ABSTRACT Common SNPs are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes. Here we show, using GWAS data from 5.4 million individuals of diverse ancestries, that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a median size of ~90 kb, covering ~21% of the genome. The density of independent associations varies across the genome and the regions of elevated density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs account for 40% of phenotypic variance in European ancestry populations but only ~10%-20% in other ancestries. Effect sizes, associated regions, and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely explained by linkage disequilibrium and allele frequency differences within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than needed to implicate causal genes and variants. Overall, this study, the largest GWAS to date, provides an unprecedented saturated map of specific genomic regions containing the vast majority of common height-associated variants.
The bioactive steroid, marinobufagenin, is an endogenous Na/K-ATPase bufadienolide inhibitor that is synthesized by adrenocortical and placental cells. Marinobufagenin binding to Na/K-ATPase initiates profibrotic cell signaling, and heightened marinobufagenin levels are implicated in the pathogenesis of hypertension, preeclampsia, and chronic kidney disease. Steroids are derived from cholesterol through the traditional steroidogenesis pathway initiated by enzyme CYP11A1, and via the acidic bile acid pathway, which is controlled by enzyme CYP27A1. The mechanism of marinobufagenin biosynthesis in mammals, however, remains unknown.Here, we show that post-transcriptional silencing of the CYP27A1 gene in human trophoblast and rat adrenocortical cells reduced the expression of CYP27A1 mRNA by 70%, reduced total bile acids 2-fold, and marinobufagenin levels by 67% when compared with nontreated cells or cells transfected with nontargeting siRNA. In contrast, silencing of the CYP11A1 gene did not affect marinobufagenin production in either cell culture, but suppressed production of progesterone 2-fold in human trophoblast cells and of corticosterone by 90% in rat adrenocortical cells when compared with cells transfected with nontargeting siRNA. In vivo, in a high-salt administration experiment, male and female Dahl salt-sensitive rats became hypertensive after 4 weeks on a high-NaCl diet, their plasma marinobufagenin levels doubled, and adrenocortical CYP27A1 mRNA and protein increased 1.6-fold and 2.0-fold.Therefore, the endogenous steroidal Na/K-ATPase inhibitor, marinobufagenin, is synthesized in mammalian placenta and adrenal cortex from cholesterol through the novel acidic bile acid pathway. These findings will help to understand the role of marinobufagenin in highly prevalent human cardiovascular diseases.
Abstract Background This study was to report a novel CREBBP mutation and phenotype in a child with Rubinstein–Taybi syndrome. Methods Case report of a 9-year-old boy. Results We described the patient’s clinical manifestations in detail, and found that in addition to the typical systemic manifestations of the syndrome, the outstanding manifestation of the child was severe intellectual deficiency and prominent ocular abnormalities. Whole-exome sequencing and sanger sequencing were performed on the patient and his parents, a large intragenic deletion, covering the exon 1 region and part of the intron 1 region of the TRAP1 gene, and the entire region from intron 27 to exon 30 of the CREBBP gene (chr16:3745393-3783894) was identified on the patient. This mutation affected the CREBBP histone acetyltransferase (HAT) domain. Conclusions This findings in our patient add to the spectrum of genetic variants described in Rubinstein–Taybi syndrome and present a RSTS patient with various ocular anomalies including early onset glaucoma.
Objective
To understand the epidemiological characteristics of hepatitis B in Longquanyi District, Chengdu City from 2011 to 2016, and to provide scientific basis for prevention and control measures and strategies against hepatitis B.
Methods
A descriptive epidemiological analysis method was used to conduct descriptive statistical analysis as well as statistical analysis of time and space scanning for the hepatitis B epidemic data in Longquanyi district of Chengdu City from 2011 to 2016.
Results
A total of 1 394 cases of hepatitis B were reported from 2011 to 2016 in Longquanyi district, Chengdu City. The average annual incidence rate was 37.15/100 000 (1 394/3 752 373) and the incidence rate showed a trend of decreasing each year (x2=216.73, P<0.01). The age of onset was mainly from 15 to 54 years old, accounting for 71.67% (999/1 394). The incidence rate of male was 48.04/100 000 (898/1 869 324), the rate aong females was 26.34/100 000 (496/1 883 052) and the difference was statistically significant (x2=119.20, P<0.01). The gender ratio was 1.81:1. The occupational composition was mainly farmers, accounting for 36.73% (512/1 394). The difference in occupational composition was statistically significant (x2=43.35, P=0.013). The case classification was mainly chronic hepatitis B, accounting for 81.99% (1 143/1 394).
Conclusions
The incidence of hepatitis B in Longquanyi district of Chengdu City showed a downward trend from 2011 to 2016. The district should continue to strengthen the prevention and control of hepatitis B for farmers, young adults and middle-aged people.
Key words:
Hepatitis B; Epidemic; Epidemiology; Research
To evaluate the surgical techniques and the efficacy for massive suprachoroidal hemorrhage (MSH).Secondary surgery performed on 11 cases of MSH occurring during or after intraocular surgery was delayed for 11 to 28 days (mean, 15.4 days). All eyes underwent posterior drainage sclerotomies under constantly maintained limbal fluid line pressure, followed by pars plana infusion and vitreoretinal surgery. The perfluorocarbon liquid was used intraoperatively in 6 cases.The drainage of the choroidal hemorrhage was successful in all cases. The blood drained from suprachoroidal space was completely liquified and chocolate in color. Tractional retinal detachment occurred in 2 eyes; 9 eyes had retinas normal in position. The mean follow-up was 7.8 months. Visual acuities were improved, >or=0.1 in 6 eyes.Immediate management of MSH includes watertight wound closure and medical treatment for elevated intraocular pressure, and secondary surgery was performed timely, including external drainage by creating sclerotomies and vitreoretinal surgery. The above methods of treatment have certain advantages and are promising for the management of MSH.
Background: Ophthalmological screening for cytomegalovirus retinitis (CMVR) for HIV/AIDS patients is important. The application of a deep learning (DL) system to AIDS-related CMVR with ultra-wide-field (UWF) fundus images is promising, but the feasibility and efficiency of this method have not been studied.Methods: We independently developed and internally validated a DL system for identifying active CMVR, inactive CMVR and non-CMVR in 6960 UWF fundus images from 862 AIDS patients and validated the system in a prospective and an external validation data set using area under curve (AUC), accuracy, sensitivity, and specificity. A heat map identified the most important area (lesions) used by the DL system for differentiating CMVR. This trial is registered with ClinicalTrials.gov, number NCT04831333. Findings The DL system showed AUCs of 0·945 (95% confidence interval [CI]: 0·929, 0·962), 0·964 (95% CI: 0·870, 0·999) and 0·968 (95% CI: 0·860, 1·000) for detecting active CMVR from non-CMVR and 0·923 (95% CI: 0·908, 0·938), 0·902 (0·857, 0·948) and 0·884 (0·851, 0·917) for detecting active CMVR from non-CMVR in the internal cross-validation, external validation, and prospective validation, respectively. It also showed the ability to differentiate active CMVR from non-CMVR and inactive CMVR as well as to identify active CMVR and inactive CMVR from non-CMVR (all AUCs in the three independent data sets >0·900). The heat maps successfully highlighted lesion locations.Interpretation: Our system showed reliable performance for detecting AIDS-rated CMVR. DL technology is promising for screening and differentiating CMVR in AIDS patients.Clinical Trial: This trial is registered with ClinicalTrials.gov, number NCT04831333. Funding: Scientific Research Project of Beijing Youan Hospital, CCMU, 2018 (YNKTQN20180201); Capital Health Research and Development of Special (2020-1-2052); Science & Technology Project of Beijing Municipal Science & Technology Commission (Z181100001818003); Beijing Municipal Administration of Hospitals' Ascent Plan (DFL20150201).Declaration of Interest: The authors have no conflicts of interest to declare.Ethical Approval: This study was conducted in accordance with the Declaration of Helsinki. Both the Ethics Committee of Beijing YouAn Hospital (LL-2018-150-K) and the Ethics Committee of Beijing Tongren Hospital (TRECKY2018-056) approved the study. Written informed consent was obtained from each subject.
Abstract Background The prevalence of cognitive impairment (CI) and dementia in end‐stage chronic kidney disease (CKD) has been estimated at 30‐60%. Cardiovascular dysfunction accompanies CKD and contributes to CI in humans and animal models. Since CKD occurs more often in females in clinical studies, the aim of this study was to determine whether cardiovascular and renal remodeling is associated with cognitive performance in the female rats with CKD. Methods Four‐month‐old female Sprague‐Dawley rats were fed with 0.25% adenine diet to induce CKD (n = 19) or a regular control diet (n = 16; CTRL) for 8weeks. Body weight (BW), blood pressure (BP), heart rate (HR), blood urea nitrogen (BUN), sodium, potassium, creatinine, hematocrit, estradiol, and behavioral tests were assessed at the end of the study. The level of anxiety was tested in open field test (OFT) and elevated plus maze (EPM). Spatial memory was tested by the ability to find a hidden platform in Morris water maze (MWM). The data were analyzed by two‐tailed unpaired t‐test and linear regression analysis (LRA). Results CKD was associated with higher creatinine and BUN, lower hematocrit, and enlarged hearts, aortae and kidneys vs. CTRL (Table 1). There was no difference in BP, estradiol, sodium and potassium, MWM, OFT and EPM performance between the groups. However, the LRA revealed the association of higher heart weights with a reduced spatial memory and higher anxiety level in both CTRL and CKD (Table 2; Figure 1A,B). The association of higher aortic weight with a reduced spatial memory, and higher kidney weight with higher anxiety levels was demonstrated in CKD only (Table 2; Figure 1C,D). Estradiol was associated with better spatial memory in CKD (LRA: R 2 = 0.264; p = 0.04). Conclusion Anxiety‐like behavior and spatial memory were associated with cardiovascular remodeling in young female rats with CKD. We suggest that (1) CKD stimulates development of cardiovascular remodeling, which may affect blood supply of cortex and hippocampus, responsible for anxiety and spatial memory, and (2) estradiol may contribute to a better cognitive performance in the young CKD female rats. The future direction is to investigate whether CKD influences the trajectory of neurocognitive and cardiovascular aging. Supported by NIA/NIH/IRP
To study polypoidal lesions and branching choroidal vascular networks in eyes with polypoidal choroidal vasculopathy by optical coherence tomography (OCT)-based angiography (OCTA).In the observational cross-sectional study, patients with polypoidal choroidal vasculopathy, as diagnosed by indocyanine green angiography, underwent OCTA.Thirty-two eyes of 31 patients with an age of 61.1 ± 7.6 years were included. Branching choroidal vascular networks were detected by indocyanine green angiography and OCTA in 25 of 32 (78 ± 73%) and in 30 of 32 (94 ± 4%) eyes, respectively, with a marginally significant difference (P = 0.06) in the detection rate between both techniques. A total of 72 polyps (area, 0.06 ± 0.06 mm; range, 0.01-0.27 mm) were detected by indocyanine green angiography, and they were consistently present on the OCTA images. By moving the reference level in the OCT angiograms to the corresponding layer, the polypoidal lesions showed cluster-like structures in 53 of 72 polypoidal lesions (74%). In 60 of the 72 polypoidal lesions (83%), cluster-like structures were detected in the en face structural OCT images at the reference plane of the OCTA images. On the cross-sectional OCT images, some internal channels of flow were seen in 50 of the 72 polypoidal lesions (69%). Larger size of the polypoidal lesions was associated with a higher prevalence of cluster-like structures on the OCTA images, some internal channels of flow on the en face structural images, and clustered vascular structures on the cross-sectional OCT images.In conclusion, OCTA is a useful technique for the noninvasive detection of branching choroidal vascular networks including visualization of details such as cluster-like structures and flow. In some eyes, OCTA was superior to indocyanine green angiography to detect polypoidal choroidal vasculopathy and to show branching choroidal vascular networks.
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