Low density lipoprotein metabolism, hepatic lipase and coronary disease: Intriguing findings from genome wide association studies

2010 ◽  
Vol 27 ◽  
pp. S18
Author(s):  
M.E. Kleber ◽  
H. Scharnagl ◽  
W. Renner ◽  
T.B. Grammer ◽  
B.T. Ivandic ◽  
...  
Keyword(s):  
Coronary Disease ◽  
Hepatic Lipase ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Low Density ◽  
Genome Wide

Identification of six novel susceptibility loci for dyslipidemia by longitudinal exome-wide association studies in Japanese

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Oguri ◽  
K Kato ◽  
H Horibe ◽  
T Fujimaki ◽  
J Sakuma ◽  
...  
Keyword(s):  
Serum Lipid ◽  
Ldl Cholesterol ◽  
Association Studies ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Cross Sectional ◽  
Genome Wide

Abstract Background The circulating concentrations of triglycerides, high density lipoprotein (HDL)-cholesterol, and low density lipoprotein (LDL)-cholesterol have a substantial genetic component. Although previous genome-wide association studies identified various genes and loci related to plasma lipid levels, those studies were conducted in a cross-sectional manner. Purpose The purpose of the study was to identify genetic variants that confer susceptibility to hypertriglyceridemia, hypo-HDL-cholesterolemia, and hyper-LDL-cholesterolemia in Japanese. We have now performed longitudinal exome-wide association studies (EWASs) to identify novel loci for dyslipidemia by examining temporal changes in serum lipid profiles. Methods Longitudinal EWASs (mean follow-up period, 5 years) for hypertriglyceridemia (2056 case, 3966 controls), hypo-HDL-cholesterolemia (698 cases, 5324 controls), and hyper-LDL-cholesterolemia (2769 cases, 3251 controls) were performed with Illumina Human Exome arrays. The relation of genotypes of 24,691 single nucleotide polymorphisms (SNPs) that passed quality control to dyslipidemia-related traits was examined with the generalized estimating equation (GEE). To compensate for multiple comparisons of genotypes with each of the three conditions, we applied Bonferroni's correction for statistical significance of association. Replication studies with cross-sectional data were performed for hypertriglyceridemia (2685 cases, 4703 controls), hypo-HDL-cholesterolemia (1947 cases, 6146 controls), and hyper-LDL-cholesterolemia (1719 cases, 5833 controls). Results Longitudinal EWASs revealed that 30 SNPs were significantly (P<2.03 × 10–6 by GEE) associated with hypertriglyceridemia, 46 SNPs with hypo-HDL-cholesterolemia, and 25 SNPs with hyper-LDL-cholesterolemia. After examination of the relation of identified SNPs to serum lipid profiles, linkage disequilibrium, and results of the previous genome-wide association studies, we newly identified rs74416240 of TCHP, rs925368 of GIT2, rs7969300 of ATXN2, and rs12231744 of NAA25 as a susceptibility loci for hypo-HDL-cholesterolemia; and rs34902660 of SLC17A3 and rs1042127 of CDSN for hyper-LDL-cholesterolemia. These SNPs were not in linkage disequilibrium with those previously reported to be associated with dyslipidemia, indicating independent effects of the SNPs identified in the present study on serum concentrations of HDL-cholesterol or LDL-cholesterol in Japanese. According to allele frequency data from the 1000 Genomes project database, five of the six identified SNPs were monomorphic or rare variants in European populations. In the replication study, all six SNPs were associated with dyslipidemia-related phenotypes. Conclusion We have thus identified six novel loci that confer susceptibility to hypo-HDL-cholesterolemia or hyper-LDL-cholesterolemia. Determination of genotypes for these SNPs at these loci may prove informative for assessment of the genetic risk for dyslipidemia in Japanese. Funding Acknowledgement Type of funding source: None

scholarly journals Investigating genetically mimicked effects of statins via HMGCR inhibition on immune-related diseases in men and women using Mendelian randomization

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Guoyi Yang ◽  
C. Mary Schooling
Keyword(s):  
Lupus Erythematosus ◽  
Multiple Testing ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Allergic Diseases ◽  
Genome Wide Association Studies ◽  
East Asians ◽  
Genome Wide

AbstractStatins have been suggested as a potential treatment for immune-related diseases. Conversely, statins might trigger auto-immune conditions. To clarify the role of statins in allergic diseases and auto-immune diseases, we conducted a Mendelian randomization (MR) study. Using established genetic instruments to mimic statins via 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition, we assessed the effects of statins on asthma, eczema, allergic rhinitis, rheumatoid arthritis (RA), psoriasis, type 1 diabetes, systemic lupus erythematosus (SLE), multiple sclerosis (MS), Crohn’s disease and ulcerative colitis in the largest available genome wide association studies (GWAS). Genetically mimicked effects of statins via HMGCR inhibition were not associated with any immune-related diseases in either study after correcting for multiple testing; however, they were positively associated with the risk of asthma in East Asians (odds ratio (OR) 2.05 per standard deviation (SD) decrease in low-density lipoprotein cholesterol (LDL-C), 95% confidence interval (CI) 1.20 to 3.52, p value 0.009). These associations did not differ by sex and were robust to sensitivity analysis. These findings suggested that genetically mimicked effects of statins via HMGCR inhibition have little effect on allergic diseases or auto-immune diseases. However, we cannot exclude the possibility that genetically mimicked effects of statins via HMGCR inhibition might increase the risk of asthma in East Asians.

Abstract 205: Impact of PLPP3 Gene Deficiency on Lipid Metabolism and Signaling

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Suchismita Halder
Keyword(s):  
Lipid Metabolism ◽  
Disease Risk ◽  
Biological Fluids ◽  
Association Studies ◽  
Cardiovascular Disease Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Genome Wide Association Studies ◽  
Low Density ◽  
Lipid Phosphate

Genome wide association studies identify heritable variants within the final intron of the PLPP3 gene that associate with coronary artery disease risk. The risk associated alleles of these variants alter activity of an enhancer sequence that acts in cis to upregulate expression of the gene in response to inflammatory and atherogenic stimuli (for example oxidized low density lipoprotein) and may have longer distance effects on expression of other genes. PLPP3 encodes lipid phosphate phosphatase 3 (LPP3) which is an integral membrane enzyme that dephosphorylates lipid phosphate esters. These substrates are bioactive signaling molecules at the cell surface including lysophosphatidic acid (LPA) and sphingosine 1 phosphate (S1P) and intracellular intermediates in pathways of lipid metabolism and signaling, for example ceramide 1 phosphate and phosphatidic acid. PLPP3 is essential for vascular development in mice. We have generated mice with inducible post-natal and tissue specific inactivation of this gene which are viable and exhibit accelerated atherosclerosis on a low density lipoprotein receptor knockout background after feeding atherogenic diets. Analysis using targeted and untargeted approaches using multistage and high resolution mass spectrometry reveal that LPP3 deficiency results in significant differences in levels of some LPP3 substrates and products in cells, tissues and biological fluids from these animals. These observations support the hypothesis that alterations in levels of these LPP3 substrates or their dephosphorylation products account for or contribute to the mechanisms by which alterations in LPP3 expression influence cardiovascular disease risk.

scholarly journals Functional Haplotype of LIPC Induces Triglyceride-Mediated Suppression of HDL-C Levels According to Genome-Wide Association Studies

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 148
Author(s):  
Yu-Huang Liao ◽  
Leay-Kiaw Er ◽  
Semon Wu ◽  
Yu-Lin Ko ◽  
Ming-Sheng Teng
Keyword(s):  
Hepatic Lipase ◽  
Association Studies ◽  
Luciferase Reporter Assay ◽  
Genome Wide Association ◽  
Luciferase Reporter ◽  
Genome Wide Association Studies ◽  
Reporter Assay ◽  
Triacylglycerol Lipase ◽  
Genome Wide ◽  
A Genome

Hepatic lipase (encoded by LIPC) is a glycoprotein in the triacylglycerol lipase family and mainly synthesized in and secreted from the liver. Previous studies demonstrated that hepatic lipase is crucial for reverse cholesterol transport and modulating metabolism and the plasma levels of several lipoproteins. This study was conducted to investigate the suppression effect of high-density lipoprotein cholesterol (HDL-C) levels in a genome-wide association study and explore the possible mechanisms linking triglyceride (TG) to LIPC variants and HDL-C. Genome-wide association data for TG and HDL-C were available for 4657 Taiwan-biobank participants. The prevalence of haplotypes in the LIPC promoter region and their effects were calculated. The cloned constructs of the haplotypes were expressed transiently in HepG2 cells and evaluated in a luciferase reporter assay. Genome-wide association analysis revealed that HDL-C was significantly associated with variations in LIPC after adjusting for TG. Three haplotypes (H1: TCG, H2: CTA and H3: CCA) in LIPC were identified. H2: CTA was significantly associated with HDL-C levels and H1: TCG suppressed HDL-C levels when a third factor, TG, was included in mediation analysis. The luciferase reporter assay further showed that the H2: CTA haplotype significantly inhibited luciferase activity compared with the H1: TCG haplotype. In conclusion, we identified a suppressive role for TG in the genome-wide association between LIPC and HDL-C. A functional haplotype of hepatic lipase may reduce HDL-C levels and is suppressed by TG.

scholarly journals High-Density Lipoproteins and the Immune System

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Hidesuke Kaji
Keyword(s):  
Immune System ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Density ◽  
Ldl Oxidation ◽  
High Density Lipoproteins ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Adaptive Immune Systems

High-density lipoprotein (HDL) plays a major role in vasodilation and in the reduction of low-density lipoprotein (LDL) oxidation, inflammation, apoptosis, thrombosis, and infection; however, HDL is now less functional in these roles under certain conditions. This paper focuses on HDL, its anti-inflammation behavior, and the mechanisms by which HDL interacts with components of the innate and adaptive immune systems. Genome-wide association studies (GWAS) and proteomic studies have elucidated important molecules involved in the interaction between HDL and the immune system. An understanding of these mechanisms is expected to be useful for the prevention and treatment of chronic inflammation due to metabolic syndrome, atherosclerosis, or various autoimmune diseases.

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