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Träfflista för sökning "WFRF:(Hong Mun Gwan) srt2:(2010-2014)"

Sökning: WFRF:(Hong Mun Gwan) > (2010-2014)

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1.
  • Bennet, Anna M, et al. (författare)
  • Genetic association of sequence variants near AGER/NOTCH4 and dementia.
  • 2011
  • Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 24:3, s. 475-84
  • Tidskriftsartikel (refereegranskat)abstract
    • We performed a survey of sequence variation in a series of 20 genes involved in inflammation-related pathways for association with dementia risk in twin and unrelated case-control samples consisting in total of 1462 Swedish dementia casesand 1929 controls. For a total of 218 tested genetic markers, strong evidence was obtained implicating a region near AGER and NOTCH4 on chromosome 6p with replication across both samples and maximum combined significance at marker rs1800625 (OR = 1.37, 95% CI 1.19–1.56, p = 1.36×10(–6)). Imputation of the associated genomic interval provided an improved signal atrs8365, near the 3UTR of AGER (p = 7.34×10(–7)). The associated region extends 120 kb encompassing 11 candidate genes.While AGER encodes a key receptor for amyloid-β protein, an analysis of network context based upon genes now confirmed to contribute to dementia risk (AβPP, PSEN1, PSEN2, CR1, CLU, PICALM, and APOE) suggested strong functional coupling to NOTCH4, with no significant coupling to the remaining candidates. The implicated region occurs in the broad HLA locus on chromosome 6p, but associated markers were not in strong LD with known variants that regulate HLA gene function, suggesting that this may represent a signal distinct from immune-system pathways.
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2.
  • Byström, Sanna, et al. (författare)
  • Affinity Proteomic Profiling of Plasma, Cerebrospinal Fluid, and Brain Tissue within Multiple Sclerosis
  • 2014
  • Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 13:11, s. 4607-4619
  • Tidskriftsartikel (refereegranskat)abstract
    • The brain is a vital organ and because it is well shielded from the outside environment, possibilities for noninvasive analysis are often limited. Instead, fluids taken from the spinal cord or circulatory system are preferred sources for the discovery of candidate markers within neurological diseases. In the context of multiple sclerosis (MS), we applied an affinity proteomic strategy and screened 22 plasma samples with 4595 antibodies (3450 genes) on bead arrays, then defined 375 antibodies (334 genes) for targeted analysis in a set of 172 samples and finally used 101 antibodies (43 genes) on 443 plasma as well as 573 cerebrospinal spinal fluid (CSF) samples. This revealed alteration of protein profiles in relation to MS subtypes for IRF8, IL7, METTL14, SLC30A7, and GAP43. Respective antibodies were subsequently used for immunofluorescence on human post-mortem brain tissue with MS pathology for expression and association analysis. There, antibodies for IRF8, IL7, and METTL14 stained neurons in proximity of lesions, which highlighted these candidate protein targets for further studies within MS and brain tissue. The affinity proteomic translation of profiles discovered by profiling human body fluids and tissue provides a powerful strategy to suggest additional candidates to studies of neurological disorders.
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3.
  • Hong, Mun-Gwan, et al. (författare)
  • A genome-wide assessment of variability in human serum metabolism
  • 2013
  • Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 34:3, s. 515-524
  • Tidskriftsartikel (refereegranskat)abstract
    • The study of the genetic regulation of metabolism in human serum samples can contribute to a better understanding of the intermediate biological steps that lead from polymorphism to disease. Here, we conducted a genome-wide association study (GWAS) to discover metabolic quantitative trait loci (mQTLs) utilizing samples from a study of prostate cancer in Swedish men, consisting of 402 individuals (214 cases and 188 controls) in a discovery set and 489 case-only samples in a replication set. A global nontargeted metabolite profiling approach was utilized resulting in the detection of 6,138 molecular features followed by targeted identification of associated metabolites. Seven replicating loci were identified (PYROXD2, FADS1, PON1, CYP4F2, UGT1A8, ACADL, and LIPC) with associated sequence variants contributing significantly to trait variance for one or more metabolites (P = 10(-13) -10(-91)). Regional mQTL enrichment analyses implicated two loci that included FADS1 and a novel locus near PDGFC. Biological pathway analysis implicated ACADM, ACADS, ACAD8, ACAD10, ACAD11, and ACOXL, reflecting significant enrichment of genes with acyl-CoA dehydrogenase activity. mQTL SNPs and mQTL-harboring genes were over-represented across GWASs conducted to date, suggesting that these data may have utility in tracing the molecular basis of some complex disease associations.
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4.
  • Hong, Mun-Gwan, et al. (författare)
  • Genome-wide and gene-based association implicates FRMD6 in Alzheimer disease
  • 2012
  • Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 33:3, s. 521-529
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) that allow for allelic heterogeneity may facilitate the discovery of novel genes not detectable by models that require replication of a single variant site. One strategy to accomplish this is to focus on genes rather than markers as units of association, and so potentially capture a spectrum of causal alleles that differ across populations. Here, we conducted a GWAS of Alzheimer disease (AD) in 2,586 Swedes and performed gene-based meta-analysis with three additional studies from France, Canada, and the United States, in total encompassing 4,259 cases and 8,284 controls. Implementing a newly designed gene-based algorithm, we identified two loci apart from the region around APOE that achieved study-wide significance in combined samples, the strongest finding being for FRMD6 on chromosome 14q (P = 2.6 × 10(-14)) and a weaker signal for NARS2 that is immediately adjacent to GAB2 on chromosome 11q (P = 7.8 × 10(-9)). Ontology-based pathway analyses revealed significant enrichment of genes involved in glycosylation. Results suggest that gene-based approaches that accommodate allelic heterogeneity in GWAS can provide a complementary avenue for gene discovery and may help to explain a portion of the missing heritability not detectable with single nucleotide polymorphisms (SNPs) derived from marker-specific meta-analysis.
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5.
  • Hong, Mun-Gwan (författare)
  • Genomics and bioinformatics strategies in the study of aging and Alzheimer disease
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • To understand complex phenotypes, medical research has evolved from the study of single genes and proteins to approaches that encompass more comprehensive catalogues of molecules. Among the more widely used are genome-wide expression and high-throughput genotyping, the latter primarily making use of single nucleotide polymorphisms (SNPs) in what has been termed genome-wide association studies (GWAS). Because of the scale of the data sets that are being produced, unique problems have emerged that necessitate the extensive use of bioinformatics tools. This thesis has entailed the analysis of several such large data sets in the context of biological pathways and introduces several bioinformatics solutions. Paper III, IV, and V deal with this topic. This thesis is primarily oriented around the study of Alzheimer disease (AD) and aging. The questions about the etiology of AD are often concurrent with questions about the biology of aging. This thesis pursues insight on genomic factors pertaining to both inquiries, acknowledging that both the AD state and aging itself are complex and multi-factorial. Two constituent papers (I and III) address aging and two papers (II and V) deal with genetic models in the study of AD. In paper I, we examined the association of age with several genetic markers in the insulin degrading enzyme (IDE) and explored possible molecular mechanisms. In contrast to women, both age-at-sampling and age-at-death of the males were significantly lower in individuals that were heterozygous at genetic loci spanning the IDE locus. Plasma insulin levels and the expression levels of the gene were found to be higher in those same heterozygous males. In paper II, SNPs in 25 genes involved in cholesterol metabolism were tested for association with AD and dementia. Genetic markers in a large linkage disequilibrium block spanning SREBF1, TOM1L2, and ATPAF2 were significantly associated with disease. Gene expression and gene network analyses supported the findings. In paper III, we investigated the biological pathway basis of age in human brain and lymphocytes. Mitochondrial genes were negatively regulated in both tissue samples, while the protein translation genes appeared to decrease in lymphocytes but increase in brain. Those observations indicated that there are common themes across tissues, but also tissue specific changes in gene regulation. We also examined the genomic architecture of the age-regulated genes, and found that the expression of non-compact genes tend to decrease with advancing age. A large number of genome-wide association studies (GWAS) have now been performed over the past few years. In paper IV, we developed a program that automates the conversion of SNPs to representative gene lists in order to facilitate the exploration of biological pathway in the context of GWAS. In paper V, we employed the software developed in study IV to identify biological pathways enriched among the genes that were significantly associated from a GWAS of AD. Genes involved in intracellular protein transmembrane transport were found to be significantly overrepresented. These results highlighted the possibility that TOMM40 contributes to AD pathology together with other translocases. Through this thesis, several biological relationships have been identified linking AD and aging. Genetic markers in IDE, a gene previously claimed to be associated with AD, also associate with age. With advancing age, mitochondrial gene expression deteriorates significantly. TOMM40 may contribute the AD pathology, together with other genes that encode proteins of the intracellular transmembrane protein transport pathway. Methodologically, pathway analyses were conducted successfully with the program, ProxyGeneLD. This enabled discoveries and discussion of the challenges that face the exploration of GWAS data sets in a pathway context. In the future, more sophisticated bioinformatics tools and enhanced gene annotation may lead to the discovery of the molecular mechanisms that dominate complex diseases and traits.
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6.
  • Häggmark, Anna, et al. (författare)
  • Plasma profiling revelas three proteins associated to amyotrophic lateral sclerosis
  • 2014
  • Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 1:8, s. 544-553
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease leading to muscular paralysis and death within 3-5 years from onset. Currently, there are no reliable and sensitive markers able to substantially shorten the diagnosis delay. The objective of the study was to analyze a large number of proteins in plasma from patients with various clinical phenotypes of ALS in search for novel proteins or protein profiles that could serve as potential indicators of disease.METHODS: Affinity proteomics in the form of antibody suspension bead arrays were applied to profile plasma samples from 367 ALS patients and 101 controls. The plasma protein content was directly labeled and protein profiles obtained using 352 antibodies from the Human Protein Atlas targeting 278 proteins. A focused bead array was then built to further profile eight selected protein targets in all available samples.RESULTS: Disease-associated significant differences were observed and replicated for profiles from antibodies targeting the proteins: neurofilament medium polypeptide (NEFM), solute carrier family 25 (SLC25A20), and regulator of G-protein signaling 18 (RGS18).INTERPRETATION: Upon further validation in several independent cohorts with inclusion of a broad range of other neurological disorders as controls, the alterations of these three protein profiles in plasma could potentially provide new molecular markers of disease that contribute to the quest of understanding ALS pathology.
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7.
  • Kumar, Jitender, et al. (författare)
  • Associations of Body Mass Index and Obesity-Related Genetic Variants with Serum Metabolites
  • 2014
  • Ingår i: Current Metabolomics. - 2213-235X. ; 2:1, s. 27-36-
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Body mass index (BMI) is one of the most important risk factors for different metabolic and cardiovascular disorders. Previously, both genetic and environmental agents associated with BMI have been described. The main focus of this exploratory study was to find the circulating metabolites associated with BMI utilizing an untargeted metabolomics approach. Additionally, significant metabolites identified were studied for their relation with BMIassociated single nucleotide polymorphisms (SNPs). Materials and Methods: A total of 971 individuals from the Cancer of the Prostate in Sweden study (discovery sample- 275 prostate cancers patients and 182 controls; replication sample- 514 prostate cancer patients) were utilized. Blood samples were collected and serum metabolic profiling was obtained using ultra-performance liquid chromatography followed by mass spectrometry. Genotyping data was available for 26 out of 32 SNPs (21 genotyped and 5 proxies) previously robustly associated with BMI in individuals of European descent. Weighted genetic risk score was generated using these SNPs and studied for its association with metabolites. Results: A total of 6138 and 5209 metabolite features were detected in discovery and replication samples, respectively. Out of 6138 metabolite features in discovery sample, 201 were found to be significantly associated with BMI (p<8.15*10-6) after multiple testing correction. These 201 features were further investigated in the replication samples and 16 were found to be significantly associated with BMI (p<2.49*10-4). Seven of these significant features were isotopes for four of the primary metabolites. Four metabolites were putatively identified: monoacylglyceride (18:1), diacylglyrcerol (32:1) and two phosphatidylcholines (34:0 and 36:0). Weighted genetic score of BMI-associated SNPs was not associated with these four metabolites. Conclusion: Four identifiable metabolites (monoacylglyceride, diacyclglyrcerol and two phosphatidylcholines) were found to be significantly associated with BMI in both discovery and replication samples. Common variants associated with BMI did not show association with these four metabolites. - See more at: http://www.eurekaselect.com/120422/article#sthash.PgqffHqv.dpuf
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8.
  • Qundos, Ulrika, et al. (författare)
  • Profiling post-centrifugation delay of serum and plasma with antibody bead arrays
  • 2013
  • Ingår i: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 95:SI, s. 46-54
  • Tidskriftsartikel (refereegranskat)abstract
    • Several biobanking initiatives have emerged to create extensive collections of specimen for biomedical studies and various analytical platforms. An affinity proteomic analysis with antibody suspension bead arrays was conducted to investigate the influence of the pre-analytical time and temperature conditions on blood derived samples. Serum and EDTA plasma prepared from 16 individuals was centrifuged and aliquots were kept either at 4. °C or in ambient temperature for 1. h and up to 36. h prior to first storage. Multiplexed protein profiles of post-centrifugation delay were generated in 384 biotinylated samples using 373 antibodies that targeted 343 unique proteins. Very few profiles were observed as significantly altered by the studied temperature and time intervals. Single binder and sandwich assays revealed decreasing levels of caldesmon 1 (CALD1) related to EDTA standard tubes and prolonged post-centrifugation delay of 36. h. Indications from changes in CALD1 levels require further confirmation in independent material, but the current data suggests that samples should preferentially be frozen during the day of collection when to be profiled with antibody arrays selected for this study. Biological significance: Affinity-based profiling of serum and plasma by microarray assays can provide unique opportunities for the discovery of biomarkers. It is though often not known how differences in sample handling after collection influence the downstream analysis. By profiling three types of blood preparations for alterations in protein profiles with respect to time and temperature post centrifugation, we addressed an important component in the analysis and of such specimen. We believe that this analysis adds valuable information to be considered when biobanking blood derived samples.This article is part of a Special Issue entitled: Standardization and Quality Control in Proteomics.
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9.
  • Reynolds, Chandra A, et al. (författare)
  • Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk.
  • 2010
  • Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 19:10, s. 2068-2078
  • Tidskriftsartikel (refereegranskat)abstract
    • We conducted dense linkage disequilibrium mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases (including 1270 with Alzheimer disease) and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for APOE (rs429358 at p approximately 10(-72)) followed by a previously reported association of ABCA1 (rs2230805 at p approximately 10(-8)). In the present study we report two additional markers near the SREBF1 locus on chromosome 17p that were also significant after multiple testing correction (best p=3.1 x 10(-6) for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids (CELSR2/PSRC1/SORT1, MLXIPL, PCSK9, GALNT2, and GCKR). The associated markers near SREBF1 reside in a large linkage disequilibrium block, extending more than 400kb across 7 candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including ATPAF2 and TOM1L2. Several markers in strong LD (r(2)>0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome-wide association studies with similar effect sizes, providing independent support of the current findings.
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10.
  • Reynolds, Chandra A, et al. (författare)
  • Sequence variation in SORL1 and dementia risk in Swedes.
  • 2010
  • Ingår i: Neurogenetics. - : Springer Science and Business Media LLC. - 1364-6753 .- 1364-6745. ; 11:1, s. 139-42
  • Tidskriftsartikel (refereegranskat)abstract
    • The gene encoding the neuronal sortilin-related receptor SORL1 has been claimed to be associated with Alzheimer's disease (AD) by independent groups and across various human populations. We evaluated six genetic markers in SORL1 in a sample of 1,558 Swedish dementia cases (including 1,270 AD cases) and 2,179 controls. For both single-marker-based and haplotype-based analyses, we found no strong support for SORL1 as a dementia or AD risk-modifying gene in our sample in isolation nor did we observe association with AD/dementia-related traits, including cerebrospinal fluid beta-amyloid(1-42), tau levels, or age at onset. However, meta-analyses of markers in this study together with previously published studies on SORL1 encompassing in excess of 13,000 individuals does suggest significant association with AD (best odds ratio = 1.097; 95% confidence interval = 1.038-1.158, p = 0.001). All six markers were significant in meta-analyses and it is notable that they occur in two distinct linkage disequilibrium blocks. These data are consistent with either allelic heterogeneity or the existence of as yet untested functional variants and these will be important considerations in further attempts to evaluate the importance of sequence variation in SORL1 with AD risk.
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