Knowledge-Driven Analysis Identifies a Gene–Gene Interaction Affecting High-Density Lipoprotein Cholesterol Levels in Multi-Ethnic Populations

Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease. We tested for gene–gene interactions affecting the level of these four lipids based on prior knowledge of established genome-wide association study (GWAS) hits, protein–protein interactions, and pathway information. Using genotype data from 9,713 European Americans from the Atherosclerosis Risk in Communities (ARIC) study, we identified an interaction between HMGCR and a locus near LIPC in their effect on HDL-C levels (Bonferroni corrected Pc = 0.002). Using an adaptive locus-based validation procedure, we successfully validated this gene–gene interaction in the European American cohorts from the Framingham Heart Study (Pc = 0.002) and the Multi-Ethnic Study of Atherosclerosis (MESA; Pc = 0.006). The interaction between these two loci is also significant in the African American sample from ARIC (Pc = 0.004) and in the Hispanic American sample from MESA (Pc = 0.04). Both HMGCR and LIPC are involved in the metabolism of lipids, and genome-wide association studies have previously identified LIPC as associated with levels of HDL-C. However, the effect on HDL-C of the novel gene–gene interaction reported here is twice as pronounced as that predicted by the sum of the marginal effects of the two loci. In conclusion, based on a knowledge-driven analysis of epistasis, together with a new locus-based validation method, we successfully identified and validated an interaction affecting a complex trait in multi-ethnic populations

Functional Promoter Polymorphisms Govern Differential Expression of HMG-CoA Reductase Gene in Mouse Models of Essential Hypertension

3-Hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase gene (Hmgcr) is a susceptibility gene for essential hypertension. Sequencing of the Hmgcr locus in genetically hypertensive BPH (blood pressure high), genetically hypotensive BPL (blood pressure low) and genetically normotensive BPN (blood pressure normal) mice yielded a number of single nucleotide polymorphisms (SNPs). BPH/BPL/BPN Hmgcr promoter-luciferase reporter constructs were generated and transfected into liver HepG2, ovarian CHO, kidney HEK-293 and neuronal N2A cells for functional characterization of the promoter SNPs. The BPH-Hmgcr promoter showed significantly less activity than the BPL-Hmgcr promoter under basal as well as nicotine/cholesterol-treated conditions. This finding was consistent with lower endogenous Hmgcr expression in liver and lower plasma cholesterol in BPH mice. Transfection experiments using 5′-promoter deletion constructs (strategically made to assess the functional significance of each promoter SNP) and computational analysis predicted lower binding affinities of transcription factors c-Fos, n-Myc and Max with the BPH-promoter as compared to the BPL-promoter. Corroboratively, the BPH promoter-luciferase reporter construct co-transfected with expression plasmids of these transcription factors displayed less pronounced augmentation of luciferase activity than the BPL construct, particularly at lower amounts of transcription factor plasmids. Electrophoretic mobility shift assays also showed diminished interactions of the BPH promoter with HepG2 nuclear proteins. Taken together, this study provides mechanistic basis for the differential Hmgcr expression in these mouse models of human essential hypertension and have implications for better understanding the role of this gene in regulation of blood pressure

Differential effects of testosterone, dihydrotestosterone and estradiol on carotenoid deposition in an avian sexually selected signal

Recent studies have demonstrated that carotenoid-based traits are under the control of testosterone (T) by up-regulation of carotenoid carriers (lipoproteins) and/or tissue-specific uptake of carotenoids. T can be converted to dihydrotestosterone (DHT) and estradiol (E2), and variation in conversion rate may partly explain some contradictory findings in the literature. Moreover, most studies on the effect of T on sexual signals have focused on the male sex only, while in many species females show the same signal, albeit to a lesser extent. We studied the effects of T, DHT, and E2 treatment in male and female diamond doves Geopelia cuneata in which both sexes have an enlarged red eye ring, which is more pronounced in males. We first showed that this periorbital ring contains very high concentration of carotenoids, of which most are lutein esters. Both T and DHT were effective in enhancing hue, UV-chroma and size in both sexes, while E2 was ineffective. However, E2 dramatically increased the concentration of circulating lipoproteins. We conclude that in both sexes both color and size of the secondary sexual trait are androgen dependent. The action of androgens is independent of lipoproteins regulation. Potential mechanisms and their consequences for trade-off are discussed

Three genes encode 3-hydroxy-3-methylglutaryl-coenzyme A reductase in Hevea brasiliensis: hmg1 and hmg3 are differentially expressed

10.1007/BF00023395Plant Molecular Biology193473-484PMBI

Signal-mediated sorting of membrane proteins between the endoplasmic reticulum and the Golgi apparatus

Each organelle of the secretory pathway is required to selectively allow transit of newly synthesized secretory and plasma membrane proteins and also to maintain a unique set of resident proteins that define its structural and functional properties. In the case of the endoplasmic reticulum (ER), residency is achieved in two ways: (a) prevention of residents from entering newly forming transport vesicles and (b) retrieval of those residents that escape. The latter mechanism is directed by discrete retrieval motifs: Soluble proteins have a H/KDEL sequence at their carboxy-terminus; membrane proteins have a dibasic motif, either di-lysine or di-arginine, located close to the terminus of their cytoplasmic domain. Recently it was found that di-lysine motifs bind the complex of cytosolic coat proteins, COP I, and that this interaction functions in the retrieval of proteins from the Golgi to the ER. Also discussed are the potential roles this interaction may have in vesicular trafficking