Genome-wide association with select biomarker traits in the Framingham Heart Study.
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.
Benjamin
Emelia J
EJ
The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA. emelia@bu.edu
Dupuis
Josée
J
Larson
Martin G
MG
Lunetta
Kathryn L
KL
Booth
Sarah L
SL
Govindaraju
Diddahally R
DR
Kathiresan
Sekar
S
Keaney
John F
JF
Keyes
Michelle J
MJ
Lin
Jing-Ping
JP
Meigs
James B
JB
Robins
Sander J
SJ
Rong
Jian
J
Schnabel
Renate
R
Vita
Joseph A
JA
Wang
Thomas J
TJ
Wilson
Peter W F
PW
Wolf
Philip A
PA
Vasan
Ramachandran S
RS
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
D015415:Biomarkers