郭利伟
中国医学科学院阜外医院 群体遗传
BACKGROUND:The large-scale meta-analysis of genome-wide association study (GWAS) recently identified a genomic locus where the genetic variant at rs820430 was strongly associated with hypertension in Chinese Han population, with its T allele conferred increased risks. However, the biological and disease-relevant mechanisms for this association remain elusive.METHODS:A group of 275 participants from rural district of Shandong Province were enrolled, rs820430 was genotyped using genomic DNA with the fluorogenic 5'-nuclease TaqMan allelic discrimination assay system (Applied Biosystems, CA). In vitro experiments were performed in this study, such as luciferase reporter assays, gel mobility shift assays (electrophoretic mobility shift assay), and chromatin immunoprecipitation.RESULTS:We found the risk T allele of rs820430 was associated with higher SLC4A7 mRNA level in cohort population. Furthermore, we characterized a cis-regulatory mechanism that the T allele of rs820430 distinctively increased c-Fos transcription factor binding, by which leading to increased SLC4A7 expression.CONCLUSIONS:The present study indicated that the disease-associated T allele of a new hypertension risk variant rs820430 linked increased hypertension risk through higher SLC4A7 expression, and rs820430 functioned as an enhancer of SLC4A7 transcription by allele distinctively increased c-Fos transcription factor binding.
American journal of hypertension 2017
OBJECTIVE:The GALNT3 gene encodes polypeptide N-acetylgalactosaminyl transferase 3 (GalNAc-T3), a member of the GalNAc-Ts family that transfers the N-acetylgalactosamine to the hydroxyl group of serine and threonine residue in the first step of O-linked oligosaccharide biosynthesis. Emerging evidences have linked GalNAc-Ts family to coronary artery disease (CAD). However the effect of GALNT3 in CAD is unknown. The present study investigated the function and mechanisms of GALNT3 gene in endothelial injury.METHODS AND RESULTS:The GALNT3 mRNA level was decreased by 48.2% in CAD patients (n = 58), compared with that of controls (n = 120). Expression of GALNT3 was also decreased in human umbilical vein endothelial cells (HUVECs) treated with CAD sera and subjected to hypoxia in vitro. Knockdown of GALNT3 promoted apoptosis and up-regulated the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-14 (MMP-14). Conversely, overexpression of GALNT3 significantly inhibited HUVECs apoptosis and down-regulated the expression of MMP-2 and MMP-14 genes, in addition, overexpression of GALNT3 attenuated hypoxia-induced apoptosis and expression of MMP-2 and MMP-14. Finally, the ratio of cytosolic p-p38 MAPK/p38 MAPK expression was significantly increased with GALNT3 knockdown and lower with GALNT3 overexpression, while the p38 MAPK inhibitor SB203580 blocked the effects of GALNT3 knockdown.CONCLUSIONS:Expression of GALNT3 was reduced in CAD patients, and down regulation of GALNT3 contributed to endothelial injury by promoting apoptosis and up-regulating the expression of MMP-2 and MMP-14 genes via p38 MAPK activation. GALNT3 may be a potential target for future therapeutic intervention for CAD.
Atherosclerosis 2016
