Human Molecular Genetics Advance Access originally published online on March 31, 2009
Human Molecular Genetics 2009 18(12):2305-2316; doi:10.1093/hmg/ddp159
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk
1 Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, 5 University St, London WC1E 6JF, UK 2 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK 3 Department of Epidemiology and Public Health, UCL, 1-19 Torrington Street, London WC1E 6BT, UK 4 Centre for Clinical Pharmacology, British Heart Foundation Laboratories at UCL, London WC1E 6JJ, UK
* To whom correspondence should be addressed at: Centre for Cardiovascular Genetics, Division of Medicine, UCL, London WC1E 6JJ, UK. Tel: +44 2076796968; Fax: +44 2076796212; Email: p.talmud{at}ucl.ac.uk
Received December 19, 2008; Accepted March 26, 2009
Individuals at risk of coronary heart disease (CHD) show multiple correlations across blood biomarkers. Single nucleotide polymorphisms (SNPs) indexing biomarker differences could help distinguish causal from confounded associations because of their random allocation prior to disease. We examined the association of 948 SNPs in 122 candidate genes with 12 CHD-associated phenotypes in 2775 middle aged men (a genic scan). Of these, 140 SNPs indexed differences in HDL- and LDL-cholesterol, triglycerides, C-reactive protein, fibrinogen, factor VII, apolipoproteins AI and B, lipoprotein-associated phospholipase A2, homocysteine or folate, some with large effect sizes and highly significant P-values (e.g. 2.15 standard deviations at P = 9.2 x 10–140 for F7 rs6046 and FVII levels). Top ranking SNPs were then tested for association with additional biomarkers correlated with the index phenotype (phenome scan). Several SNPs (e.g. in APOE, CETP, LPL, APOB and LDLR) influenced multiple phenotypes, while others (e.g. in F7, CRP and FBB) showed restricted association to the index marker. SNPs influencing six blood proteins were used to evaluate the nature of the associations between correlated blood proteins utilizing Mendelian randomization. Multiple SNPs were associated with CHD-related quantitative traits, with some associations restricted to a single marker and others exerting a wider genetic ‘footprint’. SNPs indexing biomarkers provide new tools for investigating biological relationships and causal links with disease. Broader and deeper integrated analyses, linking genomic with transcriptomic, proteomic and metabolomic analysis, as well as clinical events could, in principle, better delineate CHD causing pathways amenable to treatment.