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Title: Lipoprotein lipase S447X variant associated with VLDL, LDL and HDL diameter clustering in the MetS

Author
item FRAZIER-WOOD, ALEXIS - University Of Alabama
item GLASSER, STEPHEN - University Of Alabama
item GARVEY, W - University Of Alabama
item KABAGAMBE, EDMOND - University Of Alabama
item BORECKI, INGRID - Washington University
item TIWARI, HEMANT - University Of Alabama
item TSAI, MICHAEL - University Of Minnesota
item HOPKINS, PAUL - University Of Utah
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item ARNETT, DONNA - University Of Alabama

Submitted to: Lipids in Health and Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/19/2011
Publication Date: 8/19/2011
Citation: Frazier-Wood, A.C., Glasser, S.P., Garvey, W.T., Kabagambe, E.K., Borecki, I.B., Tiwari, H.K., Tsai, M.Y., Hopkins, P.N., Ordovas, J.M., Arnett, D.K. 2011. Lipoprotein lipase S447X variant associated with VLDL, LDL and HDL diameter clustering in the MetS. Lipids in Health and Disease. 10:143.

Interpretive Summary: The traditional lipid-related (fat) cardiovascular risk factors (i.e., cholesterol, low and high density lipoproteins) are used to estimate future disease risk; however, more detailed measures of lipoprotein profiles may facilitate the clustering of individuals within subgroups that provide a more sensitive and specific risk prediction. We have done such clustering using 1,238 individuals from the general population of the Genetics of Lipid Lowering Drugs Network (GOLDN) study and identified that lipoproteins rich in triglycerides are major determinants of risk. Since lipoprotein lipase hydrolyzes triglyceride in the very-low density lipoprotein – low-density lipoprotein (VLDL-LDL) cascade, we examined whether these lipoprotein clusters were associated with differences across two lipoprotein lipase (LPL) gene variants: D9N (rs1801177) and S447X (rs328). Our data show that one of the subgroups was enriched with more carriers (25%) of the 447X variant than the other group (14%). This is the first study to show an association between LPL genetic variants and a lipoprotein profile characterized by the presence of large VLDL particle size, which is associated with higher insulin resistance and cardiovascular risk. Future work should extend this to larger samples to confirm these findings, and examine the long term health outcomes of those with this lipoprotein diameter pattern.

Technical Abstract: Previous analysis clustered 1,238 individuals from the general population Genetics of Lipid Lowering Drugs Network (GOLDN) study by the size of their fasting very low-density, low-density and high-density lipoproteins (VLDL, LDL, HDL) using latent class analysis. From two of the eight identified groups (N = 251), approximately 75% of individuals met Adult Treatment Panel III criteria for the metabolic syndrome (MetS). Both showed small LDL diameter (mean = 19.9 nm); however, group 1 (N = 200) had medium VLDL diameter (mean = 53.1 nm) while group 2 had very large VLDL diameter (mean = 65.74 nm). Group 2 additionally showed significantly more insulin resistance (IR), and accompanying higher waist circumference and fasting glucose and triglycerides (all P less than .01). Since lipoprotein lipase hydrolyzes triglyceride in the VLDL-LDL cascade, we examined whether these two patterns of lipoprotein diameter were associated with differences across two lipoprotein lipase (LPL) gene variants: D9N (rs1801177) and S447X (rs328). Mixed linear models that controlled for age, sex, center of data collection, and family pedigree revealed no differences between the two groups for the D9N polymorphism (P = .36). However, group 2 contained significantly more carriers (25%) of the 447X variant than group 1 (14%; P = .04). This was the first study this kind to show an association between LPL and large VLDL particle size within the MetS, a pattern associated with higher IR. Future work should extend this to larger samples to confirm these findings, and examine the long term outcomes of those with this lipoprotein diameter pattern.