Genetic analysis helps dissect molecular basis of cardiovascular disease

Using highly precise measurements of plasma lipoprotein concentrations determined by nuclear magnetic resonance spectroscopy (NMR), researchers led by Daniel Chasman at Brigham and Women's Hospital and Harvard Medical School in Boston, MA, the Framingham Heart Study in Framingham, and the PROCARDIS consortium in Stockholm, Sweden and Oxford, England performed genetic association analysis across the whole genome among 17,296 women of European ancestry from the Women's Genome Health Study. This large scale analysis of the effects of common genetic variation on plasma lipoprotein profile, a critical component of cardiovascular risk, identified 43 genetic loci contributing to lipoprotein metabolism, including 10 loci not previously recognized in other whole genome analyses. The findings are published on November 20 in the open-access journal PLoS Genetics.

The findings were validated among additional populations of both men and women. The research also quantifies the contribution of common genetic variation to the concentration of plasma lipoproteins according to class, that is low-density lipoprotein (LDL), high-density lipoprotein (HDL), or very low density lipoprotein (VLDL), as well as size and cholesterol or triglyceride content.

The balance of LDL, HDL, and VLDL particle concentration is firmly established as a measure of cardiovascular risk.

These major classes of lipoprotein particles are composed of sub-species that can be categorized according to size. While the overall concentration of each of the major classes can be estimated by the clinical measures of LDL-cholesterol, HDL-cholesterol, and triglycerides, the determinations of the concentration of the sub-species by NMR methodology in the current study provide a more precise picture of lipoprotein profile. Clinical research is engaged in determining the contribution of each of the sub-species to cardiovascular risk.

"This current genetic analysis complements clinical analysis of cardiovascular risk by evaluating the genetic contribution to the concentration of each lipoprotein sub-species and helps to delineate genes and metabolic pathways that might be targeted for interventional strategies," noted Dr. Chasman. He continued "the research can be placed in the larger context of studies that are leveraging knowledge of the human genome to dissect the molecular basis of common diseases, particularly cardiovascular disease, through large scale, genome-wide genetic analysis."

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FINANCIAL DISCLOSURE: This work was funded by the Donald W. Reynolds Foundation (Las Vegas, NV), the Fondation LeDucq (Paris, France), the National Heart, Lung and Blood Institute (NHLBI; HL043851) and the National Cancer Institute (CA047988). J.O. was supported by the NHLBI (HL54776) and by the U.S. Department of Agriculture (under agreement no. 58-1950-9-001). Analysis in the Framingham Heart Study was supported by the NHLBI (HL54776). Analysis in PROCARDIS was funded by the British Heart Foundation, the EC Sixth Framework Programme (LSHM-CT- 2007- 037273), the Swedish Medical Research Council (8691), the Knut and Alice Wallenberg Foundation, and AstraZeneca AB. Other than Amgen, which provided genotyping and collaborative scientific support, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.