Apolipoprotein E-C1-C4-C2 gene cluster region and inter-individual variation in plasma lipoprotein levels: a comprehensive genetic association study in two ethnic groups

Pirim, Dilek; Radwan, Zaheda H.; Wang, Xingbin; Niemsiri, Vipavee; Hokanson, John E.; Hamman, Richard F.; Feingold, Eleanor; Bunker, Clareann H.; Demirci, Fuat; Kamboh, M. Ilyas

doi:10.1371/journal.pone.0214060

Cited by 18 publications

(22 citation statements)

References 59 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent advances in research demonstrated that long non-coding RNA is endowed with regulatory properties, as reviewed in [25]. In this respect, a recent report identified polymorphism rs5112 in APOC1P to significantly affect LDL-cholesterol levels in non-Hispanic Whites [16]. In addition, non-coding RNA APOC1P1-3 was found to reduce α-tubulin acetylation and consequently block apoptosis in breast cancer [26] and to regulate migration and inflammation in cholangiocarcinoma [27].…”

Section: Apoc1 Genementioning

confidence: 99%

See 1 more Smart Citation

Apolipoprotein C1: Its Pleiotropic Effects in Lipid Metabolism and Beyond

Fuior¹,

Gafencu²

2019

IJMS

127

View full text Add to dashboard Cite

Apolipoprotein C1 (apoC1), the smallest of all apolipoproteins, participates in lipid transport and metabolism. In humans, APOC1 gene is in linkage disequilibrium with APOE gene on chromosome 19, a proximity that spurred its investigation. Apolipoprotein C1 associates with triglyceride-rich lipoproteins and HDL and exchanges between lipoprotein classes. These interactions occur via amphipathic helix motifs, as demonstrated by biophysical studies on the wild-type polypeptide and representative mutants. Apolipoprotein C1 acts on lipoprotein receptors by inhibiting binding mediated by apolipoprotein E, and modulating the activities of several enzymes. Thus, apoC1 downregulates lipoprotein lipase, hepatic lipase, phospholipase A2, cholesterylester transfer protein, and activates lecithin-cholesterol acyl transferase. By controlling the plasma levels of lipids, apoC1 relates directly to cardiovascular physiology, but its activity extends beyond, to inflammation and immunity, sepsis, diabetes, cancer, viral infectivity, and—not last—to cognition. Such correlations were established based on studies using transgenic mice, associated in the recent years with GWAS, transcriptomic and proteomic analyses. The presence of a duplicate gene, pseudogene APOC1P, stimulated evolutionary studies and more recently, the regulatory properties of the corresponding non-coding RNA are steadily emerging. Nonetheless, this prototypical apolipoprotein is still underexplored and deserves further research for understanding its physiology and exploiting its therapeutic potential.

show abstract

Section: Apoc1 Genementioning

confidence: 99%

“…Although the three APOE alleles appear to be determinant for the plasma lipidemia [15], other apoE-independent polymorphisms found in the cluster contribute to lipid homeostasis [16].…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein C1: Its Pleiotropic Effects in Lipid Metabolism and Beyond

Fuior¹,

Gafencu²

2019

IJMS

127

View full text Add to dashboard Cite

show abstract

“…In each simulation, we randomly selected 2 or 7 of variants generated from the CEU 1000 Genomes reference as causal variants; None of the variants generated from the YRI 1000 Genomes reference samples was selected as causal, mimicking the genetic heterogeneity observed in Pirim et al (2019). Out of K = 10 studies, we considered 1, 2, 5, or 7 studies composed of the CEU samples, and the rest were YRI samples.…”

Section: Simulationsmentioning

confidence: 99%

“…The simulated CEU samples included 15 RVs in the APOE region, while the simulated YRI samples included 30 RVs. In each simulation, we randomly selected 2 or 7 of variants generated from the CEU 1000 Genomes reference as causal variants; None of the variants generated from the YRI 1000 Genomes reference samples was selected as causal, mimicking the genetic heterogeneity observed in Pirim et al (2019).…”

Section: Simulationsmentioning

confidence: 99%

An adaptive test for meta‐analysis of rare variant association studies

Yang

Kim

et al. 2019

Genetic Epidemiology

View full text Add to dashboard Cite

Single genome-wide studies may be underpowered to detect trait-associated rare variants with moderate or weak effect sizes. As a viable alternative, meta-analysis is widely used to increase power by combining different studies. The power of meta-analysis critically depends on the underlying association patterns and heterogeneity levels, which are unknown and vary from locus to locus. However, existing methods mainly focus on one or only a few combinations of the association pattern and heterogeneity level, thus may lose power in many situations. To address this issue, we propose a general and unified framework by combining a class of tests including and beyond some existing ones, leading to high power across a wide range of scenarios. We demonstrate that the proposed test is more powerful than some existing methods in simulation studies, then show their performance with the NHLBI Exome-Sequencing Project (ESP) data.One gene (B4GALNT2) was found by our proposed test, but not by others, to be statistically significantly associated with plasma triglyceride. The signal was driven by African-ancestry subjects but it was previously reported to be associated with coronary artery disease among European-ancestry subjects. We implemented our method in an R package aSPUmeta, publicly available at https://github. com/ytzhong/metaRV and will be on CRAN soon. K E Y W O R D SaSPU, genetic heterogeneity, statistical power, whole-exome sequencing, whole-genome sequencing *Tianzhong Yang and Junghi Kim contributed equally to this work.

show abstract

“…In the Finnish cohort, the 19q13.31 and 19q13.32 loci exhibited genome-wide significance for serum LDL concentration, but the 1p32 loci did not [ 15 ]. On the other hand, the loci were reported to be associated with TG and HDL in non-Hispanic Caucasians and Africans [ 16 ]. These studies indicate that the genetic variants in 19q13.32 play an important role in the lipid metabolism, including hyper-LDL-cholesterolemia.…”

Section: Introductionmentioning

confidence: 99%

A minor allele of the haplotype located in the 19q13 loci is associated with a decreased risk of hyper-LDL-cholesterolemia, and a balanced diet and high protein intake can reduce the risk

Park

Kang

2020

Lipids Health Dis

View full text Add to dashboard Cite

Background Although the human chromosome 19q13 loci are reported to be associated with hyper-LDL-cholesterolemia, the haplotype of single nucleotide polymorphism (SNP) has not been studied. Therefore, the association of the haplotype in 19q13 loci with hyper-LDL-cholesterolemia was determined and their interactions with lifestyles and nutrient intakes were evaluated in 28,445 Koreans aged > 40 years. Methods SNPs were selected from 19q13 loci that had an association with hyper-LDL-cholesterolemia with the adjustment of confounders (age, gender, area of residence, and body mass index). Haplotype was constructed from the selected SNPs. An adjusted odds ratio of the haplotype for hyper-LDL-cholesterolemia and the interaction between haplotype and lifestyles was analyzed after adjusting for covariates. Results Hyper-LDL-cholesterolemia had an association with apolipoprotein E ( APOE) _ rs7259620, translocase of outer mitochondrial membrane 40( TOMM40) _rs157581, poliovirus receptor-related 2( PVRL2) _rs403155, exocyst complex component 3-like 2( EXOC3L2) _ rs10406604 and CD3e molecule-associated protein ( CD3EAP) _rs3212986 in 19q13. The haplotype of these SNPs had a negative association with hyper-total-cholesterolemia and hyper-LDL-cholesterolemia by 0.669 and 0.684 times, respectively, after adjusting for covariates. The incidence of cardiovascular diseases, especially myocardial infarction, had a negative association with the minor alleles. The balanced diet pattern (BD) and protein intake had a significant interaction with the haplotype: the major-allele of the haplotype exhibited a positive association with hyper-LDL-cholesterolemia, compared to the minor allele, only when combined with a high intake of BD. The participants with the minor allele exhibited a lower hyper-LDL-cholesterolemia risk compared to those with the major allele only with high protein intake. Conclusion The minor allele of haplotype located in 19q13 loci protected against hyper-LDL-cholesterolemia, especially with BD and high protein intake. The minor allele also had a negative association with myocardial infarction events.

show abstract

Apolipoprotein E-C1-C4-C2 gene cluster region and inter-individual variation in plasma lipoprotein levels: a comprehensive genetic association study in two ethnic groups

Cited by 18 publications

References 59 publications

Apolipoprotein C1: Its Pleiotropic Effects in Lipid Metabolism and Beyond

Apolipoprotein C1: Its Pleiotropic Effects in Lipid Metabolism and Beyond

An adaptive test for meta‐analysis of rare variant association studies

A minor allele of the haplotype located in the 19q13 loci is associated with a decreased risk of hyper-LDL-cholesterolemia, and a balanced diet and high protein intake can reduce the risk

Contact Info

Product

Resources

About