title: The association between LRP-1 variants and chylomicron uptake after a high fat meal.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  These results require replication but strongly indicate the role of LRP1 in postprandial lipoprotein uptake and/or clearance.
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, School of Public Health, Birmingham, AL 35294, United States; Division of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas School of Public Health, Houston, TX 77030, United States. Electronic address: Lekki.Wood@Gmail.com.
authors.forename: A C
authors.initials: AC
authors.lastname: Frazier-Wood
authors.forename: E K
authors.initials: EK
authors.lastname: Kabagambe
authors.forename: M K
authors.initials: MK
authors.lastname: Wojczynski
authors.forename: I B
authors.initials: IB
authors.lastname: Borecki
authors.forename: H K
authors.initials: HK
authors.lastname: Tiwari
authors.forename: C E
authors.initials: CE
authors.lastname: Smith
authors.forename: J M
authors.initials: JM
authors.lastname: Ordovas
authors.forename: D K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D000328:Adult; D000483:Alleles; D002914:Chylomicrons / Q000097:blood / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004041:Dietary Fats / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007408:Intestinal Absorption; D015810:Linkage Disequilibrium; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D062407:Meals; D008875:Middle Aged; D008910:Minnesota; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D019518:Postprandial Period; D014589:Utah
chemical_list: D002914:Chylomicrons; D004041:Dietary Fats; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1
keywords: Candidate gene; Clearance; FDR; GOLDN; Genetics of Lipid Lowering Drugs Network; HWE; Hardy–Weinberg equilibrium; LD; LDL; LRP-1; MAF; NCI DHQ; NMR; National Cancer Institute Diet History Questionnaire; Postprandial; SNP; TGRL; Uptake; VEGAS; Versatile Gene Based Association Study; false discovery rate; linkage disequilibrium; low density lipoprotein receptor-related protein 1; low-density lipoprotein; minor allele frequency; nuclear resonance spectroscopy; single nucleotide polymorphism; triglyceride-rich lipoproteins Word count