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author:("Yang, qing")
1.  Association of a Cystatin C Gene Variant With Cystatin C Levels, CKD, and Risk of Incident Cardiovascular Disease and Mortality 
Background
Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of CKD, and strengthen risk estimates for cardiovascular disease (CVD) and mortality.
Study Design
Observational.
Setting & Population
Four population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Compostion (Health ABC) studies.
Predictors
We estimated the association of rs13038305 with eGFRcys and eGFRcr, and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305.
Outcomes
We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45–59, 60–89, and ≥90 mL/min/1.73 m2. We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis.
Results
In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%), was associated with 6.4% lower cystatin C concentration, 5.5 mL/min/1.73 m2 higher eGFRcys, and 36% [95% CI, 29%–41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14–1.20) and mortality (HR, 1.22; 95% CI, 1.19–1.24) per 10- ml/min/1.73 m2 lower eGFRcys were similar with or without rs13038305 adjustment. In total, 1134 participants (7.7%) were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, −0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD.
Limitations
rs13038305 only explains a small proportion of cystatin C variation.
Conclusions
Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.
doi:10.1053/j.ajkd.2013.06.015
PMCID: PMC3872167  PMID: 23932088
Cystatin C; chronic kidney disease; genetics; single nucleotide polymorphism; net reclassification improvement
2.  Molecular characterization of the piggyBac-like element, a candidate marker for phylogenetic research of Chilo suppressalis (Walker) in China 
BMC Molecular Biology  2014;15(1):28.
Background
Transposable elements (TEs, transposons) are mobile genetic DNA sequences. TEs can insert copies of themselves into new genomic locations and they have the capacity to multiply. Therefore, TEs have been crucial in the shaping of hosts’ current genomes. TEs can be utilized as genetic markers to study population genetic diversity. The rice stem borer Chilo suppressalis Walker is one of the most important insect pests of many subtropical and tropical paddy fields. This insect occurs in all the rice-growing areas in China. This research was carried out in order to find diversity between C. suppressalis field populations and detect the original settlement of C. suppressalis populations based on the piggyBac-like element (PLE). We also aim to provide insights into the evolution of PLEs in C. suppressalis and the phylogeography of C. suppressalis.
Results
Here we identify a new piggyBac-like element (PLE) in the rice stem borer Chilo suppressalis Walker, which is called CsuPLE1.1 (GenBank accession no. JX294476). CsuPLE1.1 is transcriptionally active. Additionally, the CsuPLE1.1 sequence varied slightly between field populations, with polymorphic indels (insertion/deletion) and hyper-variable regions including the identification of the 3′ region outside the open reading frame (ORF). CsuPLE1.1 insertion frequency varied between field populations. Sequences variation was found between CsuPLE1 copies and varied within and among field populations. Twenty-one different insertion sites for CsuPLE1 copies were identified with at least two insertion loci found in all populations.
Conclusions
Our results indicate that the initial invasion of CsuPLE1 into C. suppressalis occurred before C. suppressalis populations spread throughout China, and suggest that C. suppressalis populations have a common ancestor in China. Additionally, the lower reaches of the Yangtze River are probably the original settlement of C. suppressalis in China. Finally, the CsuPLE1 insertion site appears to be a candidate marker for phylogenetic research of C. suppressalis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12867-014-0028-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12867-014-0028-y
PMCID: PMC4273485  PMID: 25515331
Transposon; piggyBac; Molecular characterization; Evolution; Chilo suppressalis
3.  D-galactose-induced mitochondrial DNA oxidative damage in the auditory cortex of rats 
Molecular Medicine Reports  2014;10(6):2861-2867.
Chronic administration of D-galactose (D-gal) is a useful method for establishing a model of natural aging in the auditory system. Previous studies have demonstrated that NADPH oxidases (NOXs) may be an important source of reactive oxygen species (ROS) in the peripheral auditory system (PAS) and cause an increase in mitochondrial DNA (mtDNA) common deletion (CD) levels in the PAS and central auditory system (CAS) of rats with D-gal-induced aging. However, the source of the ROS in the CAS and the mechanisms of age-related hearing loss (ARHL) have yet to be elucidated. In the present study, male Sprague Dawley rats were administered a daily injection of D-gal (150, 300 and 500 mg/kg, respectively) for eight weeks. All three doses of D-gal caused a significant increase in the expression of NOX2, 8-hydroxy-2-deoxyguanosine, a biomarker of DNA oxidative damage, and uncoupling protein 2, together with a decrease in the mitochondrial total antioxidant capabilities in the auditory cortex, as compared with the control rats (injected daily with the same volume of 0.9% saline for eight weeks). The levels of the mtDNA CD were also increased in the auditory cortex of the D-gal-induced aging rats. These findings suggest that both NOX- and mitochondria-associated ROS generation may contribute to mtDNA oxidative damage in the auditory cortex of the CAS of D-gal-induced aging rats. This study may provide novel insight into the development of ARHL.
doi:10.3892/mmr.2014.2653
PMCID: PMC4227424  PMID: 25324030
D-galactose; auditory cortex; oxidative damage; mitochondria; age-related hearing loss
4.  Determination of Albendazole and Metabolites in Silkworm Bombyx mori Hemolymph by Ultrafast Liquid Chromatography Tandem Triple Quadrupole Mass Spectrometry 
PLoS ONE  2014;9(9):e105637.
Albendazole is a broad-spectrum parasiticide with high effectiveness and low host toxicity. No method is currently available for measuring albendazole and its metabolites in silkworm hemolymph. This study describes a rapid, selective, sensitive, synchronous and reliable detection method for albendazole and its metabolites in silkworm hemolymph using ultrafast liquid chromatography tandem triple quadrupole mass spectrometry (UFLC-MS/MS). The method is liquid-liquid extraction followed by UFLC separation and quantification in an MS/MS system with positive electrospray ionization in multiple reaction monitoring mode. Precursor-to-product ion transitions were monitored at 266.100 to 234.100 for albendazole (ABZ), 282.200 to 208.100 for albendazole sulfoxide (ABZSO), 298.200 to 159.100 for albendazole sulfone (ABZSO2) and 240.200 to 133.100 for albendazole amino sulfone (ABZSO2-NH2). Calibration curves had good linearities with R2 of 0.9905–0.9972. Limits of quantitation (LOQs) were 1.32 ng/mL for ABZ, 16.67 ng/mL for ABZSO, 0.76 ng/mL for ABZSO2 and 5.94 ng/mL for ABZSO2-NH2. Recoveries were 93.12%–103.83% for ABZ, 66.51%–108.51% for ABZSO, 96.85%–105.6% for ABZSO2 and 96.46%–106.14% for ABZSO2-NH2, (RSDs <8%). Accuracy, precision and stability tests showed acceptable variation in quality control (QC) samples. This analytical method successfully determined albendazole and its metabolites in silkworm hemolymph in a pharmacokinetic study. The results of single-dose treatment suggested that the concentrations of ABZ, ABZSO and ABZSO2 increased and then fell, while ABZSO2-NH2 level was low without obvious change. Different trends were observed for multi-dose treatment, with concentrations of ABZSO and ABZSO2 rising over time.
doi:10.1371/journal.pone.0105637
PMCID: PMC4177837  PMID: 25255321
5.  Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations 
BMC Genetics  2014;15:81.
Background
Hyperuricemia is associated with multiple diseases, including gout, cardiovascular disease, and renal disease. Serum urate is highly heritable, yet association studies of single nucleotide polymorphisms (SNPs) and serum uric acid explain a small fraction of the heritability. Whether copy number polymorphisms (CNPs) contribute to uric acid levels is unknown.
Results
We assessed copy number on a genome-wide scale among 8,411 individuals of European ancestry (EA) who participated in the Atherosclerosis Risk in Communities (ARIC) study. CNPs upstream of the urate transporter SLC2A9 on chromosome 4p16.1 are associated with uric acid (χ2df2=3545, p=3.19×10-23). Effect sizes, expressed as the percentage change in uric acid per deleted copy, are most pronounced among women (3.974.935.87 [ 2.55097.5 denoting percentiles], p=4.57×10-23) and independent of previously reported SNPs in SLC2A9 as assessed by SNP and CNP regression models and the phasing SNP and CNP haplotypes (χ2df2=3190,p=7.23×10-08). Our finding is replicated in the Framingham Heart Study (FHS), where the effect size estimated from 4,089 women is comparable to ARIC in direction and magnitude (1.414.707.88, p=5.46×10-03).
Conclusions
This is the first study to characterize CNPs in ARIC and the first genome-wide analysis of CNPs and uric acid. Our findings suggests a novel, non-coding regulatory mechanism for SLC2A9-mediated modulation of serum uric acid, and detail a bioinformatic approach for assessing the contribution of CNPs to heritable traits in large population-based studies where technical sources of variation are substantial.
doi:10.1186/1471-2156-15-81
PMCID: PMC4118309  PMID: 25007794
Copy number polymorphism; Hyperuricemia; Genomewide association study
6.  Identification of a New Sprouty Protein Responsible for the Inhibition of the Bombyx mori Nucleopolyhedrovirus Reproduction 
PLoS ONE  2014;9(6):e99200.
The rat sarcoma-extracellular signal regulated kinase mitogen-activated protein kinases pathway, one of the most ancient signaling pathways, is crucial for the defense against Bombyx mori nucleopolyhedrovirus (BmNPV) infection. Sprouty (Spry) proteins can inhibit the activity of this pathway by receptor tyrosine kinases. We cloned and identified a new B. mori gene with a Spry domain similar to the Spry proteins of other organisms, such as fruitfly, mouse, human, chicken, Xenopus and zebrafish, and named it BmSpry. The gene expression analysis showed that BmSpry was transcribed in all of the examined tissues and in all developmental stages from embryo to adult. BmSpry also induced expression of BmNPV in the cells. Our results indicated: (1) the knock-down of BmSpry led to increased BmNPV replication and silkworm larvae mortality; (2) over-expression of BmSpry led to reduced BmNPV replication; and (3) BmSpry regulated the activation of ERK and inhibited BmNPV replication. These results showed that BmSpry plays a crucial role in the antiviral defense of the silkworm both in vitro and in vivo.
doi:10.1371/journal.pone.0099200
PMCID: PMC4051654  PMID: 24915434
7.  Efficacy of Adding Bevacizumab in the First-Line Chemotherapy of Metastatic Colorectal Cancer: Evidence from Seven Randomized Clinical Trials 
Background. Efficacy of adding bevacizumab in first-line chemotherapy of metastatic colorectal cancer (mCRC) has been controversial. The aim of this study is to gather current data to analyze efficacy of adding bevacizumab to the most used combination first-line chemotherapy in mCRC, based on the 2012 meta-analysis reported by Macedo et al.  Methods. Medline, EMBASE and Cochrane library, meeting presentations and abstracts were searched. Eligible studies were randomized controlled trials (RCTs) which evaluated first-line chemotherapy with or without bevacizumab in mCRC. The extracting data were included and examined in the meta-analysis according to the type of chemotherapy regimen. Results. Seven trials, totaling 3436 patients, were analyzed. Compared with first-line chemothery alone, the adding of bevacizumab did not show clinical benefit for OS both in first-line therapy and the most used combination chemotherapy (HR = 0.89; 95% CI = 0.78–1.02; P = 0.08; HR = 0.93; 95% CI = 0.83–1.05; P = 0.24). In contrast with OS, the addition of bevacizumab resulted in significant improvement for PFS (HR = 0.68; 95% CI = 0.59–0.78; P < 0.00001). Moreover, it also demonstrated statistical benefit for PFS in the most used combination first-line chemotherapy (HR = 0.84; 95% CI = 0.75–0.94; P = 0.002). And the subgroup analysis indicated only capacitabine-based regimens were beneficial. Conclusions. This meta-analysis shows that the addition of bevacizumab to FOLFOX/FOLFIRI/XELOX regimens might not be beneficial in terms of OS. Benefit has been seen when PFS has been taken into account. In subgroup analysis, benefit adding bevacizumab has been seen when capecitabine-based regimens are used. Further studies are warranted to explore the combination with bevacizumab.
doi:10.1155/2014/594930
PMCID: PMC4058184  PMID: 24971091
8.  Methods for Analyzing Multivariate Phenotypes in Genetic Association Studies 
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Multivariate phenotypes are frequently encountered in genetic association studies. The purpose of analyzing multivariate phenotypes usually includes discovery of novel genetic variants of pleiotropy effects, that is, affecting multiple phenotypes, and the ultimate goal of uncovering the underlying genetic mechanism. In recent years, there have been new method development and application of existing statistical methods to such phenotypes. In this paper, we provide a review of the available methods for analyzing association between a single marker and a multivariate phenotype consisting of the same type of components (e.g., all continuous or all categorical) or different types of components (e.g., some are continuous and others are categorical). We also reviewed causal inference methods designed to test whether the detected association with the multivariate phenotype is truly pleiotropy or the genetic marker exerts its effects on some phenotypes through affecting the others.
doi:10.1155/2012/652569
PMCID: PMC3989935  PMID: 24748889
9.  Deletion of the RNA-Editing Enzyme ADAR1 Causes Regression of Established Chronic Myelogenous Leukemia in Mice 
Patients with chronic myelogenous leukemia (CML) respond well to tyrosine kinase inhibitors (TKIs) of the Bcr-Abl oncoprotein. However, intolerance and resistance to these agents remains a challenge, and TKI’s are unable to eradicate rare leukemia-initiating cells. Leukemia treatment would benefit from a better understanding of molecular signals that are necessary for the survival of leukemia-initiating cells but dispensable for normal hematopoietic stem cells. Leukemia-initiating cells in CML can arise from myeloid progenitor cells, a population that we have reported in normal hematopoiesis to depend on the RNA-editing enzyme ADAR1 (adenosine deaminase acting on RNA-1). We now report that Bcr-Abl transformed leukemic cells were ADAR1-dependent in a conditional ADAR1 knockout mouse model. ADAR1 deletion reversed leukocytosis and splenomegaly, and preferentially depleted primitive Lin-Sca+Kit+ (LSK) leukemic cells but not LSK cells lacking the leukemic oncoprotein. ADAR1 deletion ultimately normalized the peripheral white blood count, eliminating leukemic cells as assessed by PCR. These results uncover a novel requirement for ADAR1 in myeloid leukemic cells and indicate that ADAR1 may comprise a new molecular target for CML-directed therapeutics.
doi:10.1002/ijc.27851
PMCID: PMC3565035  PMID: 22987615
10.  Genome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of ALDH1L1 with Ischemic Stroke 
PLoS Genetics  2014;10(3):e1004214.
Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60×10−63], CBS [p = 3.15×10−26], CPS1 [p = 9.10×10−13], ALDH1L1 [p = 7.3×10−13] and PSPH [p = 1.17×10−16]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.
Author Summary
Elevated homocysteine (tHcy) is strongly associated with risk for common disorders such as stroke, cardiovascular disease and Alzheimer disease. Lowering tHcy levels has proven to have variable success in reducing clinical risk, so the question remains, “Are we correctly targeting these disorders by lowering tHcy?” Understanding folate one-carbon metabolism pathway (FOCM) genetic variation will aid us in developing new targets for therapy. The FOCM is essential in regulation of the epigenome, which controls genes in ways beyond nucleotide sequence. We present data generated from stroke-only and general populations where we identify strong association of genetic risk factors for variation in one-carbon metabolism function, characterized by the post-methionine load test. We show that GNMT harbors genetic and epigenetic differences that influence gene function, which may have downstream effects on the epigenome of the cell, affecting disease risk. We developed a genetic risk score that predicts post-methionine load homocysteine levels that may be useful in clinic. Finally, we identified a novel association between ischemic stroke and ALDH1L1, which emphasizes the clinical importance of this work. Our results highlight the importance of a concerted effort to target the FOCM (beyond tHcy) and parallel pathways in future pharmacogenetic work using the genetic variation we describe here.
doi:10.1371/journal.pgen.1004214
PMCID: PMC3961178  PMID: 24651765
11.  Using Gastrocnemius sEMG and Plasma α-Synuclein for the Prediction of Freezing of Gait in Parkinson's Disease Patients 
PLoS ONE  2014;9(2):e89353.
Freezing of gait (FOG) is a complicated gait disturbance in Parkinson's disease (PD) and a relevant subclinical predictor algorithm is lacking. The main purpose of this study is to explore the potential value of surface electromyograph (sEMG) and plasma α-synuclein levels as predictors of the FOG seen in PD. 21 PD patients and 15 normal controls were recruited. Motor function was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) and Freezing of gait questionnaire (FOG-Q). Simultaneously, gait analysis was also performed using VICON capture system in PD patients and sEMG data was recorded as well. Total plasma α-synuclein was quantitatively assessed by Luminex assay in all participants. Recruited PD patients were classified into two groups: PD patients with FOG (PD+FOG) and without FOG (PD-FOG), based on clinical manifestation, the results of the FOG-Q and VICON capture system. PD+FOG patients displayed higher FOG-Q scores, decreased walking speed, smaller step length, smaller stride length and prolonged double support time compared to the PD-FOG in the gait trial. sEMG data indicated that gastrocnemius activity in PD+FOG patients was significantly reduced compared to PD-FOG patients. In addition, plasma α-synuclein levels were significantly decreased in the PD+FOG group compared to control group; however, no significant difference was found between the PD+FOG and PD-FOG groups. Our study revealed that gastrocnemius sEMG could be used to evaluate freezing gait in PD patients, while plasma α-synuclein might discriminate freezing of gait in PD patients from normal control, though no difference was found between the PD+FOG and PD-FOG groups.
doi:10.1371/journal.pone.0089353
PMCID: PMC3937335  PMID: 24586710
12.  Structural and Diffusion Property Alterations in Unaffected Siblings of Patients with Obsessive-Compulsive Disorder 
PLoS ONE  2014;9(1):e85663.
Disrupted white matter integrity and abnormal cortical thickness are widely reported in the pathophysiology of obsessive-compulsive disorder (OCD). However, the relationship between alterations in white matter connectivity and cortical thickness in OCD is unclear. In addition, the heritability of this relationship is poorly understood. To investigate the relationship of white matter microstructure with cortical thickness, we measure fractional anisotropy (FA) of white matter in 30 OCD patients, 19 unaffected siblings and 30 matched healthy controls. Then, we take those regions of significantly altered FA in OCD patients compared with healthy controls to perform fiber tracking. Next, we calculate the fiber quantity in the same tracts. Lastly, we compare cortical thickness in the target regions of those tracts. Patients with OCD exhibited decreased FA in cingulum, arcuate fibers near the superior parietal lobule, inferior longitudinal fasciculus near the right superior temporal gyrus and uncinate fasciculus. Siblings showed reduced FA in arcuate fibers near the superior parietal lobule and anterior limb of internal capsule. Significant reductions in both fiber quantities and cortical thickness in OCD patients and their unaffected siblings were also observed in the projected brain areas when using the arcuate fibers near the left superior parietal lobule as the starting points. Reduced FA in the left superior parietal lobule was observed not only in patients with OCD but also in their unaffected siblings. Originated from the superior parietal lobule, the number of fibers was also found to be decreased and the corresponding cortical regions were thinner relative to controls. The linkage between disrupted white matter integrity and the abnormal cortical thickness may be a vulnerability marker for OCD.
doi:10.1371/journal.pone.0085663
PMCID: PMC3904847  PMID: 24489665
13.  Salivary DJ-1 could be an indicator of Parkinson's disease progression 
Objective: The goal of the current investigation was to explore whether salivary DJ-1 could be a potential biomarker for monitoring disease progression in Parkinson's disease (PD) by evaluating the association between salivary DJ-1 concentrations and nigrostriatal dopaminergic function.
Methods: First, in 74 patients with PD and 12 age-matched normal controls, single photon emission computed tomography (SPECT) imaging with labeled dopamine transporters (DAT) (99mTc-TRODAT-1), which has been used for measuring DAT density in PD was prformed. Then, the DJ-1 level in their saliva was analyzed by quantitative and sensitive Luminex assay and compared to caudate or putamen DAT density. Finally, based on the above, our cross-section study was carried out in 376 research volunteers (285 patients with PD and 91 healthy controls) to measure salivary DJ-1 level.
Results: From our analysis, we found a correlation between salivary concentration of DJ-1 and putamen nucleus uptake of 99mTc-TRODAT-1 in the PD group. Although salivary DJ-1 levels were not affected by UPDRS scores, gender, age, and pharmacotherapy, DJ-1 levels in H&Y 4 stage of PD were higher than those in H&Y 1-3 stage as well as those in healthy controls. Salivary DJ-1 also decreased significantly in mixed type PD patients compared to the tremor-dominant type (TDT) and akinetic-rigid dominant type (ARDT) PD patients.
Conclusions: According to the investigation in a large cohort, we reported for the first time the prognostic potential of the salivary DJ-1 as a biomarker for evaluating nigrostriatal dopaminergic function in PD.
doi:10.3389/fnagi.2014.00102
PMCID: PMC4047660  PMID: 24936184
DJ-1; saliva; Parkinson's disease; dopamine transporter; SPECT
14.  Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function 
Chasman, Daniel I. | Fuchsberger, Christian | Pattaro, Cristian | Teumer, Alexander | Böger, Carsten A. | Endlich, Karlhans | Olden, Matthias | Chen, Ming-Huei | Tin, Adrienne | Taliun, Daniel | Li, Man | Gao, Xiaoyi | Gorski, Mathias | Yang, Qiong | Hundertmark, Claudia | Foster, Meredith C. | O'Seaghdha, Conall M. | Glazer, Nicole | Isaacs, Aaron | Liu, Ching-Ti | Smith, Albert V. | O'Connell, Jeffrey R. | Struchalin, Maksim | Tanaka, Toshiko | Li, Guo | Johnson, Andrew D. | Gierman, Hinco J. | Feitosa, Mary F. | Hwang, Shih-Jen | Atkinson, Elizabeth J. | Lohman, Kurt | Cornelis, Marilyn C. | Johansson, Åsa | Tönjes, Anke | Dehghan, Abbas | Lambert, Jean-Charles | Holliday, Elizabeth G. | Sorice, Rossella | Kutalik, Zoltan | Lehtimäki, Terho | Esko, Tõnu | Deshmukh, Harshal | Ulivi, Sheila | Chu, Audrey Y. | Murgia, Federico | Trompet, Stella | Imboden, Medea | Coassin, Stefan | Pistis, Giorgio | Harris, Tamara B. | Launer, Lenore J. | Aspelund, Thor | Eiriksdottir, Gudny | Mitchell, Braxton D. | Boerwinkle, Eric | Schmidt, Helena | Cavalieri, Margherita | Rao, Madhumathi | Hu, Frank | Demirkan, Ayse | Oostra, Ben A. | de Andrade, Mariza | Turner, Stephen T. | Ding, Jingzhong | Andrews, Jeanette S. | Freedman, Barry I. | Giulianini, Franco | Koenig, Wolfgang | Illig, Thomas | Meisinger, Christa | Gieger, Christian | Zgaga, Lina | Zemunik, Tatijana | Boban, Mladen | Minelli, Cosetta | Wheeler, Heather E. | Igl, Wilmar | Zaboli, Ghazal | Wild, Sarah H. | Wright, Alan F. | Campbell, Harry | Ellinghaus, David | Nöthlings, Ute | Jacobs, Gunnar | Biffar, Reiner | Ernst, Florian | Homuth, Georg | Kroemer, Heyo K. | Nauck, Matthias | Stracke, Sylvia | Völker, Uwe | Völzke, Henry | Kovacs, Peter | Stumvoll, Michael | Mägi, Reedik | Hofman, Albert | Uitterlinden, Andre G. | Rivadeneira, Fernando | Aulchenko, Yurii S. | Polasek, Ozren | Hastie, Nick | Vitart, Veronique | Helmer, Catherine | Wang, Jie Jin | Stengel, Bénédicte | Ruggiero, Daniela | Bergmann, Sven | Kähönen, Mika | Viikari, Jorma | Nikopensius, Tiit | Province, Michael | Ketkar, Shamika | Colhoun, Helen | Doney, Alex | Robino, Antonietta | Krämer, Bernhard K. | Portas, Laura | Ford, Ian | Buckley, Brendan M. | Adam, Martin | Thun, Gian-Andri | Paulweber, Bernhard | Haun, Margot | Sala, Cinzia | Mitchell, Paul | Ciullo, Marina | Kim, Stuart K. | Vollenweider, Peter | Raitakari, Olli | Metspalu, Andres | Palmer, Colin | Gasparini, Paolo | Pirastu, Mario | Jukema, J. Wouter | Probst-Hensch, Nicole M. | Kronenberg, Florian | Toniolo, Daniela | Gudnason, Vilmundur | Shuldiner, Alan R. | Coresh, Josef | Schmidt, Reinhold | Ferrucci, Luigi | Siscovick, David S. | van Duijn, Cornelia M. | Borecki, Ingrid B. | Kardia, Sharon L.R. | Liu, Yongmei | Curhan, Gary C. | Rudan, Igor | Gyllensten, Ulf | Wilson, James F. | Franke, Andre | Pramstaller, Peter P. | Rettig, Rainer | Prokopenko, Inga | Witteman, Jacqueline | Hayward, Caroline | Ridker, Paul M | Parsa, Afshin | Bochud, Murielle | Heid, Iris M. | Kao, W.H. Linda | Fox, Caroline S. | Köttgen, Anna
Human Molecular Genetics  2012;21(24):5329-5343.
In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4–2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
doi:10.1093/hmg/dds369
PMCID: PMC3607468  PMID: 22962313
15.  RecQL4 cytoplasmic localization: implications in mitochondrial DNA oxidative damage repair 
RecQL4, one of the five human RecQ helicases, is crucial for genomic stability and RecQL4 when mutated leads to premature aging phenotypes in humans. Unlike other human RecQ helicases, RecQL4 is found both in the nucleus and the cytoplasm. While the nuclear localization signal (NLS) and the retention domain at the N-terminus are responsible for the nuclear localization of RecQL4, the signal for its cytoplasmic localization is essentially unknown. In this study, two functional nuclear exporting signals (NESs; pNES2 and pNES3) were identified at the C-terminus of RecQL4. Deletion of pNES2 drastically diminished the cytoplasmic localization of RecQL4. Strikingly, addition of ubiquitination tail at the C-terminus of RecQL4 substantially enriched the cytoplasmic fraction of RecQL4 only in the presence of functional pNES2. Immunofluorescence studies revealed that the cytoplasmic RecQL4 was localized in mitochondria. Consistent with its mitochondrial localization, a regulatory role for RecQL4 in the maintenance of mitochondrial DNA (mtDNA) copy number was demonstrated. Elevation of ectopic expression of RecQL4 increased the mtDNA copy number in HEK293 cells while RecQL4 knock down markedly decreased the mtDNA copy number in U2OS cells. Additionally, a substantially increased level of mitochondrial superoxide production, and a markedly decreased repair capacity for oxidative DNA damage were observed in the mitochondria of both RecQL4 deficient human fibroblasts and RecQL4-suppressed cancer cells. These data strongly suggest a regulatory role for RecQL4 in mitochondrial stability and function. Collectively, our study demonstrates that NES-mediated RecQL4 export to the cytoplasm is essential for the maintenance of mitochondrial genome stability.
doi:10.1016/j.biocel.2012.07.016
PMCID: PMC3461334  PMID: 22824301
RecQL4; Nuclear exporting signal (NES); Mitochondrial co-localization; ROS (Reactive oxygen species); Oxidative damage repair
16.  The Cdk1-APC/C cell cycle oscillator circuit functions as a time-delayed, ultrasensitive switch 
Nature cell biology  2013;15(5):519-525.
Despite the complexity and variety of biological oscillators, their core design invariably includes an essential negative feedback loop. In the Xenopus laevis embryonic cell cycle oscillator, this loop consists of the kinase cyclin B-Cdk1 and the ubiquitin ligase APC/CCdc20; active Cdk1 activates APC/CCdc20, which then brings about cyclin B degradation and inactivates Cdk1. Here we ask how this negative feedback loop functions quantitatively, with the aim of understanding what mechanisms keep the Cdk1-APC/CCdc20 system from settling into a stable steady state with intermediate levels of Cdk1 and APC/CCdc20 activity. We found that the system operates as a time-delayed, digital switch, with a time lag of ~15 min between Cdk1 and APC/CCdc20 activation and a tremendously high degree of ultrasensitivity (nH ≈ 17). Computational modeling shows how these attributes contribute to the generation of robust, clock-like oscillations. Principles uncovered here may also apply to other activator-repressor oscillators and help in designing robust synthetic clocks.
doi:10.1038/ncb2737
PMCID: PMC3728279  PMID: 23624406
17.  Association of Genetic Variation in the Mitochondrial Genome with Blood Pressure and Metabolic Traits 
Hypertension  2012;60(4):949-956.
Elevated blood pressure (BP) is a major risk factor for cardiovascular disease. Several studies have noted a consistent maternal effect on BP; consequently, mitochondrial DNA (mtDNA) variation has become an additional target of investigation of the missing BP heritability. Analyses of common mtDNA polymorphisms, however, have not found evidence of association with hypertension. To explore associations of relatively rare (frequency < 5%) mtDNA variants with BP, we identified uncommon/rare variants through sequencing the entire mitochondrial genome in 32 unrelated individuals with extreme-high BP in the Framingham Heart Study (FHS) and genotyped 40 mtSNPs in 7,219 FHS participants. The nonsynonymous mtSNP 5913G>A (Asp4Asn) in the cytochrome c oxidase subunit 1 of Complex IV demonstrated significant associations with BP and fasting blood glucose (FBG) levels. Individuals with the rare 5913A allele had, on average, 7 mm Hg higher systolic BP at baseline (Pempirical = 0.05) and 17 mg/dL higher mean FBG over 25 years of follow up (Pempirical = 0.009). Significant associations with FBG levels were also detected for nonsynonymous mtSNP 3316G>A (Ala4Thr) in the NADH dehydrogenase subunit 1 of Complex I. On average, individuals with rare allele 3316A had 17 and 25 mg/dL higher FBG at baseline (Pempirical = 0.01) and over 25 years of follow up (Pempirical = 0.007). Our findings provide the first evidence of putative association of variants in the mitochondrial genome with SBP and FBG in the general population. Replication in independent samples, however, is needed to confirm these putative associations.
doi:10.1161/HYPERTENSIONAHA.112.196519
PMCID: PMC3753106  PMID: 22949535
Mitochondrial genome; Association study; Genetics; Hypertension; Diabetes
18.  Indirect Comparison Showed Survival Benefit from Adjuvant Chemoradiotherapy in Completely Resected Gastric Cancer with D2 Lymphadenectomy 
Background. Little data on directly comparing chemoradiotherapy with observation has yet been published in the setting of adjuvant therapy for resected gastric cancer who underwent D2 lymphadenectomy. The present indirect comparison aims to provide more evidence on comparing the two approaches. Methods. We conducted a systematic review of randomized controlled trials, extracted time-to-event data using Tierney methods (when not reported), and performed indirect comparison to obtain the relative hazards of adjuvant chemoradiotherapy to observation on overall and disease-free survival. Results. seven randomized controlled trials were identified. Three trials compared adjuvant chemoradiotherapy with adjuvant chemotherapy, and 4 trials compared adjuvant chemotherapy with observation. Using indirect comparison, the relative hazards of adjuvant chemoradiotherapy to observation were 0.43 (95% CI: 0.33–0.55) in disease-free survival and 0.52 (95% CI: 0.38–0.71) in overall survival for completely resected gastric cancer with D2 lymphadenectomy. Conclusions. Postoperative chemoradiotherapy can prolong survival and decrease recurrence in patients with resected gastric cancer who underwent D2 gastrectomy. Molecular biomarker might be a promising direction in the prediction of clinical outcome to postoperative chemoradiotherapy, which warranted further study.
doi:10.1155/2013/634929
PMCID: PMC3806404  PMID: 24194750
19.  Familial Aggregation of Left Ventricular Geometry and Association with Parental Heart Failure: The Framingham Heart Study 
Background
Data regarding the familial aggregation of left ventricular (LV) geometry and its relations to parental heart failure (HF) are limited.
Methods and Results
We evaluated concordance of LV geometry within 1093 nuclear families in 5758 participants of the Original (parents; N=2351) and Offspring (N=3407) cohorts of the Framingham Heart Study undergoing routine echocardiography in mid-to-late adulthood. LV geometry was categorized based on cohort- and sex-specific 80th percentile cutoffs of LV mass and relative wall thickness (RWT) into normal (both <80th percentile), concentric remodeling (LV mass<80th percentile, RWT>80th percentile), concentric hypertrophy (both >80th percentile) and eccentric hypertrophy (LV mass>80th percentile, RWT<80th percentile). Within nuclear families, LV geometry was concordant among related pairs (parent-child, sibling-sibling) (P=0.0015), but not among unrelated spousal pairs (P=0.60), a finding that remained unchanged after adjusting for clinical covariates known to influence LV remodeling (age, systolic blood pressure, body mass index), excluding individuals with prevalent HF and myocardial infarction, and varying the thresholds for defining LV geometry. The prevalence of abnormal LV geometry was higher in family members of affected individuals, with recurrence risks of 1.4 for concentric remodeling (95%CI, 1.2–1.7) and eccentric hypertrophy (95%CI, 1.1–1.8), and 3.9 (95%CI, 3.2–4.6) for concentric hypertrophy. In a subset of 1497 offspring, we observed an association between parental HF (N=458) and eccentric hypertrophy in offspring (P<0.0001).
Conclusions
Our investigation of a two-generational community-based sample demonstrates familial aggregation of LV geometry, with the greatest recurrence risk for concentric LV geometry, and establishes an association of eccentric LV geometry with parental HF.
doi:10.1161/CIRCGENETICS.110.941088
PMCID: PMC3785074  PMID: 20884845
echocardiography; remodeling; risk factors
20.  Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations 
O'Seaghdha, Conall M. | Wu, Hongsheng | Yang, Qiong | Kapur, Karen | Guessous, Idris | Zuber, Annie Mercier | Köttgen, Anna | Stoudmann, Candice | Teumer, Alexander | Kutalik, Zoltán | Mangino, Massimo | Dehghan, Abbas | Zhang, Weihua | Eiriksdottir, Gudny | Li, Guo | Tanaka, Toshiko | Portas, Laura | Lopez, Lorna M. | Hayward, Caroline | Lohman, Kurt | Matsuda, Koichi | Padmanabhan, Sandosh | Firsov, Dmitri | Sorice, Rossella | Ulivi, Sheila | Brockhaus, A. Catharina | Kleber, Marcus E. | Mahajan, Anubha | Ernst, Florian D. | Gudnason, Vilmundur | Launer, Lenore J. | Mace, Aurelien | Boerwinckle, Eric | Arking, Dan E. | Tanikawa, Chizu | Nakamura, Yusuke | Brown, Morris J. | Gaspoz, Jean-Michel | Theler, Jean-Marc | Siscovick, David S. | Psaty, Bruce M. | Bergmann, Sven | Vollenweider, Peter | Vitart, Veronique | Wright, Alan F. | Zemunik, Tatijana | Boban, Mladen | Kolcic, Ivana | Navarro, Pau | Brown, Edward M. | Estrada, Karol | Ding, Jingzhong | Harris, Tamara B. | Bandinelli, Stefania | Hernandez, Dena | Singleton, Andrew B. | Girotto, Giorgia | Ruggiero, Daniela | d'Adamo, Adamo Pio | Robino, Antonietta | Meitinger, Thomas | Meisinger, Christa | Davies, Gail | Starr, John M. | Chambers, John C. | Boehm, Bernhard O. | Winkelmann, Bernhard R. | Huang, Jie | Murgia, Federico | Wild, Sarah H. | Campbell, Harry | Morris, Andrew P. | Franco, Oscar H. | Hofman, Albert | Uitterlinden, Andre G. | Rivadeneira, Fernando | Völker, Uwe | Hannemann, Anke | Biffar, Reiner | Hoffmann, Wolfgang | Shin, So–Youn | Lescuyer, Pierre | Henry, Hughes | Schurmann, Claudia | Munroe, Patricia B. | Gasparini, Paolo | Pirastu, Nicola | Ciullo, Marina | Gieger, Christian | März, Winfried | Lind, Lars | Spector, Tim D. | Smith, Albert V. | Rudan, Igor | Wilson, James F. | Polasek, Ozren | Deary, Ian J. | Pirastu, Mario | Ferrucci, Luigi | Liu, Yongmei | Kestenbaum, Bryan | Kooner, Jaspal S. | Witteman, Jacqueline C. M. | Nauck, Matthias | Kao, W. H. Linda | Wallaschofski, Henri | Bonny, Olivier | Fox, Caroline S. | Bochud, Murielle
PLoS Genetics  2013;9(9):e1003796.
Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
Author Summary
Calcium is vital to many biological processes and its serum concentration is tightly regulated. Family studies have shown that serum calcium is under strong genetic control. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. We identified seven loci (six new regions) as being robustly associated with serum calcium. Three loci implicate regions involved in rare monogenic diseases including disturbances of serum calcium levels. Several of the newly identified loci harbor genes linked to the hormonal control of serum calcium. In mice experiments, we characterized the expression of these genes in gut, kidney, and bone, and explored the influence of dietary calcium intake on the expression of these genes in these organs. Our results shed new light on the genetics of calcium homeostasis and suggest a role for dietary calcium intake in bone-specific gene expression.
doi:10.1371/journal.pgen.1003796
PMCID: PMC3778004  PMID: 24068962
21.  Impact of renal denervation on renalase expression in adult rats with spontaneous hypertension 
The aim of this study was to investigate the impact of renal denervation on the blood pressure, plasma renalase content and expression of renalase and tyrosine hydroxylase (TH) in the kidney of spontaneous hypertensive (SH) rats and to explore the mechanism of renal denervation involved in lowering blood pressure. SH rats (n=48) were randomly assigned to baseline, surgery (renal denervation), sham and control groups. WKY rats matched in age (n=12) served as the baseline control group. All rats were housed until they were 12 weeks old. The rats in the baseline group and the WKY group rats were sacrificed, and blood and kidney were collected for examination. In the renal denervation, sham and control groups, the blood pressure was continuously monitored. One and six weeks after renal denervation, 6 rats in each group were sacrificed, and blood and kidney were collected for examination. ELISA was employed to measure the plasma renalase, and western blot analysis was performed to detect the expression of TH and renalase in the kidney. Compared with the WKY rats, SH rats in the baseline group had significantly increased blood pressure and markedly elevated TH protein expression (P<0.05), but dramatically reduced plasma renalase content and protein expression of renalase in the kidney (P<0.05). One week after surgery, the mean arterial pressure and TH protein expression in the surgery group was lowered compared with the baseline group and dramatically reduced when compared with the sham and control groups (P<0.05). In the surgery group, renalase levels were markedly increased compared with the baseline, sham and control groups (P<0.05). Six weeks after renal denervation, the mean arterial pressure and TH levels in the surgery group were significantly increased while the renalase content and expression were markedly reduced compared with those at week 1, however, there were no marked differences among the surgery, sham and control groups (P>0.05). Moreover, no pronounced differences in the above variables were found between the sham and control groups at any timepoint (P>0.05). Renal denervation can lower blood pressure, which may be attributed to the suppression of sympathetic nerves, increase in plasma renalase content and renalase expression in the kidney.
doi:10.3892/etm.2012.616
PMCID: PMC3503747  PMID: 23181124
hypertension; renal denervation; renalase; tyrosine hydroxylase
22.  Transcriptome Analysis of Litopenaeus vannamei in Response to White Spot Syndrome Virus Infection 
PLoS ONE  2013;8(8):e73218.
Pacific white shrimp (Litopenaeus vannamei) is the most extensively farmed crustacean species in the world. White spot syndrome virus (WSSV) is one of the major pathogens in the cultured shrimp. However, the molecular mechanisms of the host-virus interaction remain largely unknown. In this study, the impact of WSSV infection on host gene expression in the hepatopancreas of L. vannamei was investigated through the use of 454 pyrosequencing-based RNA-Seq of cDNA libraries developed from WSSV-challenged shrimp or normal controls. By comparing the two cDNA libraries, we show that 767 host genes are significantly up-regulated and 729 genes are significantly down-regulated by WSSV infection. KEGG analysis of the differentially expressed genes indicated that the distribution of gene pathways between the up- and down-regulated genes is quite different. Among the differentially expressed genes, several are found to be involved in various processes of animal defense against pathogens such as apoptosis, mitogen-activated protein kinase (MAPK) signaling, toll-like receptor (TLR) signaling, Wnt signaling and antigen processing and presentation pathways. The present study provides valuable information on differential expression of L. vannamei genes following WSSV infection and improves our current understanding of this host-virus interaction. In addition, the large number of transcripts obtained in this study provides a strong basis for future genomic research on shrimp.
doi:10.1371/journal.pone.0073218
PMCID: PMC3753264  PMID: 23991181
23.  Selection of the Most Informative Individuals from Families with Multiple Siblings for Association Studies 
Genetic epidemiology  2009;33(4):299-307.
Association analyses may follow an initial linkage analysis for mapping and identifying genes underlying complex quantitative traits and may be conducted on unrelated subsets of individuals where only one member of a family is included. We evaluate two methods to select one sibling per sibship when multiple siblings are available: 1) one sibling with the most extreme trait value; and 2) one sibling using a combination score statistic based on extreme trait values and identity-by-descent sharing information. We compare the type I error and power. Furthermore, we compare these selection strategies with a strategy that randomly selects one sibling per sibship and with an approach that includes all siblings, using both simulation study and an application to fasting blood glucose in the Framingham Heart Study. When genetic effect is homogeneous, we find that using the combination score can increase power by 30 to 40% compared to a random selection strategy, and loses only 8 ~ 13% of power compared to the full sibship analysis, across all additive models considered, but offers at least 50% genotyping cost saving. In the presence of genetic heterogeneity, the score offers a 50% increase in power over a random selection strategy, but there is substantial loss compared to the full sibship analysis. In application to fasting blood sample, two SNPs are found in common for the selection strategies and the full sample among the 10 highest ranked SNPs. The EV strategy tends to agree with the IBD-EV strategy and the analysis of the full sample.
doi:10.1002/gepi.20380
PMCID: PMC3747668  PMID: 19025786
linkage analysis; association study; linkage disequilibrium; identity-by-descent (IBD)
24.  Expansion of Monocytic Myeloid-Derived Suppressor Cells Dampens T Cell Function in HIV-1-Seropositive Individuals 
Journal of Virology  2013;87(3):1477-1490.
T lymphocyte dysfunction contributes to human immunodeficiency virus type 1 (HIV-1) disease progression by impairing antivirus cellular immunity. However, the mechanisms of HIV-1 infection-mediated T cell dysfunction are not completely understood. Here, we provide evidence that expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) suppressed T cell function in HIV-1-infected individuals. We observed a dramatic elevation of M-MDSCs (HLA-DR−/low CD11b+ CD33+/high CD14+ CD15− cells) in the peripheral blood of HIV-1-seropositive subjects (n = 61) compared with healthy controls (n = 51), despite efficacious antiretroviral therapy for nearly 2 years. The elevated M-MDSC frequency in HIV-1+ subjects correlated with prognostic HIV-1 disease markers, including the HIV-1 load (r = 0.5957; P < 0.0001), CD4+ T cell loss (r = −0.5312; P < 0.0001), and activated T cells (r = 0.4421; P = 0.0004). Functional studies showed that M-MDSCs from HIV-1+ subjects suppressed T cell responses in both HIV-1-specific and antigen-nonspecific manners; this effect was dependent on the induction of arginase 1 and required direct cell-cell contact. Further investigations revealed that direct HIV-1 infection or culture with HIV-1-derived Tat protein significantly enhanced human MDSC generation in vitro, and MDSCs from healthy donors could be directly infected by HIV-1 to facilitate HIV-1 replication and transmission, indicating that a positive-feedback loop between HIV-1 infection and MDSC expansion existed. In summary, our studies revealed a novel mechanism of T cell dysfunction in HIV-1-infected individuals and suggested that targeting MDSCs may be a promising strategy for HIV-1 immunotherapy.
doi:10.1128/JVI.01759-12
PMCID: PMC3554138  PMID: 23152536
25.  Genome-wide association analyses identify 18 new loci associated with serum urate concentrations 
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Nature genetics  2012;45(2):145-154.
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
doi:10.1038/ng.2500
PMCID: PMC3663712  PMID: 23263486

Results 1-25 (101)