Publications by authors named "Yiyi Ma"

45 Publications

Neuroticism alters the transcriptome of the frontal cortex to contribute to the cognitive decline and onset of Alzheimer's disease.

Transl Psychiatry 2021 Feb 24;11(1):139. Epub 2021 Feb 24.

Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, 10032, USA.

Accumulating evidence has suggested that the molecular transcriptional mechanism contributes to Alzheimer's disease (AD) and its endophenotypes of cognitive decline and neuropathological traits, β-amyloid (Aβ) and phosphorylated tangles (TAU). However, it is unknown what is the impact of the AD risk factors, personality characteristics assessed by the NEO Five-Factor Inventory, on the human brain's transcriptome. Using postmortem human brain samples from 466 subjects, we found that neuroticism has a significant overall impact on the brain transcriptome (omnibus P = 0.005) but not the other four personality characteristics. Focused on those cognitive decline related gene co-expressed modules, neuroticism has nominally significant associations (P < 0.05) with four neuronal modules, which are more related to PHFtau than Aβ across all eight brain regions. Furthermore, the effect of neuroticism on cognitive decline and AD might be mediated through the expression of module 7 and TAU pathology (P = 0.008). To conclude, neuroticism has a broad impact on the transcriptome of human brains, and its effect on cognitive decline and AD may be mediated through gene transcription programs related to TAU pathology.
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http://dx.doi.org/10.1038/s41398-021-01253-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904919PMC
February 2021

Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer's disease.

Nat Commun 2020 11 30;11(1):6129. Epub 2020 Nov 30.

Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA.

The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer's disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD.
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http://dx.doi.org/10.1038/s41467-020-19737-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704703PMC
November 2020

BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 are implicated in tau pathology.

Mol Neurodegener 2020 07 29;15(1):44. Epub 2020 Jul 29.

Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA.

Background: Identified as an Alzheimer's disease (AD) susceptibility gene by genome wide-association studies, BIN1 has 10 isoforms that are expressed in the Central Nervous System (CNS). The distribution of these isoforms in different cell types, as well as their role in AD pathology still remains unclear.

Methods: Utilizing antibodies targeting specific BIN1 epitopes in human post-mortem tissue and analyzing mRNA expression data from purified microglia, we identified three isoforms expressed in neurons and astrocytes (isoforms 1, 2 and 3) and four isoforms expressed in microglia (isoforms 6, 9, 10 and 12). The abundance of selected peptides, which correspond to groups of BIN1 protein isoforms, was measured in dorsolateral prefrontal cortex, and their relation to neuropathological features of AD was assessed.

Results: Peptides contained in exon 7 of BIN1's N-BAR domain were found to be significantly associated with AD-related traits and, particularly, tau tangles. Decreased expression of BIN1 isoforms containing exon 7 is associated with greater accumulation of tangles and subsequent cognitive decline, with astrocytic rather than neuronal BIN1 being the more likely culprit. These effects are independent of the BIN1 AD risk variant.

Conclusions: Exploring the molecular mechanisms of specific BIN1 isoforms expressed by astrocytes may open new avenues for modulating the accumulation of Tau pathology in AD.
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http://dx.doi.org/10.1186/s13024-020-00387-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389646PMC
July 2020

Considerations for integrative multi-omic approaches to explore Alzheimer's disease mechanisms.

Brain Pathol 2020 09;30(5):984-991

Center for Translational and Computational Neuroimmunology, Department of Neurology, the Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY.

The past decade has seen the maturation of multiple different forms of high-dimensional molecular profiling to the point that these methods could be deployed in initially hundreds and more recently thousands of human samples. In the field of Alzheimer's disease (AD), these profiles have been applied to the target organ: the aging brain. In a growing number of cases, the same samples were profiled with multiple different approaches, yielding genetic, transcriptomic, epigenomic and proteomic data. Here, we review lessons learned so far as we move beyond quantitative trait locus (QTL) analyses which map the effect of genetic variation on molecular features to integrate multiple levels of "omic" data in an effort to identify the molecular drivers of AD. One thing is clear: no single layer of molecular or "omic" data is sufficient to capture the variance of AD or aging-related cognitive decline. Nonetheless, reproducible findings are emerging from current efforts, and there is evidence of convergence using different approaches. Thus, we are on the cusp of an acceleration of truly integrative studies as the availability of large numbers of well-characterized brain samples profiled in three or more dimensions enables the testing, comparison and refinement of analytic methods with which to dissect the molecular architecture of the aging brain.
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http://dx.doi.org/10.1111/bpa.12878DOI Listing
September 2020

Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology.

Neuron 2020 08 10;107(3):496-508.e6. Epub 2020 Jun 10.

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address:

Here, we perform a genome-wide screen for variants that regulate the expression of gene co-expression modules in the aging human brain; we discover and replicate such variants in the TMEM106B and RBFOX1 loci. The TMEM106B haplotype is known to influence the accumulation of TAR DNA-binding protein 43 kDa (TDP-43) proteinopathy, and the haplotype's large-scale transcriptomic effects include the dysregulation of lysosomal genes and alterations in synaptic gene splicing that are also seen in the pathophysiology of TDP-43 proteinopathy. Further, a variant near GRN, another TDP-43 proteinopathy susceptibility gene, shows concordant effects with the TMEM106B haplotype. Leveraging neuropathology data from the same participants, we also show that TMEM106B and APOE-amyloid-β effects converge to alter myelination and lysosomal gene expression, which then contributes to TDP-43 accumulation. These results advance our mechanistic understanding of the TMEM106B TDP-43 risk haplotype and uncover a transcriptional program that mediates the converging effects of APOE-amyloid-β and TMEM106B on TDP-43 aggregation in older adults.
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http://dx.doi.org/10.1016/j.neuron.2020.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416464PMC
August 2020

The fertility willingness and acceptability of preimplantation genetic testing in Chinese patients with autosomal dominant polycystic kidney disease.

BMC Nephrol 2020 04 25;21(1):147. Epub 2020 Apr 25.

Department of Nephrology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China.

Background: With the development and progression of genetic technology, preimplantation genetic testing (PGT) has made it possible to block the inheritance of autosomal dominant polycystic kidney disease (ADPKD) as early as possible. However, we need to know the patients' fertility intentions and their acceptance of PGT.

Methods: A questionnaire survey was conducted to collect data on the basic demographic data, quality of life, social support, fertility willingness, and level of understanding of genetic testing for blocking the inheritance of ADPKD among patients aged 18-45 years in seven hospitals from January 2018 to December 2018. After verification, statistics were calculated.

Results: A total of 260 patients with ADPKD were interviewed, including 137males (52.7%) and 123 females (47.3%). The overall fertility willingness rate was low (n = 117, 45.0%). The proportion of married patients aged 25-34 years that were at the optimal reproductive age but did not yet have children was relatively high (n = 77, 67.0%). The fertility intentions of ADPKD patients were significantly influenced by age (OR: 0.101, 95% CI 0.045-0.225, P < 0.001) and education level (OR: 2.134, 95% CI 1.162-3.917, P = 0.014). Among patients who are willing to have children, 207 (79.6%) of them would choose PGT technology. Among those who were not sure whether they would choose PGT technology, the first major concern was technical safety (49.2%).

Conclusions: The reproductive desire of childbearing ADPKD patients in China was low. Strengthening the health education of ADPKD genetic knowledge and reducing the cost of related technologies may improve the fertility intentions and reduce the barriers to acceptance of PGT.
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http://dx.doi.org/10.1186/s12882-020-01785-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183678PMC
April 2020

Assessing the global resilience of water quality sensor placement strategies within water distribution systems.

Water Res 2020 Apr 22;172:115527. Epub 2020 Jan 22.

College of Civil Engineering and Architecture, Zhejiang University, A501, Anzhong Building, Zijingang Campus, 866 Yuhangtang Rd, Hangzhou, 310058, China. Electronic address:

Water quality sensors are often spatially distributed in water distribution systems (WDSs) to detect contamination events and monitor quality parameters (e.g., chlorine residual levels), thereby ensuring safety of a WDS. The performance of a water quality sensor placement strategy (WQSPS) is not only affected by sensor spatial deployment that has been extensively analyzed in literature, but also by possible sensor failures that have been rarely explored so far. However, enumerating all possible sensor failure scenarios is computationally infeasible for a WQSPS with a large number of sensors. To this end, this paper proposes an evolutionary algorithm (EA) based method to systematically and efficiently investigate the WQSPS' global resilience considering all likely sensor failures. First, new metrics are developed in the proposed method to assess the global resilience of a WQSPS. This is followed by a proposal of an efficient optimization approach based on an EA to identify the values of global resilience metrics. Finally, the sensors within the WQSPS are ranked to identify their relative importance in maintaining the WQSPS's detection performance. Two real-world WDSs with four WQSPSs for each case study are used to demonstrate the utility of the proposed method. Results show that: (i) compared to the traditional global resilience analysis method, the proposed EA-based approach identifies improved values of global resilience metrics, (ii) the WQSPSs that deploy sensors close to large demand users are overall more resilient in handling sensor failures relative to other design solutions, thus offering important insight to facilitate the selection of WQSPSs, and (iii) sensor rankings based on the global resilience can identify those sensors whose failure would significantly reduce the WQSPS's performance thereby providing guidance to enable effective water quality sensor management and maintenance.
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http://dx.doi.org/10.1016/j.watres.2020.115527DOI Listing
April 2020

Endobronchial removal of a metallic needle using a flexible diagnostic bronchoscope and biopsy forceps. A case report from Djibouti.

Respir Med Case Rep 2019 25;28:100959. Epub 2019 Oct 25.

Second Department of Surgery, University Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.

Foreign body removal is a challenging procedure. Firstly we have to identify properly the foreign body and the position of the obstruction. Secondly we have to choose the proper removal equipment and finally the appropriate method of patient ventilation during the procedure. In our case report we present a challenging procedure with the removal of a metallic needle with minimum resources and equipment in a young girl in Djibouti, Africa.
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http://dx.doi.org/10.1016/j.rmcr.2019.100959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923513PMC
October 2019

Association between the perturbation of bile acid homeostasis and valproic acid-induced hepatotoxicity.

Biochem Pharmacol 2019 12 16;170:113669. Epub 2019 Oct 16.

Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. Electronic address:

Valproic acid (VPA), a widely prescribed antiepileptic drug, is known to induce hepatotoxicity. However, the mechanisms underlying this toxicity are not well understood. In this study, we performed a nontargeted metabolomic analysis of children with epilepsy treated with VPA (n = 23). Metabolic pathway analysis showed that the fatty acid pathway, citrate cycle, urea cycle, amino acid metabolism, and bile acid pathway were altered in children with epilepsy exhibiting VPA hepatotoxicity. In particular, the VPA-induced perturbation of bile acid homeostasis has not been observed previously. Based on these findings, we performed a targeted metabolomic analysis to characterize bile acid profiles and further determined the effects of VPA on the synthesis, transport, and regulation of bile acids in mice. The bile acid metabolomic profiles of the livers of mice treated with VPA indicated an increase in most bile acids, especially chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), as well as unconjugated bile acids. The upregulation of genes related to bile acid synthesis (CYP7A1 and CYP8B1) and the downregulation of genes related to conjugation (BAAT and BACS) and regulation (FXR and SHP) were detected in the liver, suggesting that hydrophobic bile acid production was increased and FXR signaling was impaired. Our results suggest that the perturbation of bile acid homeostasis and impaired FXR signaling are involved in VPA-induced hepatotoxicity, providing a novel insight into VPA hepatotoxicity.
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http://dx.doi.org/10.1016/j.bcp.2019.113669DOI Listing
December 2019

Using Transcriptomic Hidden Variables to Infer Context-Specific Genotype Effects in the Brain.

Am J Hum Genet 2019 09 22;105(3):562-572. Epub 2019 Aug 22.

Department of Statistics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z4; Centre for Molecular Medicine and Therapeutics, Vancouver, BC V5Z 4H4, Canada; Canadian Institute for Advanced Research, Child and Brain Development Program, Toronto M5G 1M1, Canada. Electronic address:

Deciphering the environmental contexts at which genetic effects are most prominent is central for making full use of GWAS results in follow-up experiment design and treatment development. However, measuring a large number of environmental factors at high granularity might not always be feasible. Instead, here we propose extracting cellular embedding of environmental factors from gene expression data by using latent variable (LV) analysis and taking these LVs as environmental proxies in detecting gene-by-environment (GxE) interaction effects on gene expression, i.e., GxE expression quantitative trait loci (eQTLs). Applying this approach to two largest brain eQTL datasets (n = 1,100), we show that LVs and GxE eQTLs in one dataset replicate well in the other dataset. Combining the two samples via meta-analysis, 895 GxE eQTLs are identified. On average, GxE effect explains an additional ∼4% variation in expression of each gene that displays a GxE effect. Ten of these 52 genes are associated with cell-type-specific eQTLs, and the remaining genes are multi-functional. Furthermore, after substituting LVs with expression of transcription factors (TF), we found 91 TF-specific eQTLs, which demonstrates an important use of our brain GxE eQTLs.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731371PMC
September 2019

Yinang formulation versus placebo granules as a treatment for chronic kidney disease stages III-IV in patients with autosomal dominant polycystic kidney disease: study protocol for a double-blind placebo-controlled randomized clinical trial.

Trials 2019 Aug 7;20(1):481. Epub 2019 Aug 7.

Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common potentially life-threatening inherited kidney diseases. It is the fourth most common cause of end-stage renal disease requiring renal replacement therapy. There are few management options for controlling disease progression. Hence, identification of alternative treatments for patients is important. The Chinese herbal yinang formulation (YNF), which is derived from a Chinese patent medicine, appears to have a satisfactory effect in treating ADPKD. Because a considerable proportion of ADPKD patients presenting with chronic kidney disease (CKD) stages III-IV are diagnosed with the spleen, kidney deficiency, and blood stasis syndrome according to the diagnostic criteria of traditional Chinese medicine (TCM), we hypothesize that YNF may be a complementary drug for ADPKD patients with the corresponding syndrome. Therefore, we have designed a strict clinical trial to evaluate the safety and efficacy of YNF for ADPKD patients with CKD stages III-IV exhibiting the TCM syndrome of spleen, kidney deficiency, and blood stasis.

Methods/design: This is a multi-center prospective double-blind randomized controlled trial. The total target sample size is planned to be 72 participants, with a balanced treatment allocation (1:1). The experimental intervention will be YNF plus conventional therapy and the control intervention will be a placebo plus conventional therapy for 24 weeks. An additional 24 weeks of follow-up will be conducted after treatment completion. The primary outcome will be the estimated glomerular filtration rate (eGFR). Changes in total kidney volume (TKV), serum creatinine (Scr), blood urea nitrogen (BUN), TCM symptoms, and pain will be the secondary outcomes. Adverse events (AEs) will be monitored throughout the trial.

Discussion: This study will be the first placebo-controlled randomized controlled trial to assess whether YNF plus conventional therapy has a beneficial effect on eGFR, TKV, Scr, and BUN, and whether it can alleviate TCM clinical symptoms, reduce ADPKD-related pain, and reduce the frequency of AEs for ADPKD patients with CKD stages III-IV with the spleen, kidney deficiency, and blood stasis syndrome. The results of this trial may provide an evidence-based recommendation for clinicians.

Trial Registration: Chinese Clinical Trials Register, ChiCTR-INR-16009914 . Registered on 18 November 2016.
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http://dx.doi.org/10.1186/s13063-019-3563-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686499PMC
August 2019

Lipidomic Profiling Reveals Disruption of Lipid Metabolism in Valproic Acid-Induced Hepatotoxicity.

Front Pharmacol 2019 19;10:819. Epub 2019 Jul 19.

Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China.

Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs, as VPA-induced hepatotoxicity is one of the most severe adverse reaction that can lead to death. The objective of this study was to gain an understanding of dysregulated lipid metabolism in mechanism of hepatotoxicity. Nontargeted lipidomics analysis with liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-Q-TOF/MS) was performed to explore differential lipids from the patient serum and L02 cells. Lipidomics data interpretation was augmented by gene expression analyses for the key enzymes in lipid metabolism pathways. From patient serum lipidomics, pronouncedly changed lipid species between abnormal liver function (ALF) patients and normal liver function (NLF) patients were identified. Among these lipid species, LPCs, Cers, and SMs were markedly reduced in the ALF group and showed negative relationships with liver injury severity [alanine aminotransferase (ALT) levels], while significantly increased triacylglycerols (TAG) with higher summed carbon numbers demonstrated a positive relationship with ALT levels. Regarding lipidomics in hepatic L02 cells, TAG was markedly elevated after VPA exposure, especially in TAGs with more than 53 summed carbons. Besides, gene expression analysis revealed dysregulated lipid metabolism in VPA-treated L02 cells. Peroxime proliferators-activated receptor (PPARγ) pathway played an important role in VPA-induced lipid disruption through inducing long-chain fatty acid uptake and TAG synthesis, which was also regulated by Akt pathway. Our findings present that VPA-induced lipid metabolism disruption might lead to lipotoxicity in the liver. This approach is expected to be applicable for other drug-induced toxicity assessments.
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http://dx.doi.org/10.3389/fphar.2019.00819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659130PMC
July 2019

Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype.

JAMA Neurol 2019 Sep;76(9):1099-1108

Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, Massachusetts.

Importance: Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles.

Objective: To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing.

Design, Setting, And Participants: The discovery stage included 10 441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018.

Main Outcomes And Measures: Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ε4 carriers and noncarriers. Results with P ≤ 1 × 10-5 were further evaluated in the replication data sets and combined by meta-analysis.

Results: Among 3145 patients with AD and 4213 controls lacking ε4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0; P = 2.22 × 10-7) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10-8). GPAA1 was also associated with expression in the brain of GPAA1 (β = -0.08; P = .03) and its repressive transcription factor, FOXG1 (β = 0.13; P = .003), and global cognition function (β = -0.53; P = .009). Significant gene-wide associations (threshold P ≤ 6.35 × 10-7) were observed for OR8G5 (P = 4.67 × 10-7), IGHV3-7 (P = 9.75 × 10-16), and SLC24A3 (P = 2.67 × 10-12) in 2377 patients with AD and 706 controls with ε4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women).

Conclusions And Relevance: The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ε4 alleles that reinforce known and suggest additional pathways leading to AD.
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http://dx.doi.org/10.1001/jamaneurol.2019.1456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563544PMC
September 2019

Catheterization in a patient with end-stage renal disease through persistent left superior vena cava: a rare case report and literature review.

BMC Nephrol 2019 06 4;20(1):202. Epub 2019 Jun 4.

Department of Nephrology, Changzheng Hospital, Naval Medical University, Shanghai, 200433, People's Republic of China.

Background: Persistent left superior vena cava (PLSVC) is a common vena cava malformation, and drains blood into the right atrium via the dilated coronary sinus in most cases. It is usually asymptomatic and detected incidentally during invasive procedures or imaging. Whether the hemodialysis catheters can be placed in PLSVC is still controversial now (Stylianou et al. Hemodial Int 11:42-45, 2007).

Case Presentation: Here we report a rare case of catheterization through PLSVC in an end-stage renal disease (ESRD) male patient whose PLSVC connected with pulmonary vein with insufficient blood flow eventually. Among the other 28 cases included in the literature review, 16 cases were non-tunneled catheter and 12 cases were cuffed, tunneled catheter and most of them could provide adequate blood flow.

Conclusion: PLSVC is a rare malformation and mostly asymptotic, we believe that PLSVC drains blood into the right atrium with enough inner diameter and blood flow can serve as an alternative site for conventional dialysis access. However, the feasibility of hemodialysis catheterization through it and measures to avoid serious complications are still needed to be discussed.
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http://dx.doi.org/10.1186/s12882-019-1339-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549367PMC
June 2019

CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease.

Aging Cell 2019 08 29;18(4):e12964. Epub 2019 May 29.

Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.

CpG-related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We conducted a genome-wide association study using a sliding-window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 European ancestry cohorts (12,181 cases, 12,601 controls) from the Alzheimer's Disease Genetics Consortium (ADGC) and replication sample of seven European ancestry cohorts (7,554 cases, 27,382 controls) from the International Genomics of Alzheimer's Project (IGAP). The potential functional relevance of significant associations was evaluated by analysis of methylation and expression levels in brain tissue of the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), and in whole blood of Framingham Heart Study participants (FHS). Genome-wide significant (p < 5 × 10 ) associations were identified with 171 1.0 kb-length windows spanning 932 kb in the APOE region (top p < 2.2 × 10 ), five windows at BIN1 (top p = 1.3 × 10 ), two windows at MS4A6A (top p = 2.7 × 10 ), two windows near MS4A4A (top p = 6.4 × 10 ), and one window at PICALM (p = 6.3 × 10 ). The total number of CGS-derived CpG dinucleotides in the window near MS4A4A was associated with AD risk (p = 2.67 × 10 ), brain DNA methylation (p = 2.15 × 10 ), and gene expression in brain (p = 0.03) and blood (p = 2.53 × 10 ). Pathway analysis of the genes responsive to changes in the methylation quantitative trait locus signal at MS4A4A (cg14750746) showed an enrichment of methyltransferase functions. We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage-derived genetic score to predict AD risk.
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http://dx.doi.org/10.1111/acel.12964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612647PMC
August 2019

A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease.

Alzheimers Dement 2019 03 3;15(3):441-452. Epub 2019 Jan 3.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA. Electronic address:

Introduction: The genetic architecture of Alzheimer's disease (AD) is only partially understood.

Methods: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families.

Results: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10).

Discussion: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.
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http://dx.doi.org/10.1016/j.jalz.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408965PMC
March 2019

Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

Mol Psychiatry 2020 08 14;25(8):1859-1875. Epub 2018 Aug 14.

McDonnell Genome Institute, Washington University, St. Louis, MO, USA.

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
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http://dx.doi.org/10.1038/s41380-018-0112-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375806PMC
August 2020

A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research.

Sci Data 2018 08 7;5:180142. Epub 2018 Aug 7.

Rush Alzehimer Disease Center, RUSH University, 600 South Paulina Street, Chicago IL 60612, USA.

We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a quantitative, structured neuropathologic examination after death. They include over 3,322 subjects. Here, we outline the first generation of data including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702). Generation of other omic data including ATACseq, proteomic and metabolomics profiles is ongoing. Thanks to its prospective design and recruitment of older, non-demented individuals, these data can be repurposed to investigate a large number of syndromic and quantitative neuroscience phenotypes. The many subjects that are cognitively non-impaired at death also offer insights into the biology of the human brain in older non-impaired individuals.
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http://dx.doi.org/10.1038/sdata.2018.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080491PMC
August 2018

Quality control and integration of genotypes from two calling pipelines for whole genome sequence data in the Alzheimer's disease sequencing project.

Genomics 2019 07 29;111(4):808-818. Epub 2018 May 29.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA.

The Alzheimer's Disease Sequencing Project (ADSP) performed whole genome sequencing (WGS) of 584 subjects from 111 multiplex families at three sequencing centers. Genotype calling of single nucleotide variants (SNVs) and insertion-deletion variants (indels) was performed centrally using GATK-HaplotypeCaller and Atlas V2. The ADSP Quality Control (QC) Working Group applied QC protocols to project-level variant call format files (VCFs) from each pipeline, and developed and implemented a novel protocol, termed "consensus calling," to combine genotype calls from both pipelines into a single high-quality set. QC was applied to autosomal bi-allelic SNVs and indels, and included pipeline-recommended QC filters, variant-level QC, and sample-level QC. Low-quality variants or genotypes were excluded, and sample outliers were noted. Quality was assessed by examining Mendelian inconsistencies (MIs) among 67 parent-offspring pairs, and MIs were used to establish additional genotype-specific filters for GATK calls. After QC, 578 subjects remained. Pipeline-specific QC excluded ~12.0% of GATK and 14.5% of Atlas SNVs. Between pipelines, ~91% of SNV genotypes across all QCed variants were concordant; 4.23% and 4.56% of genotypes were exclusive to Atlas or GATK, respectively; the remaining ~0.01% of discordant genotypes were excluded. For indels, variant-level QC excluded ~36.8% of GATK and 35.3% of Atlas indels. Between pipelines, ~55.6% of indel genotypes were concordant; while 10.3% and 28.3% were exclusive to Atlas or GATK, respectively; and ~0.29% of discordant genotypes were. The final WGS consensus dataset contains 27,896,774 SNVs and 3,133,926 indels and is publicly available.
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http://dx.doi.org/10.1016/j.ygeno.2018.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397097PMC
July 2019

Effect of boundary conditions on the performance of a dropshaft with an internal divider.

Water Sci Technol 2018 May;2017(2):441-449

Department of Water Conservancy and Hydropower Engineering, Hohai University, Nanjing, China.

Dropshafts with an internal divider for air circulation are proposed to reduce air entrainment in plunging type dropshafts. Dropshafts typically operate under a pressurized downstream condition and with limited air supply from the top. In this study, experiments were conducted to investigate the performance of the dropshaft with an internal divider under different downstream conditions and air inlet conditions. From the experiments, a pressurized downstream condition would increase the air pressure in the dropshaft, reduce the outside air entrainment while increase the internal air circulation. Reducing the size of the air inlet would decrease the air pressure, meanwhile cause an increase in internal air circulation and a reduction in outside air entrainment. A dimensionless parameter of 'effectiveness factor' was also proposed to measure the effectiveness of the internal air circulation on reducing the outside air entrainment. This study considers the performance of the dropshaft with a divider under the conditions close to real situations, which is important to its design and application.
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http://dx.doi.org/10.2166/wst.2018.163DOI Listing
May 2018

Designing an epigenomic study.

Mult Scler 2018 04;24(5):604-609

Center for Translational and Computational Neuro-immunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA/Cell Circuits Program, Broad Institute, Cambridge, MA, USA.

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http://dx.doi.org/10.1177/1352458517750770DOI Listing
April 2018

Novel Mutations in the PKD1 and PKD2 Genes of Chinese Patients with Autosomal Dominant Polycystic Kidney Disease.

Kidney Blood Press Res 2018 6;43(2):297-309. Epub 2018 Mar 6.

Kidney Institute of PLA, Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China.

Background/aims: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder with mutations in PKD1 or PKD2. This study aimed to identify novel PKD1 and PKD2 mutations in Chinese patients with ADPKD.

Methods: Mutational analyses of both PKD genes were performed in 120 Chinese families with inherited ADPKD using long-range PCR and targeted next-generation sequencing approaches. Sanger sequencing was performed to check the positive mutations, while multiplex ligation-dependent probe amplification was adopted to examine those without mutations for the presence of large deletions.

Results: A total of 93 mutations in PKD1 and PKD2 were identified in 98 Chinese families with ADPKD inheritance and the detection rate was 81.7% (98/120). The mutation rates of PKD1 and PKD2 were 91.4% (85/93) and 8.6% (85/93), respectively. Among the 93 mutations, 59.1% (55/93) were reported for the first time. A total of 65 mutations (26 nonsense, 33 frameshift, 2 large deletion, and 4 typical splicing mutations) were identified as definite pathogenic mutations. The remaining 28 mutations (21 missense, 3 in-frame deletion, and 4 atypical splicing mutations) were determined as probable pathogenic mutations. In addition, 9 de novo mutations were found by pedigree analysis. Correlation analysis between genotype and phenotype revealed that patients with PKD1 mutations or truncating mutations exhibited the most severe clinical outcome.

Conclusion: The newly identified sites for known mutations will facilitate the early diagnosis and prediction of prognosis in patients with ADPKD, and provide fundamental genetic information for clinical intervention to prevent the inheritance of this disease in affected families.
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http://dx.doi.org/10.1159/000487899DOI Listing
October 2018

Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project.

Dement Geriatr Cogn Disord 2018 27;45(1-2):1-17. Epub 2018 Feb 27.

University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background/aims: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP.

Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations.

Results/conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.
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http://dx.doi.org/10.1159/000485503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971141PMC
October 2018

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease.

Alzheimers Res Ther 2018 02 20;10(1):22. Epub 2018 Feb 20.

Bioinformatics Graduate Program, Boston University, Boston, MA, USA.

Background: Simultaneous consideration of two neuropathological traits related to Alzheimer's disease (AD) has not been attempted in a genome-wide association study.

Methods: We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data.

Results: Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10) and visual (P = 5.6 × 10) cortices.

Conclusions: Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.
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http://dx.doi.org/10.1186/s13195-018-0349-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819208PMC
February 2018

Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages.

Alzheimers Dement 2018 05 20;14(5):623-633. Epub 2017 Dec 20.

Department of Medicine (Biomedical Genetics), Boston University, Boston, MA, USA; Neurogenetics and Integrated Genomics, Andover Innovative Medicines (AiM) Institute, Eisai Inc, Andover, MA, USA. Electronic address:

Introduction: Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated.

Methods: We conducted genome-wide association studies for AD-related endophenotypes including hippocampal volume, logical memory scores, and cerebrospinal fluid Aβ and total/phosphorylated tau in cognitively normal (CN), mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative study.

Results: In CN subjects, study-wide significant (P < 8.3 × 10) loci were identified for total tau near SRRM4 and C14orf79 and for hippocampal volume near MTUS1. In mild cognitive impairment subjects, study-wide significant association was found with single nucleotide polymorphisms (SNPs) near ZNF804B for logical memory test of delayed recall scores. We found consistent expression patterns of C14orf40 and MTUS1 in carriers with risk alleles of expression SNPs and in brains of AD patients, compared with in the noncarriers and in brains of controls.

Discussion: Our findings for AD-related brain changes before AD provide insight about early AD-related biological processes.
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http://dx.doi.org/10.1016/j.jalz.2017.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938137PMC
May 2018

McWRI1, a transcription factor of the AP2/SHEN family, regulates the biosynthesis of the cuticular waxes on the apple fruit surface under low temperature.

PLoS One 2017 26;12(10):e0186996. Epub 2017 Oct 26.

Beijing Key Laboratory of New Technology in Agriculture Application, Plant Science and Technology College, Beijing University of Agriculture, Beijing, China.

Cuticular waxes of plant and organ surfaces play an important role in protecting plants from biotic and abiotic stress and extending the freshness, storage time and shelf life in the post-harvest agricultural products. WRI1, a transcription factor of AP2/SHEN families, had been found to trigger the related genes taking part in the biosynthesis of seed oil in many plants. But whether WRI1 is involved in the biosynthesis of the cuticular waxes on the Malus fruits surface has been unclear. We investigated the changes of wax composition and structure, the related genes and WRI1 expression on Malus asiatica Nakai and sieversii fruits with the low temperature treatments, found that low temperature induced the up-regulated expression of McWRI1, which promoted gene expression of McKCS, McLACs and McWAX in very-long-chain fatty acid biosynthesis pathway, resulting in the accumulation of alkanes component and alteration of wax structure on the fruit surface. Corresponding results were verified in McWRI1 silenced by VIGS, and WRI1 silenced down-regulated the related genes on two kinds of fruits, it caused the diversity alteration in content of some alkanes, fatty acid and ester component in two kinds of fruits. We further conducted Y1H assay to find that McWRI1 transcription factor activated the promoter of McKCS, McLAC and McWAX to regulate their expression. These results demonstrated that McWRI1 is involved in regulating the genes related synthesis of very long chain fatty acid on surface of apple fruits in storage process, providing a highlight for improvement of the modified atmosphere storage of apple fruits.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186996PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658121PMC
November 2017

The mutation-free embryo for in vitro fertilization selected by MALBAC-PGD resulted in a healthy live birth from a family carrying PKD 1 mutation.

J Assist Reprod Genet 2017 Dec 19;34(12):1653-1658. Epub 2017 Aug 19.

Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, People's Republic of China.

Background: Autosomal dominant polycystic kidney disease (ADPKD, autosomal dominant PKD or adult-onset PKD) is the most prevalent and potentially lethal kidney disease that is hereditary and lacks effective treatment. Preimplantation genetic diagnosis (PGD) of embryos in assistant reproductive technology (ART) helps to select mutation-free embryos for blocking ADPKD inheritance from the parents to their offspring. However, there are multiple pseudogenes in the PKD1 coding region, which make blocking ADPKD inheritance by PGD complicated and difficult. Therefore, this technique has not been recommended and used routinely to ADPKD family plan.

Methods And Results: Here, we report a new strategy of performing PGD in screening (target-) mutation-free embryos. We firstly used a long-range PCR amplification and next generation sequencing to identify the potential PKD1 mutant(s). After pathogenic variants were detected, multiple annealing and looping-based amplification cycles (MALBAC), a recently developed whole genome amplification method, was used to screen embryo cells. We successfully distinguished the mutated allele among pseudogenes and obtained mutation-free embryos for implantation. The first embryo transfer attempt resulted in a healthy live birth free of ADPKD condition and chromosomal anomalies which was confirmed by aminocentesis at week 18 of gestation, and by performing live birth genetic screening.

Conclusions: The first MALBAC-PGD attempt in ADPKD patient resulted in a healthy live birth free of ADPKD and chromosomal anomalies. MALBAC-PGD also enables selecting embryos without aneuploidy together and target gene mutation, thereby increasing implantation and live birth rates.
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http://dx.doi.org/10.1007/s10815-017-1018-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714816PMC
December 2017

Treatment of Persistent Gross Hematuria with Tranexamic Acid in Autosomal Dominant Polycystic Kidney Disease.

Kidney Blood Press Res 2017 11;42(1):156-164. Epub 2017 Apr 11.

Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.

Background/aims: In this retrospective study we aimed to compare the effect of tranexamic acid (TXA) vs etamsylate, two hemostatic agents, on hematuria duration in autosomal dominant polycystic kidney disease (ADPKD) patients with persistent gross hematuria.

Methods: This is a retrospective study of 40 patients with ADPKD and macroscopic hematuria. 20 patients receiving TXA and snake venom blood clotting enzyme injection were compared with 20 matched patients receiving etamsylate and snake venom blood clotting enzyme injection. The primary outcome was hematuria duration and the secondary outcomes were blood transfusion requirements and adverse events.

Results: The hematuria duration was shorter in the TXA group compared with the etamsylate group (4[3-5] d vs 7[6-10] d, P<0.001). The volume of blood transfusion tended to be less in the TXA group than in the etamsylate group (300±115 ml vs 486±195 ml, P=0.12), and the number of patients needing a blood transfusion also tended to be lower [20% (4/20) vs 35% (7/20), P=0.29]. TXA and etamsylate were equally well tolerated and no serious adverse events were observed in both groups.

Conclusions: Our study indicates that TXA treatment was more effective than etamsylate in stopping bleeding in ADPKD patients with persistent gross hematuria.
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http://dx.doi.org/10.1159/000474961DOI Listing
March 2018

The integration of epigenetics and genetics in nutrition research for CVD risk factors.

Proc Nutr Soc 2017 08 6;76(3):333-346. Epub 2016 Dec 6.

Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University,Boston, MA,USA.

There is increasing evidence documenting gene-by-environment (G × E) interactions for CVD related traits. However, the underlying mechanisms are still unclear. DNA methylation may represent one of such potential mechanisms. The objective of this review paper is to summarise the current evidence supporting the interplay among DNA methylation, genetic variants, and environmental factors, specifically (1) the association between SNP and DNA methylation; (2) the role that DNA methylation plays in G × E interactions. The current evidence supports the notion that genotype-dependent methylation may account, in part, for the mechanisms underlying observed G × E interactions in loci such as APOE, IL6 and ATP-binding cassette A1. However, these findings should be validated using intervention studies with high level of scientific evidence. The ultimate goal is to apply the knowledge and the technology generated by this research towards genetically based strategies for the development of personalised nutrition and medicine.
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http://dx.doi.org/10.1017/S0029665116000823DOI Listing
August 2017