Genome-Wide Association with Select Biomarker Traits in the Framingham Heart StudyReport as inadecuate

Genome-Wide Association with Select Biomarker Traits in the Framingham Heart Study

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Benjamin, Emelia J., Josée Dupuis, Martin G. Larson, Kathryn L. Lunetta, Sarah L. Booth, Diddahally R. Govindaraju, Sekar Kathiresan, John F. Keaney, Michelle J. Keyes, Jing-Ping Lin, James B. Meigs, Sander J. Robins, Jian Rong, Renate Schnabel, Joseph A. Vita, Thomas J. Wang, Peter W. F. Wilson, Philip A. Wolf, Ramachandran S. Vasan. -Genome-wide association with select biomarker traits in the Framingham Heart Study- BMC Medical Genetics 8 Suppl 1: S11. 2007


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 ≥ 10%, call rate ≥ 80% and Hardy-Weinberg equilibrium p ≥ 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 . 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.Rights

Copyright 2007 Benjamin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution 2.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

MED: Medicine Papers - SPH Biostatistics Papers - CAS: Mathematics: Scholarly Papers - Framingham Heart Study Papers -

Author: Benjamin, Emelia J. - Dupuis, Josée - Larson, Martin G. - Lunetta, Kathryn L. - Booth, Sarah L. - Govindaraju, Diddahally R. - K


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