Search

Hypertension or hypotension prevails as a comorbidity in patients with heart failure (HF). Although blood pressure (BP) is an important factor in managing the mortality of HF, the molecular mechanisms of changes in BP have not been clearly understood in cases of HF. We and others have demonstrated that a loss in PRDM16 causes hypertrophic cardiomyopathy, leading to HF. We aimed to determine whether BP is altered in mice that experience cardiac loss of Prdm16 and identify the underlying mechanism of BP-associated changes. BP decreased significantly only in female mice with a cardiac-null mutation of Prdm16 compared with controls, by an invasive protocol under anesthesia and by telemetric method during conscious, unrestrained status. Mice with a cardiac loss of Prdm16 had higher heart-to-body weight ratios and upregulated atrial natriuretic peptide, suggesting cardiac hypertrophy. Plasma aldosterone-to-renin activity ratios and plasma sodium levels decreased in Prdm16-deficient mice versus control. By RNA-seq and in subsequent functional analyses, Prdm16-null hearts were enriched in factors that regulate BP, including Adra1a, Nos1, Nppa, and Nppb. The inhibition of nitric oxide synthase 1 (NOS1) reverted the decrease in BP in cardiac-specific Prdm16 knockout mice. Mice with cardiac deficiency of Prdm16 present with hypotension and cardiac hypertrophy. Further, our findings suggest that the increased expression of NOS1 causes hypotension in mice with a cardiac-null mutation of Prdm16. These results provide novel insights into the molecular mechanisms of hypotension in subjects with HF and contribute to our understanding of how hypotension develops in patients with HF.

The objective of this study is to find single nucleotide polymorphisms (SNPs) associated with a risk of Type 2 diabetes (T2D) in Korean adults and to investigate the longitudinal association between these SNPs and T2D and the interaction effects of iron intake and average hemoglobin level. Data from the KoGES_Ansan and Ansung Study were used. Gene-iron interaction analysis was conducted using a two-step approach. To select candidate SNPs associated with T2D, a total of 7,935 adults at baseline were included in genome-wide association analysis (step one). After excluding T2D prevalent cases, prospective analyses were conducted with 7,024 adults aged 40-69 (step two). The association of selected SNPs and iron status with T2D and their interaction were determined using a Cox proportional hazard model. A total of 3 SNPs [rs9465871 (CDKAL1), rs10761745 (JMJD1C), and rs163177 (KCNQ1)] were selected as candidate SNPs related to T2D. Among them, rs10761745 (JMJD1C) and rs163177 (KCNQ1) were prospectively associated with T2D. High iron intake was also prospectively associated with the risk of T2D after adjusting for covariates. Average hemoglobin level was positively associated with T2D after adjusting for covariates in women. We also found significant interaction effects between rs10761745 (JMJD1C) and average hemoglobin levels on the risk of T2D among women with normal inflammation and without anemia at baseline. In conclusion, KCNQ1 and JMJD1C may prospectively contribute to the risk of T2D incidence among adults over the age of 40 and JMJD1C, but CDKAL1 may not, and iron status may interactively contribute to T2D incidence in women.

Previously, genetic polymorphisms of C12orf51 (HECTD4) (rs2074356 and/or rs11066280) have been shown to be related to alcohol consumption and type 2 diabetes (T2D). This study aimed to prospectively examine whether C12orf51 had an interaction with or independent effect on alcohol consumption and the risk of T2D. The present study included 3,244 men and 3,629 women aged 40 to 69 years who participated in the Korean Genome and Epidemiology Study (KoGES)_Ansan and Ansung Study. Cox proportional hazards models were used to estimate HRs and 95% CIs for T2D. rs2074356 and rs11066280 were associated with the risk of T2D after adjusting for alcohol consumption (rs2074356 for AA: HR = 0.39 and 95% CI = 0.17-0.87 in men, and HR = 0.36 and 95% CI = 0.13-0.96 in women; rs11066280 for AA: HR = 0.44 and 95% CI = 0.23-0.86 in men, and HR = 0.39 and 95% CI = 0.16-0.94 in women). We identified that the association of each variant (rs2074356 and rs11065756) in C12orf51 was nearly unchanged after adjusted for alcohol consumption. Therefore, the association of 2 SNPs in C12orf51 with diabetes may not be mediated by alcohol use. There was no interaction effect between alcohol consumption and the SNPs with T2D. However, even in never-drinkers, minor allele homozygote strongly influenced T2D risk reduction (rs2074356 for AA: HR = 0.35, 95% CI = 0.14-0.90, and p-trend = 0.0035 in men and HR = 0.34, 95% CI = 0.13-0.93, and p-trend = 0.2348 in women; rs11066280 for AA: HR = 0.36, 95% CI = 0.16-0.82, and p-trend = 0.0014 in men and HR = 0.39, 95% CI = 0.16-0.95, and p-trend = 0.3790 in women), while alcohol consumption did not influence the risk of T2D within each genotype. rs2074356 and rs11066280 in or near C12orf51, which is related to alcohol drinking behavior, may longitudinally decrease the risk of T2D, but not through regulation of alcohol consumption.

Recent genome-wide association studies have identified 33 human genetic loci that influence blood pressure. The 15q24 locus is one such locus that has been confirmed in Asians and Europeans. There are 21 genes in the locus within a 1-Mb boundary, but a functional link of these genes to blood pressure has not been reported. We aimed to identify a causative gene for blood pressure change in the 15q24 locus.CSK and ULK3 were selected as candidate genes based on eQTL analysis studies that showed the association between gene transcript levels and the lead SNP (rs1378942). Injection of siRNAs for mouse homologs Csk, Ulk3, and Cyp1a2 (negative control) showed reduced target gene mRNA levels in vivo. However, Csk siRNA only increased blood pressure while Ulk3 and Cyp1a2 siRNA did not change it. Further, blood pressure in Csk+/- heterozygotes was higher than in wild-type, consistent with what we observed in Csk siRNA-injected mice. We confirmed that haploinsufficiency of Csk increased the active form of Src in Csk+/- mice aorta. We also showed that inhibition of Src by PP2, a Src inhibitor decreased high blood pressure in Csk+/- mice and the active Src in Csk+/- mice aorta and in Csk knock-down vascular smooth muscle cells, suggesting blood pressure regulation by Csk through Src.Our study demonstrates that Csk is a causative gene in the 15q24 locus and regulates blood pressure through Src, and these findings provide a novel therapeutic target for the treatment of hypertension.