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Title: The association between LRP-1 variants and chylomicron uptake after a high fat meal

Author
item FRAZIER-WOOD, ALEXIS - University Of Alabama
item KABAGAMBE, EDMOND - University Of Alabama
item WOJCZYNSKI, MARY - Washington University
item BORECKI, INGRID - Washington University
item TIWARI, HEMANT - University Of Alabama
item SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item ARNETT, DONNA - University Of Alabama

Submitted to: Nutrition, Metabolism and Cardiovascular Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/27/2012
Publication Date: 2/26/2013
Citation: Frazier-Wood, A.C., Kabagambe, E.K., Wojczynski, M.K., Borecki, I.B., Tiwari, H.K., Smith, C.E., Ordovas, J.M., Arnett, D.K. 2013. The association between LRP-1 variants and chylomicron uptake after a high fat meal. Nutrition, Metabolism and Cardiovascular Diseases. DOI: 10.1016/j.numecd.2012.12.007.

Interpretive Summary: Lipoproteins are spherical particles that carry lipids, particularly cholesterol and triglyceride, in the plasma. There is a well-established association between dyslipidemias, or disorders of lipoprotein metabolism, and coronary heart disease (CHD). Elevated levels of blood cholesterol, especially low-density lipoprotein cholesterol (LDL-C), and low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for CHD. In addition, to those lipid fractions, others are found primarily in the post-meal state. This is the case with those known as chylomicrons. Some studies have shown that the so called low density lipoprotein receptor-related protein 1 (LRP1) plays a role in the uptake of chylomicrons into cells. Our goal was to determine whether genetic variants in LRP-1 were associated with post-meal chylomicron uptake in humans given an oral fat challenge. For this purpose we used the population of the Genetics of Lipid Lowering Drugs Network (GOLDN) study. These subjects ingested an oral fat load of 700 kilocalories per m(2) of body surface area at 83% fat, after an 8-hour fast. Chylomicrons were measured at fasting, and 3.5 and 6 hours after the meal. 26 variants of particular DNA sequences called Single nucleotide polymorphisms (SNPs) in the LRP-1 gene were genotyped. Chylomicrons were, as expected, zero at fasting. We tested for associations between LRP-1 SNPs and changes in chylomicron concentrations between 3.5 and 6 hours. 11 LRP-1 SNPs were significantly associated with the change in chylomicron concentration. These results require replication but strongly indicate the role of LRP1 in post-meal lipoprotein uptake and/or clearance and therefore on the individual risk of cardiovascular disease and other metabolic disorders.

Technical Abstract: In vitro studies suggest that low density lipoprotein receptor-related protein 1 (LRP1) plays a role in the secondary uptake of chylomicrons. In addition, in vivo studies using LRP-1 knockout mice show these animals exhibit delayed chylomicron clearance. Whether this is true in humans is unknown. We aimed to determine whether genetic variants in LRP-1 are associated with postprandial chylomicron uptake in humans given an oral fat challenge. As many as 817 men and women (mean age +/- standard deviation = 48.4 +/- 16.4 years) forming the study population for the Genetics of Lipid Lowering Drugs Network (GOLDN) study ingested an oral fat load of 700 kilocalories per m2 of body surface area at 83% fat, after an 8-h fast. Chylomicrons were measured by nuclear resonance spectroscopy (NMR) at fasting, and 3.5 and 6 h after the meal. 26 Single nucleotide polymorphisms (SNPs) in the LRP-1 gene were genotyped on the Affymetrix 6.0 array. Chylomicrons were, as expected, zero at fasting. Mixed linear models adjusted for age, sex, study site and pedigree tested for associations between LRP-1 SNPs and changes in chylomicron concentrations 3.5-6 h. A gene-based test across all 26 SNPs was conducted which corrected for the linkage disequilibrium (LD) between SNPs. 11 LRP-1 SNPs were significantly associated with the change in chylomicron concentration correction for multiple testing (Q < 0.05). The subsequent gene-based test, was also significant (P = 0.01). These results require replication but strongly indicate the role of LRP1 in postprandial lipoprotein uptake and/or clearance.