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Genetic and Genomic Analysis of DNA Sequence Variation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The studies in this thesis describe the application of genotyping and allele specific expression analysis to genetic studies. The role of the gene NPC1 in Triglyceride metabolism was explored in mouse models and in humans on the population level in study I. NPC1 was found to affect hepatic triglyceride metabolism, and to be relevant for controlling serum triglyceride levels in mice and potentially in humans. In study II the utility of the HapMap CEU samples was investigated for tagSNP selection in six European populations. The HapMap CEU was found to be representative for tagSNP selection in all populations while allele frequencies differed significantly in the sample from Kuusamo, Finland. In study III the power of Allele specific expression as a tool for the mapping of cis-regulatory variation was compared to standard eQTL analysis, ASE was found to be the more powerful type of analysis for a similar sample size. Finally ASE mapping was applied to regions reported to harbour long non-coding RNAs and associated SNPs were compared to published trait-associations. This revealed strong cis-regulatory SNPs of long non-coding RNAs with reported trait or disease associations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 50 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 702
Keyword [en]
SNP, NPC1, association study, allele specific expression, tagSNP, non-coding RNA
National Category
Medical Genetics
Research subject
Molecular Medicine
Identifiers
URN: urn:nbn:se:uu:diva-158486ISBN: 978-91-554-8156-8 (print)OAI: oai:DiVA.org:uu-158486DiVA: diva2:439681
Public defence
2011-10-25, Enghoffsalen, Entrance 50, bottom floor, Uppsala University Hospital, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-10-04 Created: 2011-09-08 Last updated: 2018-01-12
List of papers
1. Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels
Open this publication in new window or tab >>Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels
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2010 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 30, no 8, 1614-1620 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:

To study how Niemann-Pick disease type C1 (NPC1) influences hepatic triacylglycerol (TG) metabolism and to determine whether this is reflected in circulating lipid levels.

METHODS AND RESULTS:

 In Npc1−/− mice, the hepatic cholesterol content is increased but the TG content is decreased. We investigated lipid metabolism in Npc1−/− mouse hepatocytes and the association of NPC1 single-nucleotide polymorphisms with circulating TGs in humans. TGs were reduced in Npc1−/− mouse serum and hepatocytes. In Npc1−/− hepatocytes, the incorporation of [3H]oleic acid and [3H]acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [3H]carbons into cholesterol was increased. Inhibition of cholesterol synthesis normalized TG synthesis, content, and secretion in Npc1−/− hepatocytes, suggesting increased hepatic cholesterol neogenesis as a cause for the reduced TG content and secretion. We found a significant association between serum TG levels and 5 common NPC1 single-nucleotide polymorphisms in a cohort of 1053 men, with the lowest P=8.7×10−4 for the single-nucleotide polymorphism rs1429934. The association between the rs1429934 A allele and higher TG levels was replicated in 2 additional cohorts, which included 8041 individuals.

CONCLUSIONS:

This study provides evidence of the following: (1) in mice, loss of NPC1 function reduces hepatocyte TG content and secretion by increasing the metabolic flux of carbons into cholesterol synthesis; and (2) common variation in NPC1 contributes to serum TG levels in humans.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-130558 (URN)10.1161/ATVBAHA.110.207191 (DOI)000279886000021 ()20489167 (PubMedID)
Available from: 2010-09-09 Created: 2010-09-09 Last updated: 2017-12-12Bibliographically approved
2. Evaluation of HapMap data in six populations of European descent
Open this publication in new window or tab >>Evaluation of HapMap data in six populations of European descent
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2008 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, no 9, 1142-1150 p.Article in journal (Refereed) Published
Abstract [en]

We studied how well the European CEU samples used in the Haplotype Mapping Project (HapMap) represent five European populations by analyzing nuclear family samples from the Swedish, Finnish, Dutch, British and Australian (European ancestry) populations. The number of samples from each population (about 30 parent-offspring trios) was similar to that in the HapMap sample sets. A panel of 186 single nucleotide polymorphisms (SNPs) distributed over the 1.5 Mb region of the GRID2 gene on chromosome 4 was genotyped. The genotype data were compared pair-wise between the HapMap sample and the other population samples. Principal component analysis (PCA) was used to cluster the data from different populations with respect to allele frequencies and to define the markers responsible for observed variance. The only sample with detectable differences in allele frequencies was that from Kuusamo, Finland. This sample also separated from the others, including the other Finnish sample, in the PCA analysis. A set of tagSNPs was defined based on the HapMap data and applied to the samples. The tagSNPs were found to capture the genetic variation in the analyzed region at r(2)>0.8 at levels ranging from 95% in the Kuusamo sample to 87% in the Australian sample. To capture the maximal genetic variation in the region, the Kuusamo, HapMap and Australian samples required 58, 63 and 73 native tagSNPs, respectively. The HapMap CEU sample represents the European samples well for tagSNP selection, with some caution regarding estimation of allele frequencies in the Finnish Kuusamo sample, and a slight reduction in tagging efficiency in the Australian sample.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-16557 (URN)10.1038/ejhg.2008.77 (DOI)000258929800017 ()18398430 (PubMedID)
Available from: 2008-05-28 Created: 2008-05-28 Last updated: 2017-12-08Bibliographically approved
3. The power of allele-specific gene expression analysis for identification of cis-regulatory SNPs
Open this publication in new window or tab >>The power of allele-specific gene expression analysis for identification of cis-regulatory SNPs
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(English)Manuscript (preprint) (Other academic)
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-158485 (URN)
Available from: 2011-09-08 Created: 2011-09-08 Last updated: 2011-10-04
4. Identification of trait-associated single nucleotide polymorphisms with cis-regulatory effects on long non-coding RNAs
Open this publication in new window or tab >>Identification of trait-associated single nucleotide polymorphisms with cis-regulatory effects on long non-coding RNAs
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(English)Manuscript (preprint) (Other academic)
National Category
Genetics
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-158483 (URN)
Available from: 2011-09-08 Created: 2011-09-08 Last updated: 2012-02-06

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