We aimed to evaluate the performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine–cystatin C equation in a cohort of elderly Chinese participants.
Materials and methods
Glomerular filtration rate (GFR) was measured in 431 elderly Chinese participants by the technetium-99m diethylene-triamine-penta-acetic acid (99mTc-DTPA) renal dynamic imaging method, and was calibrated equally to the dual plasma sample 99mTc-DTPA-GFR. Performance of the CKD-EPI creatinine–cystatin C equation was compared with the Cockcroft–Gault equation, the re-expressed 4-variable Modification of Diet in Renal Disease (MDRD) equation, and the CKD-EPI creatinine equation.
Although the bias of the CKD-EPI creatinine–cystatin C equation was greater than with the other equations (median difference, 5.7 mL/minute/1.73 m2 versus a range from 0.4–2.5 mL/minute/1.73 m2; P<0.001 for all), the precision was improved with the CKD-EPI creatinine–cystatin C equation (interquartile range for the difference, 19.5 mL/minute/1.73 m2 versus a range from 23.0–23.6 mL/minute/1.73 m2; P<0.001 for all comparisons), leading to slight improvement in accuracy (median absolute difference, 10.5 mL/minute/1.73 m2 versus 12.2 and 11.4 mL/minute/1.73 m2 for the Cockcroft–Gault equation and the re-expressed 4-variable MDRD equation, P=0.04 for both; 11.6 mL/minute/1.73 m2 for the CKD-EPI creatinine equation, P=0.11), as the optimal scores of performance (6.0 versus a range from 1.0–2.0 for the other equations). Higher GFR category and diabetes were independent factors that negatively correlated with the accuracy of the CKD-EPI creatinine–cystatin C equation (β=−0.184 and −0.113, P<0.001 and P=0.02, respectively).
Compared with the creatinine-based equations, the CKD-EPI creatinine–cystatin C equation is more suitable for the elderly Chinese population. However, the cost-effectiveness of the CKD-EPI creatinine–cystatin C equation for clinical use should be considered.
elderly; equation; glomerular filtration rate; serum creatinine; cystatin C
Genetic variants in 296 genes in regions identified through admixture mapping of hypertension, BMI, and lipids were assessed for association with hypertension, blood pressure, BMI, and HDL-C.
This study identified coding SNPs identified from HapMap2 data that were located in genes on chromosomes 5, 6, 8, and 21, where ancestry association evidence for hypertension, BMI or HDL-C was identified in previous admixture mapping studies. Genotyping was performed in 1,733 unrelated African-Americans from the National Heart, Lung and Blood Institute’s (NHLBI) Family Blood Pressure Project, and gene-based association analyses were conducted for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), BMI, and HDL-C. A gene score based on the number of minor alleles of each SNP in a gene was created and used for gene-based regression analyses, adjusting for age, age2, sex, local marker ancestry, and BMI, as applicable. An individual’s African ancestry estimated from 2,507 ancestry-informative markers was also adjusted for to eliminate any confounding due to population stratification.
CXADR (rs437470) on chromosome 21 was associated with SBP and DBP with or without adjusting for local ancestry (p < 0.0006). F2RL1 (rs631465) on chromosome 5 was associated with BMI (p = 0.0005). Local ancestry in these regions was associated with the respective traits as well.
This study suggests that CXADR and F2RL1 likely play important roles in blood pressure and obesity variation, respectively; and these findings are consistent with other studies, so replication and functional analyses are necessary.
Blood pressure; Obesity; African Americans; Genetic Association Studies
Robust production of type I interferon (IFN-α/β) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its ‘downstream’ mediators, the p70 ribosomal S6 protein kinases p70S6K1 and p70S6K2, during pDC activation by Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and subsequent activation of the interferon-regulatory factor IRF7, which resulted in impaired IFN-α/β production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed antiviral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in less IFN-α/β production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling is crucial in TLR-mediated IFN-α/β responses by pDCs.
Many patients with cancer experience depression and anxiety, and an associated decrease in quality of life (QOL) during radiation therapy (RT). The main objective of the study was to determine the benefits of psychosocial interventions for cancer patients who received RT.
Patients with cancer (n = 178) who agreed to participate in the study were randomized to the intervention arm (n = 89) or the control arm (n = 89). Patients in the intervention group received psychosocial care during RT, whereas the control group received RT only. The benefits of the intervention were evaluated using the Zung Self-rating Depression Scale (SDS) to measure depression, the Self-rating Anxiety Scale (SAS) to assess anxiety, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) to survey health-related QOL. The association between intervention and survival was also assessed.
Patients randomly assigned to the intervention arm showed significant improvements on symptoms of depression (p < 0.05) and anxiety (p < 0.05), health-related QOL (p < 0.05) (i.e. better global health status, and physical and emotional functioning, and less insomnia) when compared with controls. In the subset analysis, female patients, those that received high dose irradiation, and those that underwent adjuvant chemotherapy could benefit more from psychosocial intervention. There was no difference between the two groups in disease-free survival (DFS) (2-year DFS 79.8% in the intervention arm and 76.4% in the control arm; p = 0.527) and overall survival (OS) (2-year OS 83.1% in the intervention arm and 84.3% in the control arm; p = 0.925)
Psychosocial intervention is a cost-effective approach that can improve a patient’s mood and QOL both during and after RT. However, the intervention was not found to reduce the risk of cancer recurrence and death.
Cancer; Radiation oncology; Psychosocial intervention; Anxiety; Depression; Quality of life
This study was undertaken to assess the diagnostic value of 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography with computed tomography ([18F]-FDG-PET/CT) in the detection of radiation toxicity in normal bone marrow using Tibet minipigs as a model. Eighteen Tibet minipigs were caged in aseptic rooms and randomly divided into six groups. Five groups (n = 3/group) were irradiated with single doses of 2, 5, 8, 11 and 14 Gy of total body irradiation (TBI) using an 8-MV X-ray linear accelerator. These pigs were evaluated with [18F]-FDG-PET/CT, and their marrow nucleated cells were counted. The data were initially collected at 6, 24 and 72 h after treatment and were then collected on Days 5–60 post-TBI at 5-day intervals. At 24 and 72 h post-TBI, marrow standardized uptake value (SUV) data showed a dose-dependent decrease in the radiation dose range from 2–8 Gy. Upon long-term observation, SUV and marrow nucleated cell number in the 11-Gy and 14-Gy groups showed a continuous and marked reduction throughout the entire time course, while Kaplan–Meier curves of survival showed low survival. In contrast, the SUVs in the 2-, 5- and 8-Gy groups showed early transient increases followed by a decline from approximately 72 h through Days 5–15 and then normalized or maintained low levels through the endpoint; marrow nucleated cell number and survival curves showed approximately the same trend and higher survival, respectively. Our findings suggest that [18F]-FDG-PET/CT may be helpful in quickly assessing the absorbed doses and predicting the prognosis in patients.
[18F]-FDG-PET/CT; total body irradiation; bone marrow; Tibet minipigs
MicroRNAs are a class of non-coding RNAs that function as key regulators of gene expression at the post-transcriptional level. In our previous research, we found that miR-23a was significantly up-regulated in human gastric adenocarcinoma cells. In the current study, we demonstrate that miR-23a suppresses paclitaxel-induced apoptosis and promotes the cell proliferation and colony formation ability of gastric adenocarcinoma cells. We have identified tumor suppressor interferon regulator factor 1 (IRF1) as a direct target gene of miR-23a. We performed a fluorescent reporter assay to confirm that miR-23a bound to the IRF1 mRNA 3′UTR directly and specifically. The ectopic expression of IRF1 markedly promoted paclitaxel-induced apoptosis and inhibited cell viability and colony formation ability, whereas the knockdown of IRF1 had the opposite effects. The restoration of IRF1 expression counteracted the effects of miR-23a on the paclitaxel-induced apoptosis and cell proliferation of gastric adenocarcinoma cells. Quantitative real-time PCR showed that miR-23a is frequently up-regulated in gastric adenocarcinoma tissues, whereas IRF1 is down-regulated in cancer tissues. Altogether, these results indicate that miR-23a suppresses paclitaxel-induced apoptosis and promotes cell viability and the colony formation ability of gastric adenocarcinoma cells by targeting IRF1 at the post-transcriptional level.
The hepatitis B virus X (HBx) protein has long been recognized as an important transcriptional transactivator of several genes. Human aldo-keto reductase family 1, member C1 (AKR1C1), a member of the family of AKR1CS, is significantly increased in HBx-expressed cells.
This study aimed to investigate the possible mechanism of HBx in regulating AKR1C1 expression in HepG2.2.15 cells and the role of AKR1C1 for HBV-induced HCC.
Materials and Methods
RT-PCR was performed to detect AKR1C1 expression on mRNA level in HepG2 and HepG2.2.15 cell. The promoter activity of AKR1C1 was assayed by transient transfection and Dual-luciferase reporter assay system. The AKR1C1 promoter sequence was screened using the TFSEARCH database and the ALIBABA 2.0 software. The potential transcription factors binding sites were identified using 5’ functional deletion analysis and site-directed mutagenesis.
In this study, we found that HBx promoted AKR1C1 expression in HepG2.2.15 cells. Knockdown of HBx inhibited AKR1C1 activation. The role of HBx expression in regulating the promoter activity of human AKR1C1 gene was analyzed. The 5’functional deletion analysis identified that the region between -128 and -88 was the minimal promoter region of HBx to activate AKR1C1 gene expression. Site-directed mutagenesis studies suggested that nuclear factor-Y (NF-Y) plays an important role in this HBx-induced AKR1C1 activation.
In HepG184.108.40.206 cell, HBx can promote AKR1C1 promoter activity and thus activates the basal transcription of AKR1C1 gene. This process is mediated by the transcription factor NF-Y. This study explored the mechanism for the regulation of HBV on AKR1C1 expression and has provided a new understanding of HBV-induced HCC.
Hepatitis B Virus X Protein; HepG2 Cells; 3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase
The reconstruction of large bone defects, including rib defects, remains a challenge for surgeons. In this study, we used biodegradable polydioxanone (PDO) cages to tissue engineer ribs for the reconstruction of 4cm-long costal defects.
PDO sutures were used to weave 6cm long and 1cm diameter cages. Demineralized bone matrix (DBM) which is a xenograft was molded into cuboids and seeded with second passage bone marrow mesenchymal stem cells (BMSCs) that had been osteogenically induced. Two DBM cuboids seeded with BMSCs were put into the PDO cage and used to reconstruct the costal defects. Radiographic examination including 3D reconstruction, histologic examination and mechanical test was performed after 24 postoperative weeks.
All the experimental subjects survived. In all groups, the PDO cage had completely degraded after 24 weeks and been replaced by fibrous tissue. Better shape and radian were achieved in PDO cages filled with DBM and BMSCs than in the other two groups (cages alone, or cages filled with acellular DBM cuboids). When the repaired ribs were subjected to an outer force, the ribs in the PDO cage/DBMs/BMSCs group kept their original shape while ribs in the other two groups deformed. In the PDO cage/DBMs/BMSCs groups, we also observed bony union at all the construct interfaces while there was no bony union observed in the other two groups. This result was also confirmed by radiographic and histologic examination.
This study demonstrates that biodegradable PDO cage in combination with two short BMSCs/DBM cuboids can repair large rib defects. The satisfactory repair rate suggests that this might be a feasible approach for large bone repair.
Tissue engineering; Rib reconstruction; PDO; Long defect of bone
Eighteen new 11,20-epoxy-3Z,5E-dien briaranes, gemmacolides AA–AR (1–18), were isolated together with three known analogs, dichotellides F (19) and I (20), and juncenolide C (21), from the South China Sea gorgonian Dichotella gemmacea. The structures of the compounds were elucidated by detailed spectroscopic analysis and comparison with reported data. The absolute configuration was determined based on the ECD experiment. In the in vitro bioassay, compounds 1–3, 5, 6, 8–12, and 14–19 exhibited different levels of growth inhibition activity against A549 and MG63 cell lines. Preliminary structure-activity analysis suggests that 12-O-isovalerate may increase the activity whereas 13- or 14-O-isovalerate may decrease the activity. Contribution of substitutions at C-2 and C-16 remains uncertain.
structure activity relationship; briarane diterpenoids; biological activity; Dichotella gemmacea; gorgonian
Variation in human skin and eye color is substantial and especially apparent in admixed populations, yet the underlying genetic architecture is poorly understood because most genome-wide studies are based on individuals of European ancestry. We study pigmentary variation in 699 individuals from Cape Verde, where extensive West African/European admixture has given rise to a broad range in trait values and genomic ancestry proportions. We develop and apply a new approach for measuring eye color, and identify two major loci (HERC2[OCA2] P = 2.3×10−62, SLC24A5 P = 9.6×10−9) that account for both blue versus brown eye color and varying intensities of brown eye color. We identify four major loci (SLC24A5 P = 5.4×10−27, TYR P = 1.1×10−9, APBA2[OCA2] P = 1.5×10−8, SLC45A2 P = 6×10−9) for skin color that together account for 35% of the total variance, but the genetic component with the largest effect (∼44%) is average genomic ancestry. Our results suggest that adjacent cis-acting regulatory loci for OCA2 explain the relationship between skin and eye color, and point to an underlying genetic architecture in which several genes of moderate effect act together with many genes of small effect to explain ∼70% of the estimated heritability.
Differences in skin and eye color are some of the most obvious traits that underlie human diversity, yet most of our knowledge regarding the genetic basis for these traits is based on the limited range of variation represented by individuals of European ancestry. We have studied a unique population in Cape Verde, an archipelago located off the West African coast, in which extensive mixing between individuals of Portuguese and West African ancestry has given rise to a broad range of phenotypes and ancestral genome proportions. Our results help to explain how genes work together to control the full range of pigmentary phenotypic diversity, provide new insight into the evolution of these traits, and provide a model for understanding other types of quantitative variation in admixed populations.
Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here we present an integrative Personal Omics Profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14-month period. Our iPOP analysis revealed various medical risks, including Type II diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high coverage genomic and transcriptomic data, which provide the basis of our iPOP, discovered extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and disease states by connecting genomic information with additional dynamic omics activity.
Seven new polyoxygenated steroids (1–7) were isolated together with seven known analogues (8–14) from the South China Sea soft coral, Sarcophyton sp. The structures of the new compounds were identified on the basis of extensive spectroscopic analysis and comparison with reported data. All the steroids are characterized with 3β,5α,6β-hydroxy moiety, displaying carbon skeletons of cholestane, ergostane, gorgostane and 23,24-dimethyl cholestane. In the in vitro bioassay, metabolites exhibited different levels of antimicrobial activity against bacterial species Escherichia coli and Bacillus megaterium, and fungal species Microbotryum violaceum and Septoria tritici. No inhibition was detected towards microalga Chlorella fusca. Preliminary structure-activity analysis suggests that the 11α-acetoxy group may increase both antibacterial and antifungal activities. The terminal-double bond and the cyclopropane moiety at the side chain may also contribute to the bioactivity.
Sarcophyton sp.; steroid; bioactivity; antibacterial; antifungal
Height is a complex trait under strong genetic influence. To date, numerous genetic loci have been associated with height in individuals of European ancestry. However, few large-scale discovery genome-wide association studies (GWAS) of height in minority populations have been conducted and thus information about population-specific height regulation is limited. We conducted a GWA analysis of height in 8149 African-American (AA) women from the Women's Health Initiative. Genetic variants with P< 5 × 10−5 (n = 169) were followed up in a replication data set (n = 20 809) and meta-analyzed in a total of 28 958 AAs and African-descent individuals. Twelve single-nucleotide polymorphisms (SNPs) representing 7 independent loci were significantly associated with height at P < 5 × 10−8. We identified novel SNPs in 17q23 (TMEM100/PCTP) and Xp22.3 (ARSE) reflecting population-specific regulation of height in AAs and replicated five loci previously reported in European-descent populations [4p15/LCORL, 11q13/SERPINH1, 12q14/HMGA2, 17q23/MAP3K3 (mitogen-activated protein kinase3) and 18q21/DYM]. In addition, we performed an admixture mapping analysis of height which is both complementary and supportive to the GWA analysis and suggests potential associations between ancestry and height on chromosomes 4 (4q21), 15 (15q26) and 17 (17q23). Our findings provide insight into the genetic architecture of height and support the investigation of non-European-descent populations for identifying genetic factors associated with complex traits. Specifically, we identify new loci that may reflect population-specific regulation of height and report several known height loci that are important in determining height in African-descent populations.
AIM: To elucidate high mobility group-box 3 (HMGB3) protein expression in gastric adenocarcinoma, its potential prognostic relevance, and possible mechanism of action.
METHODS: Ninety-two patients with gastric adenocarcinomas surgically removed entered the study. HMGB3 expression was determined by immunohistochemistry through a tissue microarray procedure. The clinicopathologic characteristics of all patients were recorded, and regular follow-up was made for all patients. The inter-relationship of HMGB3 expression with histological and clinical factors was analyzed using nonparametric tests. Survival analysis was carried out by Kaplan-Meier (log-rank) and multivariate Cox (Forward LR) analyses between the group with overexpression of HMGB3 and the group with low or no HMGB3 expression to determine the prognosis value of HMGB3 expression on overall survival. Further, HMGB3 expression was knocked down by small hairpin RNAs (shRNAs) in the human gastric cancer cell line BGC823 to observe its influence on cell biological characteristics. The MTT method was utilized to detect gastric cancer cell proliferation changes, and cell cycle distribution was analyzed by flow cytometry.
RESULTS: Among 92 patients with gastric adenocarcinomas surgically removed in this study, high HMGB3 protein expression was detected in the gastric adenocarcinoma tissues vs peritumoral tissues (P < 0.001). Further correlation analysis with patients’ clinical and histology variables revealed that HMGB3 overexpression was obviously associated with extensive wall penetration (P = 0.005), a positive nodal status (P = 0.004), and advanced tumor-node-metastasis (TNM) stage (P = 0.001). But there was no correlation between HMGB3 overexpression and the age and gender of the patient, tumor localization or histologic grade. Statistical Kaplan-Meier survival analysis disclosed significant differences in overall survival between the HMGB3 overexpression group and the HMGB3 no or low expression group (P = 0.006). The expected overall survival time was 31.00 ± 3.773 mo (95%CI = 23.605-38.395) for patients with HMGB3 overexpression and 49.074 ± 3.648 mo (95%CI = 41.925-57.311) for patients with HMGB3 no and low-level expression. Additionally, older age (P = 0.040), extensive wall penetration (P = 0.008), positive lymph node metastasis (P = 0.005), and advanced TNM tumor stage (P = 0.007) showed negative correlation with overall survival. Multivariate Cox regression analysis indicated that HMGB3 overexpression was an independent variable with respect to age, gender, histologic grade, extent of wall penetration, lymph nodal metastasis, and TNM stage for patients with resectable gastric adenocarcinomas with poor prognosis (hazard ratio = 2.791, 95%CI = 1.233-6.319, P = 0.019). In the gene function study, after HMGB3 was knocked down in the gastric cell line BGC823 by shRNA, the cell proliferation rate was reduced at 24 h, 48 h and 72 h. Compared to BGC823 shRNA-negative control (NC) cells, the cell proliferation rate in cells that had HMGB3 shRNA transfected was significantly decreased (P < 0.01). Finally, cell cycle analysis by FACS showed that BGC823 cells that had HMGB3 knocked down were blocked in G1/G0 phase. The percentage of cells in G1/G0 phase in BGC823 cells with shRNA-NC and with shRNA-HMGB3 was 46.84% ± 1.7%, and 73.03% ± 3.51% respectively (P = 0.001), whereas G2/M cells percentage decreased from 26.51% ± 0.83% to 17.8% ± 2.26%.
CONCLUSION: HMGB3 is likely to be a useful prognostic marker involved in gastric cancer disease onset and progression by regulating the cell cycle.
High mobility group-box 3; Gastric adenocarcinoma; Prognosis; Cell proliferation; Cell cycle
Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In our model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data, we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and “ancient” Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.com.
With modern genotyping technology, it is now possible to obtain large amounts of genetic data from many populations in a species. An important question that can be addressed with these data is: what is the history of these populations? There is a long history in population genetics of inferring the relationships among populations as a bifurcating tree, analogous to phylogenetic trees for representing the evolution of species. However, it has long been recognized that, since populations from the same species exchange genes, simple bifurcating trees may be an incorrect representation of population histories. We have developed a method to address this issue, using a model which allows for both population splits and gene flow. In application to humans, we show that we are able to identify a number of both previously known and unknown episodes of gene flow in history, including gene flow into Cambodia of a population only distantly related to modern East Asia. In application to dogs, we show that the boxer and basenji breeds have a considerable component of ancestry from grey wolves subsequent to domestication.
Salt absorption via alveolar epithelial Na+ channels (ENaC) is a critical step for maintaining an airspace free of flooding. Previously, we found that 8-(4-chlorophenylthio)-guanosine-3′,5′-cyclic monophosphate-Na (CPT-cGMP) activated native and heterologous ENaC. To investigate the potential pharmacological relevance, we applied this compound intratracheally to human lungs and found that ex vivo alveolar fluid clearance was increased significantly. Furthermore, this compound eliminated self-inhibition in human lung H441 cells and in oocytes expressing human αβγ but not δβγ channels. To further elucidate this novel mechanism, we constructed mutants abolishing (βΔV348 and γH233R) or augmenting (αY458A and γM432G) self-inhibition. The mutants eliminating self-inhibition lost their responses to CPT-cGMP, whereas those enhancing self-inhibition facilitated the stimulatory effects of this compound. CPT-cGMP was unable to activate a high Po mutant (βS520C) and plasmin proteolytically cleaved channels. Our data suggest that elimination of self-inhibition of αβγ ENaC may be a novel mechanism for CPT-cGMP to stimulate salt reabsorption in human lungs.
lung fluid reabsorption; amiloride-sensitive sodium channel; CPT-cGMP; ENaC self-inhibition
Pigmentation of the skin, hair, and eyes varies both within and between human populations. Identifying the genes and alleles underlying this variation has been the goal of many candidate gene and several genome-wide association studies (GWAS). Most GWAS for pigmentary traits to date have been based on subjective phenotypes using categorical scales. But skin, hair, and eye pigmentation vary continuously. Here, we seek to characterize quantitative variation in these traits objectively and accurately and to determine their genetic basis. Objective and quantitative measures of skin, hair, and eye color were made using reflectance or digital spectroscopy in Europeans from Ireland, Poland, Italy, and Portugal. A GWAS was conducted for the three quantitative pigmentation phenotypes in 176 women across 313,763 SNP loci, and replication of the most significant associations was attempted in a sample of 294 European men and women from the same countries. We find that the pigmentation phenotypes are highly stratified along axes of European genetic differentiation. The country of sampling explains approximately 35% of the variation in skin pigmentation, 31% of the variation in hair pigmentation, and 40% of the variation in eye pigmentation. All three quantitative phenotypes are correlated with each other. In our two-stage association study, we reproduce the association of rs1667394 at the OCA2/HERC2 locus with eye color but we do not identify new genetic determinants of skin and hair pigmentation supporting the lack of major genes affecting skin and hair color variation within Europe and suggesting that not only careful phenotyping but also larger cohorts are required to understand the genetic architecture of these complex quantitative traits. Interestingly, we also see that in each of these four populations, men are more lightly pigmented in the unexposed skin of the inner arm than women, a fact that is underappreciated and may vary across the world.
Chronic kidney disease (CKD) is recognized worldwide as a public health problem, and its prevalence increases as the population ages. However, the applicability of formulas for estimating the glomerular filtration rate (GFR) based on serum creatinine (SC) levels in elderly Chinese patients with CKD is limited.
Materials and methods
Based on values obtained with the technetium-99m diethylenetriaminepentaacetic acid (99mTc-DTPA) renal dynamic imaging method, 319 elderly Chinese patients with CKD were enrolled in this study. Serum creatinine was determined by the enzymatic method. The GFR was estimated using the Cockroft–Gault (CG) equation, the Modification of Diet in Renal Disease (MDRD) equations, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Jelliffe-1973 equation, and the Hull equation.
The median of difference ranged from −0.3–4.3 mL/min/1.73 m2. The interquartile range (IQR) of differences ranged from 13.9–17.6 mL/min/1.73 m2. Accuracy with a deviation less than 15% ranged from 27.6%–32.9%. Accuracy with a deviation less than 30% ranged from 53.6%–57.7%. Accuracy with a deviation less than 50% ranged from 74.9%–81.5%. None of the equations had accuracy up to the 70% level with a deviation less than 30% from the standard glomerular filtration rate (sGFR). Bland–Altman analysis demonstrated that the mean difference ranged from −3.0–2.4 mL/min/1.73 m2. However, the agreement limits of all the equations, except the CG equation, exceeded the prior acceptable tolerances defined as 60 mL/min/1.73 m2. When the overall performance and accuracy were compared in different stages of CKD, GFR estimated using the CG equation showed promising results.
Our study indicated that none of these equations were suitable for estimating GFR in the elderly Chinese population investigated. At present, based on overall performance, as well as performance in different CKD stages, the CG equation may be the most accurate for estimating GFR in elderly Chinese patients with CKD.
elderly; equation; glomerular filtration rate; serum creatinine; Chinese
Henoch-Schönlein purpura (HSP) is a small-vessel vasculitis mediated by IgA-immune complex deposition. It is characterized by the clinical tetrad of non-thrombocytopenic palpable purpura, abdominal pain, arthritis and renal involvement. The diagnosis of HSP is difficult, especially when abdominal symptoms precede cutaneous lesions. We report a rare case of paroxysmal drastic abdominal pain with gastrointestinal bleeding presented in HSP. The diagnosis was verified by renal damage and the occurrence of purpura.
Henoch-Schönlein purpura; Abdominal pain; Gastrointestinal bleeding
Atopic diseases, such as atopic dermatitis (AD) and asthma, are closely related to clinical phenotypes with hypersensitivity, and often share some similar genetic and pathogenic bases. Our recent GWAS identified three susceptibility gene/loci FLG (rs11204971 and rs3126085), 5q22.1 (rs10067777, rs7701890, rs13360927 and rs13361382) and 20q13.33 (rs6010620) to AD. The effect of these AD associated polymorphisms in asthma is so far unknown. To investigate whether AD relevant genetic variants is identical to asthma and reveal the differences in genetic factors between AD and asthma in Chinese Han population, seven AD associated single nucleotide polymorphisms (SNPs) as well as 3 other SNPs (rs7936562 and rs7124842 at 11q13.5 and rs4982958 at 14q11.2) from our previous AD GWAS were genotyped in 463 asthma patients and 985 controls using Sequenom MassArray system. We found rs4982958 at 14q11.2 was significantly associated with asthma (P = 3.04×10−4, OR = 0.73). We also detected one significant risk haplotype GGGA from the 4 SNPs (rs10067777, rs7701890, rs13360927 and rs13361382) at 5q22.1 in AD cases (Pcorrection = 3.60×10−10, OR = 1.26), and the haplotype was suggestive of risk in asthma cases in this study (P = 0.014, Pcorrection = 0.084, OR = 1.38). These SNPs (rs11204971, rs3126085, rs7936562, rs712484 and rs6010620) at AD susceptibility genes/loci FLG, 11q13.5 and 20q13.33 were not associated with asthma in this study. Our results further comfirmed that 14q11.2 was an important candidate locus for asthma and demonstrated that 5q22.1 might be shared by AD and asthma in Chinese Han population.
For most of the world, human genome structure at a population level is shaped by interplay between ancient geographic isolation and more recent demographic shifts, factors that are captured by the concepts of biogeographic ancestry and admixture, respectively. The ancestry of non-admixed individuals can often be traced to a specific population in a precise region, but current approaches for studying admixed individuals generally yield coarse information in which genome ancestry proportions are identified according to continent of origin. Here we introduce a new analytic strategy for this problem that allows fine-grained characterization of admixed individuals with respect to both geographic and genomic coordinates. Ancestry segments from different continents, identified with a probabilistic model, are used to construct and study “virtual genomes” of admixed individuals. We apply this approach to a cohort of 492 parent–offspring trios from Mexico City. The relative contributions from the three continental-level ancestral populations—Africa, Europe, and America—vary substantially between individuals, and the distribution of haplotype block length suggests an admixing time of 10–15 generations. The European and Indigenous American virtual genomes of each Mexican individual can be traced to precise regions within each continent, and they reveal a gradient of Amerindian ancestry between indigenous people of southwestern Mexico and Mayans of the Yucatan Peninsula. This contrasts sharply with the African roots of African Americans, which have been characterized by a uniform mixing of multiple West African populations. We also use the virtual European and Indigenous American genomes to search for the signatures of selection in the ancestral populations, and we identify previously known targets of selection in other populations, as well as new candidate loci. The ability to infer precise ancestral components of admixed genomes will facilitate studies of disease-related phenotypes and will allow new insight into the adaptive and demographic history of indigenous people.
Admixed individuals, such as African Americans and Latinos, arise from mating between individuals from different continents. Detailed knowledge about the ancestral origin of an admixed population not only provides insight regarding the history of the population itself, but also affords opportunities to study the evolutionary biology of the ancestral populations. Applying novel statistical methods, we analyzed the high-density genotype data of nearly 1,500 Mexican individuals from Mexico City, who are admixed among Indigenous Americans, Europeans, and Africans. The relative contributions from the three continental-level ancestral populations vary substantially between individuals. The European ancestors of these Mexican individuals genetically resemble Southern Europeans, such as the Spaniard and the Portuguese. The Indigenous American ancestry of the Mexicans in our study is largely attributed to the indigenous groups residing in the southwestern region of Mexico, although some individuals have inherited varying degrees of ancestry from the Mayans of the Yucatan Peninsula and other indigenous American populations. A search for signatures of selection, focusing on the parts of the genomes derived from an ancestral population (e.g. Indigenous American), identifies regions in which a genetic variant may have been favored by natural selection in that ancestral population.
Current genome-wide association studies (GWAS) often involve populations that have experienced recent genetic admixture. Genotype data generated from these studies can be used to test for association directly, as in a non-admixed population. As an alternative, these data can be used to infer chromosomal ancestry, and thus allow for admixture mapping. We quantify the contribution of allele-based and ancestry-based association testing under a family-design, and demonstrate that the two tests can provide non-redundant information. We propose a joint testing procedure, which efficiently integrates the two sources information. The efficiencies of the allele, ancestry and combined tests are compared in the context of a GWAS. We discuss the impact of population history and provide guidelines for future design and analysis of GWAS in admixed populations.
We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455) and clinical coronary artery disease (CAD).
Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with non-carriers.
The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in nineteen case-control studies of non-fatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.
Over 17 000 cases and 39 000 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the nineteen studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with non-carriers. Regression analyses and fixed effect meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early onset disease (<50 years of age for males and <60 years for females) compared with similarly aged controls as well as all non-European subgroups.
The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
kinesin-like protein 6; KIF6; coronary artery disease; myocardial infarction; polymorphism
Based on the presumed capability of a prebiotic pocket-like entity to accommodate substrates whose stereochemistry enables the creation of chemical bonds, it is suggested that a universal symmetrical region identified within all contemporary ribosomes originated from an entity that we term the ‘proto-ribosome’. This ‘proto-ribosome’ could have evolved from an earlier machine that was capable of performing essential tasks in the RNA world, called here the ‘pre-proto-ribosome’, which was adapted for producing proteins.
proto-ribosome; ribosomal symmetrical region; peptide bond formation; RNA world
The mechanisms that initiate T helper type 2 (TH2) responses are poorly understood. Here we demonstrate that cysteine protease–induced TH2 responses occur via ‘cooperation’ between migratory dermal dendritic cells (DCs) and basophils positive for interleukin 4 (IL-4). Subcutaneous immunization with papain plus antigen induced reactive oxygen species (ROS) in lymph node DCs and in dermal DCs and epithelial cells of the skin. ROS orchestrated TH2 responses by inducing oxidized lipids that triggered the induction of thymic stromal lymphopoietin (TSLP) by epithelial cells mediated by Toll-like receptor 4 (TLR4) and the adaptor protein TRIF; by suppressing production of the TH1-inducing molecules IL-12 and CD70 in lymph node DCs; and by inducing the DC-derived chemokine CCL7, which mediated recruitment of IL-4+ basophils to the lymph node. Thus, the TH2 response to cysteine proteases requires DC-basophil cooperation via ROS-mediated signaling.