Stroke is the second leading cause of death and the leading cause of serious, long-term disability worldwide.¹ Clinical trials have documented that lowering blood pressure reduces the risk of stroke in hypertensive^2,3 and normotensive patients with a history of stroke or transient ischemic attack.^4-6 Although the benefit of lowering blood pressure for primary and secondary prevention of stroke has been established, the effect of immediate antihypertensive treatment in patients with acute ischemic stroke and elevated blood pressure is uncertain.^7,8 Elevated blood pressure is common during acute ischemic stroke. In the US National Hospital Ambulatory Medical Care Survey, 76.5% of patients with acute ischemic stroke had systolic blood pressures of 140 mm Hg or greater on arrival at the emergency department.⁹ Observational studies have reported that a decrease in blood pressure within the first 48 hours after symptom onset was associated with poorer, better, or no difference in adverse clinical outcomes among patients with acute ischemic stroke.^10-12 There are no published clinical trials with sufficient statistical power to address the question of whether lowering blood pressure reduces adverse clinical outcomes among patients with acute ischemic stroke.

Objective: To examine the association between serum matrix metalloproteinases-9 (MMP-9) levels and prognosis of acute ischemic stroke. Methods: We measured serum MMP-9 levels in 3,186 participants (2,008 men and 1,178 women) from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). Study outcome data on death, major disability (modified Rankin Scale score ≥3), and vascular disease were collected at 3 months after stroke onset. Results: During 3 months of follow-up, 767 participants (24.6%) experienced major disability or died. Serum MMP-9 was significantly associated with an increased risk of death and major disability after adjustment for age, sex, time from onset to randomization, current smoking, alcohol drinking, admission NIH Stroke Scale score, diastolic blood pressure, plasma glucose, white blood cell counts, use of antihypertensive medications, and history of hypertension, coronary heart disease, and diabetes mellitus. For example, 1-SD (0.32 ng/mL) higher log–MMP-9 was associated with an odds ratio (95% confidence interval) of 1.16 (1.06–1.28) for the combined outcome of death and major disability, 1.12 (1.01–1.23) for major disability, and 1.29 (1.01–1.66) for death. The addition of serum MMP-9 to conventional risk factors improved risk prediction of the combined outcome of death or major disability (net reclassification index 9.1%, p = 0.033; integrated discrimination improvement 0.4%, p = 0.004). Conclusions: Higher serum MMP-9 levels in the acute phase of ischemic stroke were associated with increased risk of mortality and major disability, suggesting that serum MMP-9 could be an important prognostic factor for ischemic stroke.

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10⁻⁸) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10⁻⁹), NCOA2 (P = 1.6 × 10⁻⁸), and NID2-PTGDR (P = 4.2 × 10⁻⁸), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10⁻¹⁰). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log₁₀Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10⁻⁵) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.

Objective: DNA methylation has been associated with both early life stress and depression. This study examined the combined association of DNA methylation at multiple CpG probes in five stress-related genes with depressive symptoms and tested whether these genes methylation mediated the association between childhood trauma and depression in two monozygotic (MZ) twin studies. Methods: The current analysis comprised 119 MZ twin pairs (84 male pairs [mean = 55 years] and 35 female pairs [mean = 36 years]). Peripheral blood DNA methylation of five stress-related genes (BDNF, NR3C1, SLC6A4, MAOA, and MAOB) was quantified by bisulfite pyrosequencing or 450K BeadChip. We applied generalized Poisson linear-mixed models to examine the association between each single CpG methylation and depressive symptoms. The joint associations of multiple CpGs in a single gene or all five stress-related genes as a pathway were tested by weighted truncated product method. Mediation analysis was conducted to test the potential mediating effect of stress gene methylation on the relationship between childhood trauma and depressive symptoms. Results: Multiple CpG probes showed nominal individual associations, but very few survived multiple testing. Gene-based or gene-set approach, however, revealed significant joint associations of DNA methylation in all five stress-related genes with depressive symptoms in both studies. Moreover, two CpG probes in the BDNF and NR3C1 mediated approximately 20% of the association between childhood trauma and depressive symptoms. Conclusions: DNA methylation at multiple CpG sites are jointly associated with depressive symptoms and partly mediates the association between childhood trauma and depression. Our results highlight the importance of testing the combined effects of multiple CpG loci on complex traits and may unravel a molecular mechanism through which adverse early life experiences are biologically embedded.

We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26 600 East Asian participants (stage 1) followed by replication study of up to 28 783 participants (stage 2). For novel loci, statistical significance was determined by a P <5.0×10 ^–8 in joint analysis of stage 1 and stage 2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of transethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P <1.4×10 ^–3 . No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for transethnic replication including rs17249754 at ATP2B1 ( P =7.5×10 ^–15 ), rs2681492 at ATP2B1 ( P =3.4×10 ^–7 ), rs11191593 at NT5C2 (1.1×10 ^–6 ), rs3824755 at CYP17A1 ( P =1.2×10 ^–6 ), and rs13149993 at FGF5 ( P =2.4×10 ^–4 ). Two additional variants showed suggestive evidence of transethnic replication (consistency in effect direction and P <0.05), including rs319690 at MAP4 ( P =0.014) and rs1173771 at NPR3 ( P =0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 ( P =1.2×10 ^–5 ) and rs11191593 at NT5C2 ( P =1.1×10 ^–3 ), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 ( P =6.1×10 ^–3 ) and rs2681492 at ATP2B1 ( P =9.0×10 ^–3 ). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mm Hg for mean arterial pressure and from 0.03 to 0.21 mm Hg for pulse pressure. In conclusion, we present the first evidence of transethnic replication of several mean arterial and pulse pressure loci in an East Asian population.