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Lundmark, Per
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Publications (10 of 11) Show all publications
Adoue, V., Schiavi, A., Light, N., Carlsson Almlöf, J., Lundmark, P., Ge, B., . . . Pastinen, T. (2014). Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs. Molecular Systems Biology, 10(10), 754
Open this publication in new window or tab >>Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs
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2014 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 10, no 10, p. 754-Article in journal (Refereed) Published
Abstract [en]

Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-234588 (URN)10.15252/msb.20145114 (DOI)000344595300005 ()25326100 (PubMedID)
Available from: 2014-10-21 Created: 2014-10-21 Last updated: 2018-01-11Bibliographically approved
Penell, J., Lind, L., Fall, T., Syvänen, A.-C., Axelsson, T., Lundmark, P., . . . Lind, P. M. (2014). Genetic variation in the CYP2B6 Gene is related to circulating 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) concentrations: an observational population-based study. Environmental health, 13, 34
Open this publication in new window or tab >>Genetic variation in the CYP2B6 Gene is related to circulating 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) concentrations: an observational population-based study
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2014 (English)In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 13, p. 34-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Since human CYP2B6 has been identified as the major CYP enzyme involved in the metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and that human 2B6 is a highly polymorphic CYP, with known functional variants, we evaluated if circulating concentrations of a major brominated flame retardant, BDE-47, were related to genetic variation in the CYP2B6 gene in a population sample.

METHODS:

In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (men and women all aged 70), 25 single nucleotide polymorphisms (SNPs) in the CYP2B6 gene were genotyped. Circulating concentrations of BDE-47 were analyzed by high-resolution gas chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS).

RESULTS:

Several SNPs in the CYP2B6 gene were associated with circulating concentrations of BDE-47 (P = 10-4 to 10-9). The investigated SNPs came primarily from two haplotypes, although the correlation between the haplotypes was rather high. Conditional analyses adjusting for the SNP with the strongest association with the exposure (rs2014141) did not provide evidence for independent signals.

CONCLUSION:

Circulating concentrations of BDE-47 were related to genetic variation in the CYP2B6 gene in an elderly population.

National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-225448 (URN)10.1186/1476-069X-13-34 (DOI)000336098900001 ()24885815 (PubMedID)
Available from: 2014-06-03 Created: 2014-06-03 Last updated: 2017-12-05Bibliographically approved
Almlöf, J., Lundmark, P., Lundmark, A., Ge, B., Pastinen, T., Goodall, A. H., . . . Syvänen, A.-C. (2014). Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes. PLoS ONE, 9(7), e102612
Open this publication in new window or tab >>Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e102612-Article in journal (Refereed) Published
Abstract [en]

We applied genome-wide allele-specific expression analysis of monocytes from 188 samples. Monocytes were purified from white blood cells of healthy blood donors to detect cis-acting genetic variation that regulates the expression of long non-coding RNAs. We analysed 8929 regions harboring genes for potential long non-coding RNA that were retrieved from data from the ENCODE project. Of these regions, 60% were annotated as intergenic, which implies that they do not overlap with protein-coding genes. Focusing on the intergenic regions, and using stringent analysis of the allele-specific expression data, we detected robust cis-regulatory SNPs in 258 out of 489 informative intergenic regions included in the analysis. The cis-regulatory SNPs that were significantly associated with allele-specific expression of long non-coding RNAs were enriched to enhancer regions marked for active or bivalent, poised chromatin by histone modifications. Out of the lncRNA regions regulated by cis-acting regulatory SNPs, 20% (n = 52) were co-regulated with the closest protein coding gene. We compared the identified cis-regulatory SNPs with those in the catalog of SNPs identified by genome-wide association studies of human diseases and traits. This comparison identified 32 SNPs in loci from genome-wide association studies that displayed a strong association signal with allele-specific expression of non-coding RNAs in monocytes, with p-values ranging from 6.7×10-7 to 9.5×10-89. The identified cis-regulatory SNPs are associated with diseases of the immune system, like multiple sclerosis and rheumatoid arthritis.

National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-230152 (URN)10.1371/journal.pone.0102612 (DOI)000339992400093 ()25025429 (PubMedID)
Available from: 2014-08-19 Created: 2014-08-19 Last updated: 2017-12-05Bibliographically approved
Deloukas, P., Kanoni, S., Willenborg, C., Farrall, M., Assimes, T. L., Thompson, J. R., . . . Samani, N. J. (2013). Large-scale association analysis identifies new risk loci for coronary artery disease. Nature Genetics, 45(1), 25-33
Open this publication in new window or tab >>Large-scale association analysis identifies new risk loci for coronary artery disease
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2013 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 1, p. 25-33Article in journal (Refereed) Published
Abstract [en]

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-188806 (URN)10.1038/ng.2480 (DOI)000312838800009 ()23202125 (PubMedID)
Available from: 2012-12-19 Created: 2012-12-19 Last updated: 2018-07-06Bibliographically approved
Lind, L., Syvänen, A.-C., Axelsson, T., Lundmark, P., Hagg, S. & Larsson, A. (2013). Variation in genes in the endothelin pathway and endothelium-dependent and endothelium-independent vasodilation in an elderly population. Acta Physiologica, 208(1), 88-94
Open this publication in new window or tab >>Variation in genes in the endothelin pathway and endothelium-dependent and endothelium-independent vasodilation in an elderly population
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2013 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 208, no 1, p. 88-94Article in journal (Refereed) Published
Abstract [en]

Aim Indirect evidences by blockade of the endothelin receptors have suggested a role of endothelin in endothelium-dependent vasodilation. This study aimed to investigate whether circulating levels of endotehlin-1 or genetic variations in genes in the endothelin pathway were related to endothelium-dependent vasodilation. Methods In 1016 seventy-year-old participants of the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (52% women), we measured endothelium-dependent vasodilation using the invasive forearm technique with acetylcholine given in the brachial artery (EDV) and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). Plasma endothelin-1 levels were measured and 60 SNPs in genes in the endothelin pathway (ECE1, EDN1, EDNRA, EDNRB) were genotyped. Results No significant associations were found between circulating endothelin levels and EDV or FMD. No single genotype was related to EDV or FMD following adjustment for multiple testing, but a genotype score for 3 SNPs (rs11618266 in EDNRB, rs17675063 in EDNRA, rs3026868 in ECE1) was significantly related to EDV (beta coefficient 0.070, 95% CI 0.0250.12, P=0.002) when adjusting for gender, systolic blood pressure, HDL and LDL cholesterol, serum triglycerides, BMI, diabetes, smoking, antihypertensive medication or statins and CRP. This score was also related to nitroprusside-induced vasodilation in the forearm. Conclusion A combination of genotypes in the endothelin pathway was related to both endothelium-dependent and endothelium-independent vasodilation in forearm resistance vessels, but not in the brachial artery in an elderly population, giving evidence for a role of the endothelin system in resistance vessel reactivity independent of major cardiovascular risk factors.

Keywords
endothelin, endothelium, vasodilation, vasoreactivity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-200657 (URN)10.1111/apha.12068 (DOI)000317678000011 ()
Available from: 2013-06-03 Created: 2013-06-03 Last updated: 2017-12-06Bibliographically approved
Huang, J., Sabater-Lleal, M., Asselbergs, F. W., Tregouet, D., Shin, S.-Y., Ding, J., . . . Hamsten, A. (2012). Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. Blood, 120(24), 4873-81
Open this publication in new window or tab >>Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation
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2012 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 24, p. 4873-81Article in journal (Refereed) Published
Abstract [en]

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-188802 (URN)10.1182/blood-2012-06-436188 (DOI)000313115300031 ()22990020 (PubMedID)
Available from: 2012-12-19 Created: 2012-12-19 Last updated: 2017-12-06Bibliographically approved
Davison, L. J., Wallace, C., Cooper, J. D., Cope, N. F., Wilson, N. K., Smyth, D. J., . . . Todd, J. A. (2012). Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene. Human Molecular Genetics, 21(2), 322-333
Open this publication in new window or tab >>Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene
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2012 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 2, p. 322-333Article in journal (Refereed) Published
Abstract [en]

The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-189255 (URN)10.1093/hmg/ddr468 (DOI)21989056 (PubMedID)
Note

Per Lundmark and Ann-Christine Syvänen (Institution for Medical Sciences, Uppsala University, Uppsala, Sweden) contributed to this study.

Available from: 2012-12-28 Created: 2012-12-28 Last updated: 2017-12-06Bibliographically approved
Almlöf, J. C., Lundmark, P., Lundmark, A., Ge, B., Maouche, S., Göring, H. H., . . . Syvänen, A.-C. (2012). Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression. PLoS ONE, 7(12), e52260
Open this publication in new window or tab >>Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e52260-Article in journal (Refereed) Published
Abstract [en]

A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.

Keywords
messenger RNA, allele specific gene expression analysis, article, blood donor, DNA flanking region, gene expression, gene frequency, gene mapping, genetic analysis, genetic association, genotype, genotyping expression analysis, human, human cell, intermethod comparison, monocyte, quantitative trait locus mapping, sample size, single nucleotide polymorphism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-195164 (URN)10.1371/journal.pone.0052260 (DOI)000313618800062 ()
Available from: 2013-02-22 Created: 2013-02-21 Last updated: 2017-12-06Bibliographically approved
Lundmark, P. E. (2011). Genetic and Genomic Analysis of DNA Sequence Variation. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Genetic and Genomic Analysis of DNA Sequence Variation
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. p. 50
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 702
Keywords
SNP, NPC1, association study, allele specific expression, tagSNP, non-coding RNA
National Category
Medical Genetics
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-158486 (URN)978-91-554-8156-8 (ISBN)
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
Warensjö, E., Ingelsson, E., Lundmark, P., Lannfelt, L., Syvänen, A.-C., Vessby, B. & Risérus, U. (2007). Polymorphisms in the SCD1 gene: associations with body fat distribution and insulin sensitivity. Obesity, 15(7), 1732-1740
Open this publication in new window or tab >>Polymorphisms in the SCD1 gene: associations with body fat distribution and insulin sensitivity
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2007 (English)In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 15, no 7, p. 1732-1740Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:

Obesity and insulin resistance are major risk factors for metabolic diseases and are influenced by lifestyle and genetics. The lipogenic enzyme, stearoyl-coenzyme A-desaturase (SCD), is related to obesity. Further, SCD1-deficent mice are protected against obesity and insulin resistance. We hypothesized that genetic polymorphisms in the SCD1 gene would be associated with obesity, insulin sensitivity, and estimated SCD activity in humans.

RESEARCH METHODS AND PROCEDURES:

The study population was 1143 elderly Swedish men taking part of a population-based cohort study, the Uppsala Longitudinal Study of Adult Men. Associations between single nucleotide polymorphisms and obesity (waist circumference and BMI), insulin sensitivity (assessed by hyperinsulinemic euglycemic clamp), and estimated SCD activity (fatty acid ratios) were analyzed using linear regression analysis.

RESULTS:

Subjects homozygous for the rare alleles of rs10883463, rs7849, rs2167444, and rs508384 had decreased BMI and waist circumference and improved insulin sensitivity. The rare allele of rs7849 demonstrated the strongest effect on both insulin sensitivity [regression coefficient (beta)=1.19, p=0.007] and waist circumference (beta=-4.4, p=0.028), corresponding to 23% higher insulin sensitivity and 4 cm less waist circumference.

CONCLUSION:

This study indicates that genetic variations in the SCD1 gene are associated with body fat distribution and insulin sensitivity, results that accord well with animal data. These results need confirmation in other populations with a larger sample size.

Keywords
stearoyl-coenzyme A-desaturase, waist circumference, insulin sensitivity, single-nucleotide polymorphism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-96455 (URN)10.1038/oby.2007.206 (DOI)000248242900014 ()
Available from: 2007-11-16 Created: 2007-11-16 Last updated: 2017-12-14Bibliographically approved
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