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Objective: We aimed to investigate the correlation between serum lipoprotein-associated phospholipase A2 (Lp-PLA2) level and acute ischemic stroke (AIS) severity and recurrence, which could indicate the diagnostic and prognostic values of Lp-PLA2., Methods: Two hundred and fifty-one AIS patients who were diagnosed in the department of neurology, China-Japan Union Hospital, from April 2018 to June 2019 and 100 non-cerebrovascular disease patients were included in this study. Demographic data and clinical materials including age, sex, BMI, medical history, bad habits, imaging data, blood tests, etc., were collected. Stroke severity and risk were evaluated, respectively. AIS patients were followed up for 6 months for stroke recurrence monitoring., Results: The AIS group had significantly higher Lp-PLA2 level than the control group. High Lp-PLA2 level was the independent risk factor of AIS (OR 1.010; 95% CI 1.007-1.013, P<0.001). Admission NIHSS was compared between Lp-PLA2 categories dichotomized by median. Serum Lp-PLA2 level was positively correlated with NIHSS (r=0.268, P<0.001). Mild stroke group and severe stroke group were defined based on NIHSS. Compared with the mild stroke group, the severe stroke group had higher smoking ratio, posterior circulation stenosis incidence, LDL level, Lp-PLA2 level and admission Essen score. Logistic regression showed Lp-PLA2 levels per 50ng/mL (OR 1.381, 95% CI 1.212-1.573, P<0.001) and Lp-PLA2 category (OR 2.420, 95% CI 1.363-4.297, P=0.003) were both independently associated with severe stroke. During the 6-month follow-up of all 251 AIS patients, 31 stroke recurrence cases were observed. Both Lp-PLA2 levels per 50ng/mL (OR 1.420, 95% CI 1.212-1.664, P<0.001) and Lp-PLA2 category (OR 2.726, 95% CI 1.201-6.178, P=0.016) were significantly associated with the stroke recurrence. Under the receiver Operating Characteristic curve, Lp-PLA2 showed significant predicting ability for stroke recurrence (AUC 0.723; 95% CI 0.620-0.826, P<0.001)., Conclusion: High serum Lp-PLA2 level is correlated with AIS incidence, disease severity and recurrence, which could be utilized to guide clinical practice., (Copyright © 2020 Elsevier España, S.L.U. All rights reserved.)

Background:  Lipoprotein-associated phospholipase A2 (Lp-PLA2) is being evaluated as a therapeutic target for treatment of atherosclerosis. This is the first study to examine the effects of darapladib, a novel selective Lp-PLA2 inhibitor, on Lp-PLA2 activity in Japanese dyslipidemic patients with/without the Val279Phe (V279F) single-nucleotide polymorphism (SNP) of the PLA2G7 gene. Exploratory analysis to examine the effects of V279F on Lp-PLA2 inhibition of darapladib was also performed., Methods and Results:  This was a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial of darapladib in 107 Japanese patients with dyslipidemia receiving statins. Patients were randomized to placebo (n=25), darapladib 40 mg (n=28), 80 mg (n=28), or 16 0mg (n=26). All darapladib doses produced sustained dose-dependent inhibition of Lp-PLA2 activity of approximately 49%, 58%, and 67%, respectively (P<0.001 for all comparisons). The inhibitory effect achieved a plateau by 1 week. Patients with the V279F homogenous mutation who have no circulating levels of Lp-PLA2, were excluded from the study. The Lp-PLA2 activity was inhibited in both homozygous wild-type and heterozygote genotypes of the V279F polymorphism subjects to a similar extent, although the heterogeneous mutation has almost half the level of Lp-PLA2 activity compared with that of wild-type in Japanese people. The most common adverse events were odor related. No major safety concerns were noted., Conclusions:  Darapladib produced sustained inhibition of Lp-PLA2 activity in Japanese dyslipidemic patients with/without the V279F SNP of Lp-PLA2.

High plasma lipoprotein phospholipase A2 activity (Lp-PLA2) is reported to be a risk factor for dementia. A loss of function polymorphism in the Lp-PLA2 gene - PLA2G7 V279F - is found almost exclusively in Asians. In 1,952 subjects with late-onset AD and 2,079 non-demented controls recruited from Japan, the PLA2G7 null allele was not associated with risk or age at onset of AD: logistic regression OR 0.98 (95% CI 0.86-1.12, p=0.81) per additional null allele, adjusted for age/age at onset, gender, and APOE ε4. Genetic deficiency of Lp-PLA2 activity is not associated with a reduced risk of AD in the Japanese population.

Although the plasma platelet-activating factor-acetylhydrolase (pPAF-AH) gene (PLA2G7) polymorphisms are reportedly associated with atherosclerotic diseases, their effects in hypertensive patients have not been well examined. Thus, we genotyped V279F, a loss-of-function mutation commonly seen in the Japanese, and I198T and A379V commonly seen in Caucasians, and investigated the (1) ethnic differences in the frequencies and (2) association of these variants with prevalence of carotid plaque in 733 treated hypertensive Japanese patients. The distribution of V279F (V allele 75.1% and F allele 24.9%) in hypertensive patients was similar to that previously reported in the healthy Japanese; however, allele frequencies of I198T (I allele 71.7% and T allele 28.3%) and A379V (A allele 84.7% and V allele 15.3%) were markedly different from those reported in Caucasians. In addition, V279F and I198T showed a strong linkage disequilibrium (D'=1.0, r(2)=0.89). The phenotypes showed no difference among genotypes for each polymorphism except for the blood pressure level in I198T in women. Carotid plaque was significantly more prevalent in subjects with 279F and 198T than in those with the wild type among men but not women, whereas A379V did not affect it. In multivariate logistic regression analyses, 279F and 198T were detected as an independent risk factor even after adjustments for other atherosclerotic risk factors in men. Taken together, our data suggest an ethnic difference and the possible involvement of genetic polymorphisms of PLA2G7 in the prevalence of carotid atherosclerosis in the hypertensive Japanese, especially in men.

Objective: To investigate a possible association with plasma platelet activating factor acetylhydrolase (PAF-AH) gene mutation with the risk of abdominal aortic aneurysm (AAA)., Summary Background Data: Plasma platelet activating factor acetylhydrolase is known to catalyze platelet activating factor (PAF), thereby inactivating its inflammatory function. Deficiency of this enzyme is caused by a missense mutation (G994 -->T) in exon 9 of the plasma PAF-AH gene., Methods: We did a case-control study including 131 patients (median age 73.4 [range 50-84] years) and 106 controls matched for age and sex. Genomic DNA was analyzed for the mutant allele by a specific polymerase-chain reaction. Plasma PAF-AH activity was measured in both groups., Results: The frequency of the mutant allele (T allele) in the plasma PAF-AH gene in AAA patients was significantly higher than in control subjects. The association of the missense mutation with AAA was statistically significant and independent of other risk factors. Among AAA patients with normal genomic type, plasma PAF-AH activity was strongly correlated to the plasma concentration of low density lipoprotein cholesterol (LDL-C), while the correlation was not observed among AAA patients with heterozygotes genotype. Patients having AAA with both T allele and hyperlipidemia were more likely to have other atherosclerotic diseases such as ischemic heart disease, stroke and peripheral arterial occlusive diseases than patients with the normal genomic type and normal lipid level., Conclusions: The genetic mutation of plasma PAF-AH gene appear to be an independent risk factor for AAA. Our findings need to be confirmed in a larger, prospective study including patients from different populations.

LIS1 is a genetic entity that is responsible for lissencephaly. Previously we have reported isolated lissencephaly sequence (ILS) in a Japanese patient carrying a balanced chromosomal translocation that disrupted the LIS1 gene. We examined mutations of LIS1 in 12 additional Japanese patients, 8 of them with ILS and 4 with Miller-Dieker syndrome (MDS). Fluorescence in situ hybridization (FISH) analysis disclosed deletions of part of the LIS1 gene or of the chromosomal region surrounding it in three of the ILS cases and in three of the MDS cases. In one of the remaining five ILS cases, SSCP analysis and subsequent sequence analysis identified a 1-bp deletion in exon IV, which can be expected to result in premature termination of the gene product. Our results indicate that in Japan, as elsewhere, abnormality of the LIS1 gene is a common cause of MDS/ILS.