Genetic variants and mRNA expression of KLF4 and KLF5 with hypertension: A combination of case-control study and cohort study.

Hypertension (HT) is a major risk factor for cardiovascular diseases. Krüppel-like factors (KLFs) are important transcription factors in eukaryotes. Studies have reported that KLF4 and KLF5 are correlated with several cardiovascular diseases, whereas population studies for associations between HT and KLF4 or KLF5 have been rarely reported. Thus, the current study aimed to examines the association of genetic variants and mRNA expression levels of KLF4 and KLF5 with HT, as well as the effect of antihypertensive drugs on the expression levels. The associations of one single-nucleotide polymorphism (SNP) in KLF4 and three SNPs in KLF5 with HT were investigated using a combination of case-control and cohort studies. The study population were selected from a community-based population cohort in four different regions of Jiangsu Province. Risks of HT were estimated through logistic and Cox regression analyses, respectively. In addition, mRNA expression levels of KLF4 and KLF5 were measured in 246 controls and 385 HT cases selected from the cohort study as mentioned above. Among the HT cases, 263 were not taking antihypertensive drugs [AHD(-)] and 122 were taking antihypertensive drugs [AHD(+)]. In the case-control study, SNP rs9573096 (C>T) in KLF5 was significantly associated with an increased risk of HT in the additive model (adjusted odds ratio [OR], 1.106; 95% confidence interval [CI], 1.009 to 1.212). In the cohort study of the normotensive population, rs9573096 in KLF5 was also significantly associated with an increased risk of HT in the additive model (adjusted hazards ratio [HR], 1.199; 95% CI, 1.070 to 1.344). KLF4 and KLF5 mRNA expression levels were significantly higher in the AHD(-) group than in the control group ( P < 0.05), but lower in the AHD(+) group than in the AHD(-) group ( P < 0.05). The current study demonstrated the associations of KLF4 and KLF5 genetic variants with hypertension, and the indicative discriminations of mRNA expression levels of KLF4 and KLF5 for risk of hypertension and antihypertensive treatment.

Multicenter Validation of lncRNA and Target mRNA Diagnostic and Prognostic Biomarkers of Acute Ischemic Stroke From Peripheral Blood Leukocytes.

BACKGROUND: Long noncoding RNA (lncRNA) and mRNA profiles in leukocytes have shown potential as biomarkers for acute ischemic stroke (AIS). This study aimed to identify altered lncRNA and target mRNA profiles in peripheral blood leukocytes as biomarkers and to assess the diagnostic value and association with AIS prognosis. METHODS AND RESULTS: Differentially expressed lncRNAs (DElncRNAs) and differentially expressed target mRNAs (DEmRNAs) were screened by RNA sequencing in the discovery set, which consisted of 10 patients with AIS and 20 controls. Validation sets consisted of a multicenter (311 AIS versus 303 controls) and a nested case-control study (351 AIS versus 352 controls). The discriminative value of DElncRNAs and DEmRNAs added to the traditional risk factors was estimated with the area under the curve. NAMPT-AS, FARP1-AS1, FTH1, and NAMPT were identified in the multicenter case-control study (P<0.05). LncRNA NAMPT-AS was associated with cis-target mRNA NAMPT and trans-target mRNA FTH1 in all validation sets (P<0.001). Similarly, AIS cases exhibited upregulated lncRNA FARP-AS1 and FTH1 expression (P<0.001) in the nested case-control study (P<0.001). Furthermore, lncRNA FARP1-AS1 expression was upregulated in AIS patients at discharge with an unfavorable outcome (P<0.001). Positive correlations were found between NAMPT expression level and NIHSS scores of AIS patients (P<0.05). Adding 2 lncRNAs and 2 target mRNAs to the traditional risk factor model improved area under the curve by 22.8% and 5.2% in the multicenter and the nested case-control studies, respectively. CONCLUSIONS: lncRNA NAMPT-AS and FARP1-AS1 have potential as diagnostic biomarkers for AIS and exhibit good performance when combined with target mRNA NAMPT and FTH1.

Interactive effect of increased high sensitive C-reactive protein and dyslipidemia on cardiovascular diseases: a 12-year prospective cohort study.

BACKGROUND: Dyslipidemia and inflammation are significant factors for the onset of cardiovascular diseases (CVD); however, studies regarding their interactions on the risk of CVD are scarce. This study aimed to assess the interaction of dyslipidemia and high-sensitivity C-reactive protein (hs-CRP) on CVD. METHODS: This prospective cohort enrolled 4,128 adults at baseline in 2009 and followed them up until May 2022 for collecting CVD events. Cox-proportional hazard regression analysis estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) of the associations of increased hs-CRP (≥ 1 mg/L) and dyslipidemia with CVD. The additive interactions were explored using the relative excess risk of interaction (RERI) and the multiplicative interactions were assessed with HRs (95% CI) while the multiplicative interactions were assessed by the HRs (95% CI) of interaction terms. RESULTS: The HRs of the association between increased hs-CRP and CVD were 1.42 (95% CI: 1.14-1.79) and 1.17 (95% CI: 0.89-1.53) among subjects with normal lipid levels and subjects with dyslipidemia, respectively. Stratified analyses by hs-CRP levels showed that among participants with normal hs-CRP (< 1 mg/L), TC ≥ 240 mg/dL, LDL-C ≥ 160 mg/dL, non-HDL-C ≥ 190 mg/dL, ApoB < 0.7 g/L, and LDL/HDL-C ≥ 2.02 were associated with CVD [HRs (95%CIs): 1.75 (1.21-2.54), 2.16 (1.37-3.41), 1.95 (1.29-2.97), 1.37 (1.01-1.67), and 1.30 (1.00-1.69), all P < 0.05, respectively]. While in the population with increased hs-CRP, only ApoAI > 2.10 g/L had a significant association with CVD [HR (95% CI): 1.69 (1.14-2.51)]. Interaction analyses showed that increased hs-CRP had multiplicative and additive interactions with LDL-C ≥ 160 mg/dL and non-HDL-C ≥ 190 mg/dL on the risk of CVD [HRs (95%CIs): 0.309 (0.153-0.621), and 0.505 (0.295-0.866); RERIs (95%CIs): -1.704 (-3.430-0.021 and - 0.694 (-1.476-0.089), respectively, all P < 0.05]. CONCLUSION: Overall our findings indicate negative interactions between abnormal blood lipid levels and hs-CRP on the risk of CVD. Further large-scale cohort studies with trajectories measurement of lipids and hs-CRP might verify our results as well explore the biological mechanism behind that interaction.

Sex and age differences in the association between high sensitivity C-reactive protein and all-cause mortality: A 12-year prospective cohort study.

To explore the influence of age on hs-CRP among men and women and investigate the impact of hs-CRP on all-cause death, this prospective cohort enrolled 4128 community adults from 2009 to 2022 for all-cause death. Age and sex-specific hs-CRP percentile curves were generated using the GAMLSS method. Cox-proportional hazard regression analysis was applied to estimate the hazard ratios (HRs) and 95 % confidence intervals (CIs). During the follow-up with a median of 12.59 years, 701 cases of all-cause death were identified. Among men, the smoothed centile curves of hs-CRP gradually increased from age 35 onwards whereas, the smoothed centile curves of hs-CRP continuously increased as age increased among women. Compared with the reference group, the adjusted HR of the association between elevated hs-CRP and all-cause death was 1.33 (95 % CI: 1.11-1.61). The adjusted HRs of the associations between elevated hs-CRP and all-cause death were higher in women [1.40 (95 % CI: 1.07-1.83)] than men [1.28 (95 % CI: 0.99-1.65) and in subjects aged < 65 years [1.77 (95 % CI: 1.19-2.62)] than in subjects aged ≥ 65 years [1.27 (95 % CI: 1.03-1.57)]. Our findings highlight the need of investigating sex and age differences in biological pathways that link inflammation and mortality.

Association of THBS1 genetic variants and mRNA expression with the risks of ischemic stroke and long-term death after stroke.

Background: Thrombospondin-1 (THBS1) derived from platelets and acted as a critical mediator of hemostasis promoting platelet activation in thrombus formation. The biological connection of genetic variants and mRNA expression of THBS1 with ischemic stroke (IS) warrants further validation with population-based evidence. Objective: To evaluate the association of single nucleotide polymorphisms (SNPs) and mRNA expression of THBS1 with the risks of IS and long-term death after stroke. Methods: A case-control study consisted of 4,584 IS patients recruited from five hospitals in Jiangsu, China, and 4,663 age-gender-matched controls free of IS. A cohort study enrolled 4,098 participants free of stroke and lasted from 2009 to 2022. Early collected 3158 IS patients aged between 35 and 80 years were followed up an average of 5.86-year to follow up their long-term death outcomes. Two tagSNPs of the THBS1 gene, rs2236471 and rs3743125, were genotyped in all subjects and THBS1 mRNA expression of peripheral leukocyte was measured using RT-qPCR in 314 IS cases and 314 controls. Results: There is no significant difference in genotype and haplotype frequencies of rs2236741 and rs3743125 between IS cases and controls (all P > 0.05). Furthermore, the cohort studies did not observe significant associations between THBS1 variants and the risk of IS incidence or long-term death after IS (all P > 0.05). The THBS1 mRNA expression level (2-Δ Δ CT ) in IS cases was approximately equal to that in controls (1.01 vs. 0.99, P = 0.833). In addition, THBS1 mRNA expression had no significant association with all-cause death, stroke death, and IS death of IS patients (all P > 0.05). Conclusion: Therefore, our study suggested that there is no significant association of THBS1 polymorphisms and mRNA expression level with the risk of IS and long-term death after IS.

The relationship between lipid risk score and new-onset hypertension in a prospective cohort study.

Background: Dyslipidemia and hypertension are both important risk factors for atherosclerotic cardiovascular diseases. However, the relationship between dyslipidemia and incident hypertension remains to be elucidated comprehensively. The main purpose of this study was to construct the lipid risk score to explore the risk prediction effect of integrated lipid indices on new-onset hypertension. Methods: This prospective cohort study with 2116 non-hypertensive subjects was conducted from 2009 to 2020. New hypertension events during the follow-up period were recorded and verified. The lipid risk score was calculated by summing coded total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol weighted with corresponding effect sizes. Cox regression analysis was used to estimate the association between the lipid risk score or lipid indices and incident hypertension in the subgroup of age (< 55 and≥ 55 years at baseline). Results: After a median of 10.75-year follow-up, 637 incident hypertension cases were identified. The restricted cubic spline showed that the lipid risk score had a positive linear correlation with hypertension (P< 0.001). Among people< 55 years, with every increase of 0.94 in lipid risk score, the risk of hypertension increased by 37% (adjusted HR [95%CI]: 1.369 [1.164-1.610]). This association was not modified by overweight or obesity. Conclusions: The integrated lipid risk score, independent of traditional risk factors, has a significantly predictive effect on hypertension in people younger than 55 years. This finding may aid in identifying high-risk individuals for hypertension, as well as facilitating early intervention and management to reduce adverse cardiovascular events. Comprehensive lipid management should be attached importance in the prevention and control of hypertension.