Discovery of High-Density Lipoprotein Gene Targets from Classical Genetics to Genome-Wide Association Studies

2016 ◽  
pp. 119-159 ◽  
Author(s):  
Lita A. Freeman ◽  
Alan T. Remaley
Keyword(s):  
High Density Lipoprotein ◽  
Association Studies ◽  
Density Lipoprotein ◽  
High Density ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Classical Genetics

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

The Yin and Yang of High-density Lipoprotein and Atherosclerotic Cardiovascular Disease: Focusing on Functionality and Cholesterol Efflux to Reframe the HDL Hypothesis

2021 ◽  
Vol 28 ◽  
Author(s):  
Shiva Ganjali ◽  
Gerald F. Watts ◽  
Maciej Banach ◽  
Željko Reiner ◽  
Petr Nachtigal ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
High Density Lipoprotein ◽  
Cholesterol Efflux ◽  
Association Studies ◽  
Plasma Concentrations ◽  
Density Lipoprotein ◽  
High Density ◽  
Atherosclerotic Cardiovascular Disease ◽  
Genome Wide Association Studies ◽  
Increased Risk

Abstract: The inverse relationship between low plasma high-density lipoprotein cholesterol (HDL-C) concentrations and increased risk of Atherosclerotic Cardiovascular Disease (ASCVD) is well-known. However, plasma HDL-C concentrations are highly variable in subjects with ASCVD. In clinical outcome trials, pharmacotherapies that increase HDL-C concentrations are not associated with a reduction in ASCVD events. A causal relationship between HDL-C and ASCVD has also been questioned by Mendelian randomization studies and genome-wide association studies of genetic variants associated with plasma HDL-C concentrations. The U-shaped association between plasma HDL-C concentrations and mortality observed in several epidemiological studies implicates both low and very high plasma HDL-C concentrations in the etiology of ASCVD and non-ASCVD mortality. These data do not collectively support a causal association between HDL-C and ASCVD risk. Therefore, the hypothesis concerning the association between HDL and ASCVD has shifted from focus on plasma concentrations to the concept of functionality, in particular cellular cholesterol efflux and HDL holoparticle transport. In this review, we focus on these new concepts and provide a new framework for understanding and testing the role of HDL in ASCVD.

scholarly journals A Genome-Wide Association Study of Monozygotic Twin-Pairs Suggests a Locus Related to Variability of Serum High-Density Lipoprotein Cholesterol

2012 ◽  
Vol 15 (6) ◽  
pp. 691-699 ◽  
Author(s):  
Ida Surakka ◽  
John B. Whitfield ◽  
Markus Perola ◽  
Peter M. Visscher ◽  
Grant W. Montgomery ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
High Density Lipoprotein Cholesterol ◽  
Serum Lipid ◽  
Density Lipoprotein ◽  
Monozygotic Twin ◽  
High Density ◽  
Genome Wide Association ◽  
Lipoprotein Cholesterol ◽  
Genome Wide ◽  
A Genome

Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene–environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (P = 3.98 × 10−8). We followed up the association in further genotyped monozygotic twins (N = 1,261), which showed a moderate association for the variant (P = 0.200, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (P = 4.03 × 10−8).

scholarly journals Rice Galaxy: an open resource for plant science

2018 ◽  
Author(s):  
Venice Juanillas ◽  
Alexis Dereeper ◽  
Nicolas Beaume ◽  
Gaetan Droc ◽  
Joshua Dizon ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Association Studies ◽  
Open Data ◽  
Bacterial Pathogen ◽  
Population Diversity ◽  
High Density ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Germplasm Collections ◽  
Genome Wide

AbstractBackgroundRice molecular genetics, breeding, genetic diversity, and allied research (such as rice-pathogen interaction) have adopted sequencing technologies and high density genotyping platforms for genome variation analysis and gene discovery. Germplasm collections representing rice diversity, improved varieties and elite breeding materials are accessible through rice gene banks for use in research and breeding, with many having genome sequences and high density genotype data available. Combining phenotypic and genotypic information on these accessions enables genome-wide association analysis, which is driving quantitative trait loci (QTL) discovery and molecular marker development. Comparative sequence analyses across QTL regions facilitate the discovery of novel alleles. Analyses involving DNA sequences and large genotyping matrices for thousands of samples, however, pose a challenge to non-computer savvy rice researchers.FindingsWe adopted the Galaxy framework to build the federated Rice Galaxy resource, with shared datasets, tools, and analysis workflows relevant to rice research. The shared datasets include high density genotypes from the 3,000 Rice Genomes project and sequences with corresponding annotations from nine published rice genomes. Rice Galaxy includes tools for designing single nucleotide polymorphism (SNP) assays, analyzing genome-wide association studies, population diversity, rice-bacterial pathogen diagnostics, and a suite of published genomic prediction methods. A prototype Rice Galaxy compliant to Open Access, Open Data, and Findable, Accessible, Interoperable, and Reproducible principles is also presented.ConclusionsRice Galaxy is a freely available resource that empowers the plant research community to perform state-of-the-art analyses and utilize publicly available big datasets for both fundamental and applied science.

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.

scholarly journals A modified forward multiple regression in high-density genome-wide association studies for complex traits

2009 ◽  
Vol 33 (6) ◽  
pp. 518-525 ◽  
Author(s):  
Xiangjun Gu ◽  
Ralph F. Frankowski ◽  
Gary L. Rosner ◽  
Mary Relling ◽  
Bo Peng ◽  
...  
Keyword(s):  
Multiple Regression ◽  
Complex Traits ◽  
Association Studies ◽  
High Density ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide
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