👤 Osamu Ohmori

Atherosclerotic disease, including coronary heart disease (CHD), is one of the chronic inflammatory conditions, and an imbalance between pro-inflammatory and anti-inflammatory cytokines plays a role in the process of atherosclerosis. Interleukin (IL)-27, one of the IL-12 family members, is recognized to play a dual role in regulating immune responses with both pro-inflammatory and anti-inflammatory properties. IL-27 is secreted from monocytes, T cells, and endothelial cells, and its expression is upregulated in atherosclerotic plaques. We previously reported that no significant difference was observed in plasma IL-27 levels between patients with stable CHD and those without it. However, the prognostic value of IL-27 levels has not been fully elucidated. We studied the relation of plasma IL-27 levels to cardiovascular events in 402 patients undergoing elective coronary angiography for suspected CHD. We defined cardiovascular events as cardiovascular death, myocardial infarction, unstable angina, stroke, or coronary revascularization. Of the 402 study patients, CHD was present in 209 (52%) patients. Plasma IL-27 levels were not markedly different between patients with CHD and those without it (median 0.23 vs. 0.23 ng/mL). During a follow-up of 7.6 ± 4.5 years, cardiovascular events were observed in 70 patients (17%). In comparison to the 332 patients with no event, the 70 patients who had cardiovascular events showed significantly higher IL-27 levels (median 0.29 vs. 0.22 ng/mL) and more frequently had an IL-27 level of >0.25 ng/mL (59% vs. 40%) ( Show less

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10 Show less

Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials. Show less

Previous studies suggest that elevated total homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which correlates with plasma total homocysteine levels, are risk factors for schizophrenia (SCZ). Recently, a large genome-wide association study (GWAS) of plasma total homocysteine levels in individuals of European ancestry identified many single-nucleotide polymorphisms (SNPs) (n=13,974). The primary purpose of this study was to examine the association between these plasma total homocysteine-related SNPs and SCZ in the Japanese population. First, we investigated associations between six SNPs and plasma total homocysteine levels in non-psychiatric subjects in the Japanese population (n=1030). Then, we evaluated the cumulative effects of three SNPs on SCZ risk by calculating the Genotype Risk Score (GRS) (1120 cases, 2643 controls). Of the six SNPs examined, we replicated similar associations with the European GWAS at four loci (CENPQ, CPS1, MTHFR, and MUT). GRS based on three SNPs (CENPQ, CPS1, and MTHFR) was significantly associated with SCZ. Our findings suggest that common polygenic variations, which are associated with the plasma total homocysteine levels, may contribute to the risk of SCZ. Show less