230811
IS  - 1471-2350 (Electronic)
IS  - 1471-2350 (Linking)
VI  - 8 Suppl 1
IP  - Suppl 1
DP  - 2007 Sep 19
TI  - Genome-wide association with select biomarker traits in the Framingham Heart 
      Study.
PG  - S11
AB  - 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. 
      CONCLUSION: 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.
FAU - Benjamin, Emelia J
AU  - Benjamin EJ
AD  - The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, 
      MA, USA. emelia@bu.edu
FAU - Dupuis, Josee
AU  - Dupuis J
FAU - Larson, Martin G
AU  - Larson MG
FAU - Lunetta, Kathryn L
AU  - Lunetta KL
FAU - Booth, Sarah L
AU  - Booth SL
FAU - Govindaraju, Diddahally R
AU  - Govindaraju DR
FAU - Kathiresan, Sekar
AU  - Kathiresan S
FAU - Keaney, John F Jr
AU  - Keaney JF Jr
FAU - Keyes, Michelle J
AU  - Keyes MJ
FAU - Lin, Jing-Ping
AU  - Lin JP
FAU - Meigs, James B
AU  - Meigs JB
FAU - Robins, Sander J
AU  - Robins SJ
FAU - Rong, Jian
AU  - Rong J
FAU - Schnabel, Renate
AU  - Schnabel R
FAU - Vita, Joseph A
AU  - Vita JA
FAU - Wang, Thomas J
AU  - Wang TJ
FAU - Wilson, Peter W F
AU  - Wilson PW
FAU - Wolf, Philip A
AU  - Wolf PA
FAU - Vasan, Ramachandran S
AU  - Vasan RS
LA  - eng
GR  - R01 HL076784/HL/NHLBI NIH HHS/United States
GR  - AG028321/AG/NIA NIH HHS/United States
GR  - HL064753/HL/NHLBI NIH HHS/United States
GR  - HL076784/HL/NHLBI NIH HHS/United States
GR  - 1S10RR163736-01A1/RR/NCRR NIH HHS/United States
GR  - 1K23 HL083102/HL/NHLBI NIH HHS/United States
GR  - 2 K24HL04334/HL/NHLBI NIH HHS/United States
GR  - K24 HL004334/HL/NHLBI NIH HHS/United States
GR  - AG14759/AG/NIA NIH HHS/United States
GR  - N01-HC25195/HC/NHLBI NIH HHS/United States
GR  - M01-RR-01066/RR/NCRR NIH HHS/United States
GR  - HL71039/HL/NHLBI NIH HHS/United States
GR  - R01 AG028321/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20070919
PL  - England
TA  - BMC Med Genet
JT  - BMC medical genetics
JID - 100968552
RN  - 0 (Biomarkers)
SB  - IM
MH  - Adult
MH  - *Biomarkers
MH  - Cardiovascular Diseases/*genetics
MH  - Cohort Studies
MH  - Female
MH  - *Genome, Human
MH  - Genotype
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Multivariate Analysis
MH  - Phenotype
MH  - Polymorphism, Single Nucleotide
PMC - PMC1995615
EDAT- 2007/10/16 09:00
MHDA- 2007/11/08 09:00
PMCR- 2007/09/19
CRDT- 2007/10/16 09:00
PHST- 2007/10/16 09:00 [pubmed]
PHST- 2007/11/08 09:00 [medline]
PHST- 2007/10/16 09:00 [entrez]
PHST- 2007/09/19 00:00 [pmc-release]
AID - 1471-2350-8-S1-S11 [pii]
AID - 10.1186/1471-2350-8-S1-S11 [doi]
PST - epublish
SO  - BMC Med Genet. 2007 Sep 19;8 Suppl 1(Suppl 1):S11. doi: 
      10.1186/1471-2350-8-S1-S11.