on September 3, 2009
Published online before print September 3, 2009, doi: 10.1161/ATVBAHA.109.190405
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Submitted on April 28, 2009
Accepted on August 26, 2009
Ion Mobility Analysis of Lipoprotein Subfractions Identifies Three Independent Axes of Cardiovascular Risk
Kiran Musunuru ;
From the Center for Human Genetic Research and Cardiovascular Research Center, Cardiology Division (K.M., S.K.), Massachusetts General Hospital, Boston, and Broad Institute of MIT and Harvard (K.M., S.K.), Cambridge, Mass; University Hospital Malmö (M.O.-M., G.B., B.H., G.E., O.M.), Lund University, Malmö, Sweden; Quest Diagnostics Nichols Institute (M.P.C., S.L., W.A.S., R.E.R.), San Juan Capistrano, Calif; Life Sciences Division (P.T.W.), Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley, Calif; and the Children's Hospital Oakland Research Institute (R.M.K.), Oakland, Calif.
* To whom correspondence should be addressed. E-mail: rkrauss{at}chori.org.
Objective—Whereas epidemiological studies show that levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) predict incident cardiovascular disease (CVD), there is limited evidence relating lipoprotein subfractions and composite measures of subfractions to risk for CVD in prospective cohort studies.
Methods and Results—We tested whether combinations of lipoprotein subfractions independently predict CVD in a prospective cohort of 4594 initially healthy men and women (the Malmö Diet and Cancer Study, mean follow-up 12.2 years, 377 incident cardiovascular events). Plasma lipoproteins and lipoprotein subfractions were measured at baseline with a novel high-resolution ion mobility technique. Principal component analysis (PCA) of subfraction concentrations identified 3 major independent (ie, zero correlation) components of CVD risk, one representing LDL-associated risk, a second representing HDL-associated protection, and the third representing a pattern of decreased large HDL, increased small/medium LDL, and increased triglycerides. The last corresponds to the previously described "atherogenic lipoprotein phenotype." Several genes that may underlie this phenotype—CETP, LIPC, GALNT2, MLXIPL, APOA1/A5, LPL—are suggested by SNPs associated with the combination of small/medium LDL and large HDL.
Conclusion—PCA on lipoprotein subfractions yielded three independent components of CVD risk. Genetic analyses suggest these components represent independent mechanistic pathways for development of CVD.
Key words: lipids • lipoproteins • cardiovascular diseases • genetics