The human UGT2B17 gene varies in copy number from zero to two per individual and also differs in mean number between populations from Africa, Europe, and East Asia. We show that such a high degree of geographical variation is unusual and investigate its evolutionary history. This required first reinterpreting the reference sequence in this region of the genome, which is misassembled from the two different alleles separated by an artifactual gap. A corrected assembly identifies the polymorphism as a 117 kb deletion arising by nonallelic homologous recombination between approximately 4.9 kb segmental duplications and allows the deletion breakpoint to be identified. We resequenced approximately 12 kb of DNA spanning the breakpoint in 91 humans from three HapMap and one extended HapMap populations and one chimpanzee. Diversity was unusually high and the time to the most recent common ancestor was estimated at approximately 2.4 or approximately 3.0 million years by two different methods, with evidence of balancing selection in Europe. In contrast, diversity was low in East Asia where a single haplotype predominated, suggesting positive selection for the deletion in this part of the world.
SummaryBackgroundThe age-specific association between blood pressure and vascular disease has been studied mostly in high-income countries, and before the widespread use of brain imaging for diagnosis of the main stroke types (ischaemic stroke and intracerebral haemorrhage). We aimed to investigate this relationship among adults in China.Methods512 891 adults (59% women) aged 30–79 years were recruited into a prospective study from ten areas of China between June 25, 2004, and July 15, 2008. Participants attended assessment centres where they were interviewed about demographic and lifestyle characteristics, and their blood pressure, height, and weight were measured. Incident disease was identified through linkage to local mortality records, chronic disease registries, and claims to the national health insurance system. We used Cox regression analysis to produce adjusted hazard ratios (HRs) relating systolic blood pressure to disease incidence. HRs were corrected for regression dilution to estimate associations with long-term average (usual) systolic blood pressure.FindingsDuring a median follow-up of 9 years (IQR 8–10), there were 88 105 incident vascular and non-vascular chronic disease events (about 90% of strokes events were diagnosed using brain imaging). At ages 40–79 years (mean age at event 64 years [SD 9]), usual systolic blood pressure was continuously and positively associated with incident major vascular disease throughout the range 120–180 mm Hg: each 10 mm Hg higher usual systolic blood pressure was associated with an approximately 30% higher risk of ischaemic heart disease (HR 1·31 [95% CI 1·28–1·34]) and ischaemic stroke (1·30 [1·29–1·31]), but the association with intracerebral haemorrhage was about twice as steep (1·68 [1·65–1·71]). HRs for vascular disease were twice as steep at ages 40–49 years than at ages 70–79 years. Usual systolic blood pressure was also positively associated with incident chronic kidney disease (1·40 [1·35–1·44]) and diabetes (1·14 [1·12–1·15]). About half of all vascular deaths in China were attributable to elevated blood pressure (ie, systolic blood pressure >120 mm Hg), accounting for approximately 1 million deaths (<80 years of age) annually.InterpretationAmong adults in China, systolic blood pressure was continuously related to major vascular disease with no evidence of a threshold down to 120 mm Hg. Unlike previous studies in high-income countries, blood pressure was more strongly associated with intracerebral haemorrhage than with ischaemic stroke. Even small reductions in mean blood pressure at a population level could be expected to have a major impact on vascular morbidity and mortality.FundingUK Wellcome Trust, UK Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, Chinese Ministry of Science and Technology, and the National Science Foundation of China.
Graphical Abstract Highlights d CD19 + EVs through CD39 and CD73 hydrolyze ATP from tumor cells into adenosine d CD19 + EVs blunt post-chemotherapeutic CD8 T cell responses via adenosine d Tumor B cells produce more EVs by enhancing HIF-1a-mediated Rab27a transcription d IEBVs-Rab27a siRNA is a potential tool for improving chemotherapeutic effect SUMMARY Systemic immunosuppression greatly affects the chemotherapeutic antitumor effect. Here, we showed that CD19 + extracellular vesicles (EVs) from B cells through CD39 and CD73 vesicle-incorporated proteins hydrolyzed ATP from chemotherapy-treated tumor cells into adenosine, thus impairing CD8 + T cell responses. Serum CD19 + EVs were increased in tumor-bearing mice and patients. Patients with fewer serum CD19 + EVs had a better prognosis after chemotherapy. Upregulated hypoxia-inducible factor-1a (HIF-1a) promoted B cells to release CD19 + EVs by inducing Rab27a mRNA transcription. Rab27a or HIF-1a deficiency in B cells inhibited CD19 + EV production and improved the chemotherapeutic antitumor effect. Silencing of Rab27a in B cells by inactivated Epstein-Barr viruses carrying Rab27a siRNA greatly improved chemotherapeutic efficacy in humanized immunocompromised NOD Prkdc scid Il2rg À/À mice. Thus, decreasing CD19 + EVs holds high potential to improve the chemotherapeutic antitumor effect.
National Natural Science Foundation of China and National Key Research and Development Program.
BackgroundAutism spectrum disorders (ASDs) are a group of neurodevelopmental conditions with a demonstrated genetic etiology. Rare (<1% frequency) copy number variations (CNVs) account for a proportion of the genetic events involved, but the contribution of these events in non-European ASD populations has not been well studied. Here, we report on rare CNVs detected in a cohort of individuals with ASD of Han Chinese background.MethodsDNA samples were obtained from 104 ASD probands and their parents who were recruited from Harbin, China. Samples were genotyped on the Affymetrix CytoScan HD platform. Rare CNVs were identified by comparing data with 873 technology-matched controls from Ontario and 1,235 additional population controls of Han Chinese ethnicity.ResultsOf the probands, 8.6% had at least 1 de novo CNV (overlapping the GIGYF2, SPRY1, 16p13.3, 16p11.2, 17p13.3-17p13.2, DMD, and NAP1L6 genes/loci). Rare inherited CNVs affected other plausible neurodevelopmental candidate genes including GRID2, LINGO2, and SLC39A12. A 24-kb duplication was also identified at YWHAE, a gene previously implicated in ASD and other developmental disorders. This duplication is observed at a similar frequency in cases and in population controls and is likely a benign Asian-specific copy number polymorphism.ConclusionsOur findings help define genomic features relevant to ASD in the Han Chinese and emphasize the importance of using ancestry-matched controls in medical genetic interpretations.
Rationale: Little evidence from large-scale cohort studies exists about the relationship of solid fuel use with hospitalization and mortality from major respiratory diseases. Objectives: To examine the associations of solid fuel use and risks of acute and chronic respiratory diseases. Methods: A cohort study of 277,838 Chinese never-smokers with no prior major chronic diseases at baseline. During 9 years of follow-up, 19,823 first hospitalization episodes or deaths from major respiratory diseases, including 10,553 chronic lower respiratory disease (CLRD), 4,398 chronic obstructive pulmonary disease (COPD), and 7,324 acute lower respiratory infection (ALRI), were recorded. Cox regression yielded adjusted hazard ratios (HRs) for disease risks associated with self-reported primary cooking fuel use. Measurements and Main Results: Overall, 91% of participants reported regular cooking, with 52% using solid fuels. Compared with clean fuel users, solid fuel users had an adjusted HR of 1.36 (95% confidence interval, 1.32–1.40) for major respiratory diseases, whereas those who switched from solid to clean fuels had a weaker HR (1.14, 1.10–1.17). The HRs were higher in wood (1.37, 1.33–1.41) than coal users (1.22, 1.15–1.29) and in those with prolonged use (≥40 yr, 1.54, 1.48–1.60; <20 yr, 1.32, 1.26–1.39), but lower among those who used ventilated than nonventilated cookstoves (1.22, 1.19–1.25 vs. 1.29, 1.24–1.35). For CLRD, COPD, and ALRI, the HRs associated with solid fuel use were 1.47 (1.41–1.52), 1.10 (1.03–1.18), and 1.16 (1.09–1.23), respectively. Conclusions: Among Chinese adults, solid fuel use for cooking was associated with higher risks of major respiratory disease admissions and death, and switching to clean fuels or use of ventilated cookstoves had lower risk than not switching.
There is a large room for improvement in awareness about ASD and treatment in the Chinese communities. Insufficient knowledge about ASD and inappropriate attitudes towards mental health service use may impede the efforts of early identification and intervention. Health education and promotion are needed to improve people's knowledge about ASD and available mental health services.
SummaryBackgroundIn developed countries, smoking is associated with increased risk of diabetes. Little is known about the association in China, where cigarette consumption has increased (first in urban, then in rural areas) relatively recently. Moreover, uncertainty remains about the effect of smoking cessation on diabetes in China and elsewhere. We aimed to assess the associations of smoking and smoking cessation with risk of incident diabetes among Chinese adults.MethodsThe prospective China Kadoorie Biobank enrolled 512 891 adults (59% women) aged 30–79 years during 2004–08 from ten diverse areas (five urban and five rural) across China. Participants were interviewed at study assessment clinics, underwent physical measurements, and had a non-fasting blood sample taken. Participants were separated into four categories according to smoking history: never-smokers, ever-regular smokers, ex-smokers, and occasional smokers. Incident diabetes cases were identified through linkage with diabetes surveillance systems, the national health insurance system, and death registries. All analyses were done separately in men and women and Cox regression was used to yield adjusted hazards ratios (HRs) for diabetes associated with smoking.Findings68% (n=134 975) of men ever smoked regularly compared with 3% (n=7811) of women. During 9 years' follow-up, 13 652 new-onset diabetes cases were recorded among 482 589 participants without previous diabetes. Among urban men, smokers had an adjusted HR of 1·18 (95% CI 1·12–1·25) for diabetes. HRs increased with younger age at first smoking regularly (1·12, 1·20, and 1·27 at ≥25 years, 20–24 years, and <20 years, respectively; p for trend=0·00073) and with greater amount smoked (1·11, 1·15, 1·42, and 1·63 for <20, 20–29, 30–39 and ≥40 cigarettes per day; p for trend<0·0001). Among rural men, similar, albeit more modest, associations were seen. Overall, HRs were more extreme at higher levels of adiposity. Among men who stopped by choice, there was no excess risk within 5 years of cessation, contrasting with those who stopped because of illness (0·92 [0·75–1·12] vs 1·42 [1·23–1·63]). Among the few women who ever smoked regularly, the excess risk of diabetes was significant (1·33 [1·20–1·47]).InterpretationAmong Chinese adults, smoking was associated with increased risk of diabetes, with no significant excess risk following voluntary smoking cessation.FundingWellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, Ministry of Science and Technology, National Natural Science Foundation of China, and China Scholarship Council.
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