Moyamoya disease is an idiopathic vascular disorder of intracranial arteries. Its susceptibility locus has been mapped to 17q25.3 in Japanese families, but the susceptibility gene is unknown. Genome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q25.3 (P<10^-4). Fine mapping demonstrated a 1.5-Mb disease locus bounded by D17S1806 and rs2280147. We conducted exome analysis of the eight index cases in these families, with results filtered through Ng criteria. There was a variant of p.N321S in PCMTD1 and p.R4810K in RNF213 in the 1.5-Mb locus of the eight index cases. The p.N321S variant in PCMTD1 could not be confirmed by the Sanger method. Sequencing RNF213 in 42 index cases confirmed p.R4810K and revealed it to be the only unregistered variant. Genotyping 39 SNPs around RNF213 revealed a founder haplotype transmitted in 42 families. Sequencing the 260-kb region covering the founder haplotype in one index case did not show any coding variants except p.R4810K. A case-control study demonstrated strong association of p.R4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 111.8 (P = 10⁻¹¹⁹). Sequencing of RNF213 in East Asian cases revealed additional novel variants: p.D4863N, p.E4950D, p.A5021V, p.D5160E, and p.E5176G. Among Caucasian cases, variants p.N3962D, p.D4013N, p.R4062Q and p.P4608S were identified. RNF213 encodes a 591-kDa cytosolic protein that possesses two functional domains: a Walker motif and a RING finger domain. These exhibit ATPase and ubiquitin ligase activities. Although the mutant alleles (p.R4810K or p.D4013N in the RING domain) did not affect transcription levels or ubiquitination activity, knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels. We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease.

Blood and/or breast milk have been used to assess human exposure to various environmental contaminants. Few studies have been available to compare the concentrations in one matrix with those in another. The goals of this study were to determine the current levels of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in Japanese women, with analysis of the effects of lifestyle and dietary habits on these levels, and to develop a quantitative structure–activity relationship (QSAR) with which to predict the ratio of serum concentration to breast milk concentration. We measured PBDEs and PCBs in 89 paired samples of serum and breast milk collected in four regions of Japan in 2005. The geometric means of the total concentrations of PBDE (13 congeners) in milk and serum were 1.56 and 2.89 ng/g lipid, respectively, whereas those of total PCBs (15 congeners) were 63.9 and 37.5 ng/g lipid, respectively. The major determinant of total PBDE concentration in serum and milk was the geographic ...

Background The effects of coffee and green, black and oolong teas and caffeine intake on cardiovascular disease (CVD) mortality have not been well defined in Asian countries. Methods To examine the relationship between the consumption of these beverages and risk of mortality from CVD, 76 979 individuals aged 40–79 years free of stroke, coronary heart disease (CHD) and cancer at entry were prospectively followed. The daily consumption of beverages was assessed by questionnaires. Results 1362 deaths were documented from strokes and 650 deaths from CHD after 1 010 787 person-years of follow-up. Compared with non-drinkers of coffee, the multivariable HR and 95% CI for those drinking 1–6 cups/week, 1–2 cups/day and ≥3 cups/day were 0.78 (0.50 to 1.20), 0.67 (0.47 to 0.96) and 0.45 (0.17 to 0.87) for strokes among men (p=0.009 for trend). Compared with non-drinkers of green tea, the multivariable HR for those drinking 1–6 cups/week, 1–2 cups/day, 3–5 cups/day and ≥6 cups/day were 0.34 (0.06–1.75), 0.28 (0.07–1.11), 0.39 (0.18–0.85) and 0.42 (0.17–0.88) for CHD among women (p=0.038 for trend). As for oolong tea, the multivariable HR of those drinking 1–6 cups/week and ≥1 cups/day were 1.00 (0.65–1.55) and 0.39 (0.17–0.88) for total CVD among men (p=0.049 for trend). Risk reduction for total CVD across categories of caffeine intake was most prominently observed in the second highest quintile, with a 38% lower risk among men and 22% among women. Conclusions Consumption of coffee, green tea and oolong tea and total caffeine intake was associated with a reduced risk of mortality from CVD.

Neonicotinoids, which are novel pesticides, have entered into usage around the world because they are selectively toxic to arthropods and relatively non-toxic to vertebrates. It has been suggested that several neonicotinoids cause neurodevelopmental toxicity in mammals. The aim was to establish the relationship between oral intake and urinary excretion of neonicotinoids by humans to facilitate biological monitoring, and to estimate dietary neonicotinoid intakes by Japanese adults. Deuterium-labeled neonicotinoid (acetamiprid, clothianidin, dinotefuran, and imidacloprid) microdoses were orally ingested by nine healthy adults, and 24 h pooled urine samples were collected for 4 consecutive days after dosing. The excretion kinetics were modeled using one- and two-compartment models, then validated in a non-deuterium-labeled neonicotinoid microdose study involving 12 healthy adults. Increased urinary concentrations of labeled neonicotinoids were observed after dosing. Clothianidin was recovered unchanged within 3 days, and most dinotefuran was recovered unchanged within 1 day. Around 10% of the imidacloprid dose was excreted unchanged. Most of the acetamiprid was metabolized to desmethyl-acetamiprid. Spot urine samples from 373 Japanese adults were analyzed for neonicotinoids, and daily intakes were estimated. The estimated average daily intake of these neonicotinoids was 0.53–3.66 μg/day. The highest intake of any of the neonicotinoids in the study population was 64.5 μg/day for dinotefuran, and this was <1% of the acceptable daily intake.

Background: P.R4810K of RNF 213 (mysterin: rs112735431), which is an AAA ⁺ ATP ase, is the susceptibility polymorphism for moyamoya disease ( MMD ) in East Asians. However, the role of RNF 213 R4810K in the etiology of MMD is unknown. Methods and Results: To clarify the role of RNF 213 in known angiogenic pathways, RNF 213 expression was analyzed in endothelial cells ( EC s) treated with several angiogenic and antiangiogenic factors, including interferons ( IFN s). RNF 213 was upregulated by IFN ‐β through signal transducer and activator of transcription x in the promoter and mediated antiangiogenic activity of IFN ‐β. RNF 213 wild‐type ( WT ) overexpression could not lower angiogenesis without IFN ‐β, but RNF 213 R4810K overexpression could. To correlate biochemical function as ATP ase and the role of RNF 213 oligomer formation with antiangiogenic activity, we investigated the effects of mutations in the AAA ⁺ module. A mutation of the Walker B motif ( WEQ ), which stabilizes oligomerization, inhibited angiogenesis, but AAA ⁺ module deletion, which cannot initiate oligomerization, did not. Intriguingly, R4810K, similar to WEQ , decreased ATP ase activity, suggesting its antiangiogenic activity through stabilizing oligomers. To confirm the antiangiogenic effect of RNF 213 upregulation in vivo, vascular EC ‐ or smooth muscle cell‐specific Rnf213 R4757K (R4810K ortholog) or WT transgenic (Tg) mice were exposed to hypoxia. Cerebral angiogenesis by hypoxia was suppressed in EC‐specific Rnf213 R4757K Tg mice, whereas it was not suppressed in other mice. Conclusions: This study suggests the importance of inflammatory signals as environmental factors and R4810K carriers for susceptibility to cerebral hypoxia. A specific inhibitor of ATP binding to the first AAA ⁺ could be a promising therapeutic candidate for MMD .