Unknown,Transcriptomics,Genomics,Proteomics

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Evidence of mechanism how rs7575840 influences apolipoprotein B containing lipid particles

ABSTRACT: Objective: Recent genome-wide association studies (GWAS) identified a variant rs7575840 in the apolipoprotein B (APOB) gene region to be associated with LDL-C. However, the underlying functional mechanism of this variant that resides 6.5 kb upstream of APOB has remained unknown. Our objective was to investigate rs7575840 for association with refined apoB containing lipid particles; for replication in a non-Caucasian Mexican population; and for underlying functional mechanism. Methods and Results Our data show that rs7575840 is associated with serum apoB levels (P=4.85x10-10) and apoB containing lipid particles, very small VLDL, IDL and LDL particles (P=2x10-5 - 9x10-7) in the Finnish METSIM study sample (n=7,710). Fine mapping of the APOB region using 43 SNPs replicated the association of rs7575840 with apoB in a Mexican study sample (n=2,666, P=3.33x10-05). Furthermore, our transcript analyses of adipose RNA samples from 175 Finnish METSIM subjects indicate that rs7575840 alters expression of APOB (P=1.13x10-10) and a regional non-coding RNA (BU630349) (P=7.86x10-6) in adipose tissue. Conclusions It has been difficult to convert GWAS associations into mechanistic insights. Our data show that rs7575840 is associated with serum apoB levels and apoB containing lipid particles as well as influences expression of APOB and a regional transcript BU630349 in adipose tissue. We thus provide evidence how a common genome-wide significant SNP rs7575840 may affect serum apoB, LDL-C, and TC levels. 175 samples, no replicates

ORGANISM(S): Homo sapiens

SUBMITTER: Blake Haas

PROVIDER: E-GEOD-27666 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:LRP1 and, in particular the region that spans the C-terminal half of domain CR9 (from Gly1127 to Cys1140), named LP3, is essential for aggregated LDL internalization and human coronary vascular smooth muscle cells (hcVSMC)-cholesterol loading. Here, we investigated whether LP3 and its retro-enantio version (DP3) are protective against sphingomyelinase (SMase) and phospholipase 2 (PLA2)-induced LDL aggregation, the structural basis underlying this protection and the impact that LRP1-derived peptides might have on hcVSMC-cholesterol loading and cholesterol-modulated signaling pathways. For this purpose, biochemical, biophysical, molecular, proteomic, and cellular experiments were performed. Turbidimetry measurements show that LP3 and DP3 inhibit LDL aggregation induced by SMase and PLA2 in a dose-dependent manner, although the efficacy of DP3 is higher. Gel filtration chromatography (GFC) and transmission electron microscopy (TEM) show that LP3, and more efficiently DP3, almost completely counteract the increased percentage of aggregated LDL induced by both SMase and PLA2, respectively. Native polyacrilamide gradient gel electrophoresis (GGE), agarose gel electrophoresis (AGE) and high-performance thin layer chromatography (HPTLC) partitioning of LDL phospholipids indicated that LP3 and DP3 prevent SMase-induced alterations in LDL size, electric charge and phospholipid content but not those induced by PLA2. In contrast, LP3 and DP3 show high efficacy to counteract changes in ApoB-100 conformation induced by both SMase and PLA2. Together, these results indicate that LRP1-derived peptides protect LDL against aggregation induced by SMase and PLA2 through a common mechanism based on their capacity to prevent ApoB-100 conformational changes. Proteomics and computational modeling methods suggest that LRP1 derived peptides are able to establish strong electrostatic interactions with a specific ApoB-100 basic region. TLC and confocal microscopy show that DP3 with higher efficacy than LP3 significantly reduce intracellular cholesteryl ester accumulation induced by SMase-LDL in hcVSMC. Moreover, proteomics studies evidence several signaling pathways modulated by SMase-LDL that are counteracted specifically by DP3. These findings demonstrate that LRP1 derivative peptides protect against LDL aggregation and preserve vascular cells against cholesterol loading and associated alterations in critical signal pathways

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Evidence of mechanism how rs7575840 influences apolipoprotein B containing lipid particles

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