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

Abstract

Background and aims: 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.

Methods and 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).

Conclusion: These results require replication but strongly indicate the role of LRP1 in postprandial lipoprotein uptake and/or clearance.

Trial registration: ClinicalTrials.gov NCT00083369.

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.