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BackgroundThrombospondin-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.ObjectiveTo evaluate the association of single nucleotide polymorphisms (SNPs) and mRNA expression of THBS1 with the risks of IS and long-term death after stroke.MethodsA 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.ResultsThere 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–ΔΔCT) 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).ConclusionTherefore, 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.

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.

Haemorrhagic stroke (HS) is a devastating form of stroke with a high fatality rate. The lack of rapid lesion detection limits early diagnosis of HS. Several susceptibility genes of HS found in genome-wide association studies (GWAS) warrant transcriptional-level biomarkers for useful utility. 13 GWAS level loci with minor allele frequency ≥ 0.05 were selected out of 95 loci related to HS. After validation, the mRNA expression in peripheral leukocytes of 11 genes (PMF1, SLC25A44, CASZ1, NINJ2, WNK1, DYRK1A, LRCH1, LDLR, SMARCA4, AQP9, and LIPC) were measured in the HS case-control study (64 HS cases vs. 128 controls), and then verified in an ischemic stroke (IS) case-control study (67 IS cases vs. 61 controls). LIPC (P=0.002) and CASZ1 (P=0.040) were downregulated in HS patients, while SLC25A44 was upregulated (P=0.009). In the IS case-control study, the differential expression of LIPC (P=0.034) and SLC25A44 (P<0.001) was observed. Although CASZ1 expression was not different between IS cases and controls (P=0.419) with fold change (FC) of 1.205, the direction of expression was opposite to that in HS case-control study (FC=0.747). The ROCtrfgs of traditional risk factors and gene score which was estimated by combining LIPC, CASZ1, and SLC25A44 expression weights, improved the utility for HS identification by 14.1% compared with ROC (P=0.001). Expression of LIPC, CASZ1, and SLC25A44 could serve as potential biomarkers for identifying HS. CASZ1 might be a cause-specific indicator for differentiating HS from IS. Transcriptional score of these three genes could improve performance of the traditional risk model for HS identification.

BackgroundThrombospondin Type 1 Domain Containing Protein 1 (THSD1) has been suggested to be a new regulator of endothelial barrier function in the angiogenesis process, preserving vascular integrity. We sought to characterize the association of THSD1 genetic variants and mRNA expression with the risk of hemorrhagic stroke (HS) with population-based evidence.MethodsA case–control study was conducted with 843 HS cases and 1,400 healthy controls. A cohort study enrolled 4,080 participants free of stroke at baseline in 2009 and followed up to 2022. A synonymous variant, the main tag SNP rs3803264 of the THSD1 gene, was genotyped in all subjects, and peripheral leukocyte THSD1 mRNA expression was detected using RT-qPCR in 57 HS cases and 119 controls.ResultsIn the case–control study, rs3803264 AG/GG variations are associated with a decreased risk of HS with odd ratio (OR) and 95% confidence interval (CI) of the dominant model of 0.788 (0.648–0.958), p = 0.017. In addition, rs3803264 and dyslipidemia had a multiplicative interaction [OR (95% CI) = 1.389 (1.032, 1.869), p = 0.030]. In the cohort study, a similar association strength of rs3803264 dominant model and the risk of HS was observed with the incidence rate ratio (IRR) of 0.734 and p-value of 0.383. Furthermore, the risk of HS showed a non-linear as THSD1 mRNA expression increased (p for non-linearity &lt;0.001). For the subjects without hypertension, we observed THSD1 mRNA expression had a negative correlation with systolic blood pressure (SBP; ρ = −0.334, p = 0.022).ConclusionSNP rs3803264 polymorphisms in THSD1 are associated with the decreased risk of HS and interacted with dyslipidemia, and a non-linear association was observed between THSD1 mRNA expression and the risk of HS.