CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients

Abstract

Familial combined hyperlipidemia (FCHL) is a common, complex genetic disorder characterized by a pernicious lipoprotein profi le that markedly increases the risk of premature coronary heart disease (CHD) ( 1-3 ). Affected individuals within families display elevated levels of serum cholesterol and/or triglyceride, plus raised apoB ( 1,(4)(5)(6)(7)(8). Patients may also exhibit high concentrations of cholesterol-enriched VLDL, triglyceride-enriched-HDL and small dense LDL ( 2, 3 ). Precise defi nition, however, is somewhat contentious, refl ecting etiological uncertainty.Abstract The purpose of this study was to determine the core biological processes perturbed in the subcutaneous adipose tissue of familial combined hyperlipidemia (FCHL) patients. Annotation of FCHL and control microarray datasets revealed a distinctive FCHL transcriptome, characterized by gene expression changes regulating fi ve overlapping systems: the cytoskeleton, cell adhesion and extracellular matrix; vesicular traffi cking; lipid homeostasis; and cell cycle and apoptosis. Expression values for the cell-cycle inhibitor CDKN2B were increased, replicating data from an independent FCHL cohort. In 3T3-L1 cells, CDKN2B knockdown induced C/EBP ␣ expression and lipid accumulation. The minor allele at SNP site rs1063192 (C) was predicted to create a perfect seed for the human miRNA-323b-5p. A miR323b-5p mimic signifi cantly reduced endogenous CDKN2B protein levels and the activity of a CDKN2B 3 ′ UTR luciferase reporter carrying the rs1063192 C allele. Although the allele displayed suggestive evidence of association with reduced CDKN2B mRNA in the MuTHER adipose tissue dataset, family studies suggest the association between increased CDKN2B expression and FCHL-lipid abnormalities is driven by factors external to this gene locus. In conclusion, from a comparative annotation analysis of two separate FCHL adipose tissue transcriptomes and a subsequent focus on CDKN2B, we propose that dysfunctional adipogenesis forms an integral part of FCHL pathogenesis. -Horswell, S.

Association study of the miRNA-binding site polymorphisms of CDKN2A/B genes with gestational diabetes mellitus susceptibility

“…In addition, we found that the rs1063192 CC genotype was associated with lower total cholesterol and LDL cholesterol levels. Similar to our findings, an association between the rare rs1063192 allele and lower plasma triglycerides has been documented [29]. rs1063192 has been implication in myocardial infarction, although it is unclear how this SNP affects lipid metabolism [33].…”

“…Consistent with our findings, a recent study suggested that human CDKN2B transcripts harboring the minor C allele at rs1063192 are a direct target of miR-323b-5p. Additionally, this study showed that transfection of HEK293 cells with a miR-323b-5p mimic reduced CDKN2B protein levels despite having no significant impact on CDKN2B mRNA, indicating that miR-323b-5p functions to inhibit translation of its predicted target gene CDKN2B [29]. Taken together, the C allele of rs1063192 enhanced binding of miR-323b-5p, resulting in decreased CDKN2B protein expression.…”

A Genome-Wide Scan for MicroRNA-Related Genetic Variants Associated With Primary Open-Angle Glaucoma

“…Among them, rs1063192 and rs3217992 have been shown previously to affect the miRNA–mRNA interaction in vitro. 21,54 These two SNPs reside in the 3′UTR of CDKN2B and are not in strong LD ( R 2 > 0.8) with any other known CDKN2B variants. The CDKN2B gene encodes a cyclin-dependent kinase inhibitor and with its antisense ( CDKN2B-AS1 ) lies in a well-known glaucoma-associated locus on Chr.9p21.…”

Retinoic Acid Mediates Visceral-Specific Adipogenic Defects of Human Adipose-Derived Stem Cells

“…Of these, CDKN2B and CRBP1 are known to have an anti-adipogenic function (41,42). NR2F1 is expressed more in VS ASCs, and its paralog, NR2F2 , has anti-adipogenic capacity as well (43).…”