李梦婷
中国医学科学院阜外医院 群体遗传研究室
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
Our previous study found expression of GALNT3 gene was reduced in coronary artery disease (CAD) patients, and it contributed to endothelial injury by regulating apoptosis and matrix metalloproteinase (MMP) expression. GALNT3 gene may be a potential target for future therapeutic intervention of CAD. However, none reports linking the GALNT3 gene to susceptibility of CAD. This study investigated the variant associations of GALNT3 gene and CAD. Thirteen single nucleotide polymorphism (SNP) in and around the GALNT3 gene were tagged and analyzed in CAD patients (n = 1515) and control individuals (n = 5019), and the SNPs with CAD were tested with multiple logistic regression analysis in an additive genetic model (with one degree of freedom) after adjusting for age and sex. Expression of GALNT3 gene was detected by real-time PCR and Western blot. Luciferase reporter assays were used to detect the allele-specific effect of rs4621175 on transcriptional activity. Two GALNT3 markers, rs13427924 and rs4621175, were significantly associated with CAD (odds ratio [OR] = 0.87, p = 1.01 × 10-3 and OR = 0.75, p = 2.51 × 10-4, respectively), and the risk A allele of rs4621175 was associated with lower GALNT3 expression in both mRNA and protein level; also, A allele showed decreased reporter activity. In addition, we found the level of GALNT3 negatively correlated with MMP-2 gene expression. This study identified GALNT3 as a novel gene that rendered patients susceptible to CAD, and the A allele of a disease-associated variant rs4621175 linked reduced CAD risk through decreased GALNT3 expression. These results confirmed the role of GALNT3 gene in CAD and provided new insights into the genetic regulation of the GALNT3 gene with respect to the pathogenesis of CAD.
DNA and cell biology 2017
BACKGROUND:We aimed to examine the associations of voltage-dependent calcium-channel genes CACNA1A and CACNA1C with blood pressure (BP) changes and hypertension incidence in a longitudinal family study.METHODS:A total of 1,768 Han Chinese participants from the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study were eligible for the current study. Nine BP measurements were obtained at baseline and each follow-up visit using a random-zero sphygmomanometer. Mixed-effect models were used to assess additive associations of 176 tag single-nucleotide polymorphisms (SNPs) in CACNA1A and CACNA1C with longitudinal BP changes and hypertension incidence. The truncated product method was used for gene-based analysis. The Bonferroni correction was used for adjustment of multiple testing.RESULTS:During an average of 7.2 years of follow-up, 512 (32.1%) participants developed hypertension. CACNA1A SNP rs8182538 was significantly associated with longitudinal diastolic BP (DBP) change after Bonferroni correction ( Pinteraction = 9.90×10 -5 ), with mean DBP increases of 0.85, 1.03, and 1.19mm Hg per year for participants with genotypes C/C , C/T , and T/T , respectively. A similar trend was observed for the association of rs8182538 with systolic BP (SBP) change. In the gene-based analysis, CACNA1A and CACNA1C were significantly associated with DBP change ( P = 2.0×10 -5 ) and SBP change ( P = 1.4×10 -4 ) after Bonferroni correction, respectively. The gene-based associations remained significant after removing rs8182538 within CACNA1A and rs758116 within CACNA1C in sensitivity analysis.CONCLUSIONS:Our findings indicated that CACNA1A and CACNA1C might contribute to BP changes over time in Han Chinese population. Further replication of these findings is warranted.
American journal of hypertension 2016
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
