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Andersson Escher, Stefan
Publications (10 of 17) Show all publications
Stitziel, N. O., Stirrups, K. E., Masca, N. G. D., Erdmann, J., Ferrario, P. G., Koenig, I. R., . . . Schunkert, H. (2016). Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. New England Journal of Medicine, 374(12), 1134-1144
Open this publication in new window or tab >>Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
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2016 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 374, no 12, p. 1134-1144Article in journal (Refereed) Published
Abstract [en]

BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-119276 (URN)10.1056/NEJMoa1507652 (DOI)000372585100006 ()
Note

Errata New England Journal of Medicine (2016) 374(19), p 1898 DOI: 10.1056/NEJMxx160012

Available from: 2016-06-02 Created: 2016-04-15 Last updated: 2018-06-07Bibliographically approved
Hellman, U., Lundgren, H.-E., Westermark, P., Stafberg, C., Nahi, H., Tachlinski, S., . . . Suhr, O. B. (2015). A genealogical and clinical study of the phenotypical variation within the Swedish transthyretin His88Arg (p. His108Arg) amyloidosis family. European Journal of Medical Genetics, 58(4), 211-215
Open this publication in new window or tab >>A genealogical and clinical study of the phenotypical variation within the Swedish transthyretin His88Arg (p. His108Arg) amyloidosis family
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2015 (English)In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 58, no 4, p. 211-215Article in journal (Refereed) Published
Abstract [en]

In 2005 we reported the first case of transthyretin His88Arg (p. His108Arg) amyloidosis, a mutation characterised by cardiomyopathy. Six additional gene carriers of whom five have clinical symptoms of disease have now been identified in Sweden, and we have been able to identify a possible founder and to characterise the Swedish phenotype of the transthyretin (TTR) His88Arg mutation. Genealogical studies of church records were used to identify the individuals with the disease and their families. Routine clinical investigations of neurological and heart manifestation of the disease were utilised. We found that genealogically all seven individuals were related and originated from the same region in Sweden. Amyloid deposits were demonstrated in biopsies and the TTR His88Arg mutation was identified in all patients. Patients had a late onset disease (similar to 50 years of age) and all exhibited a severe amyloid cardiomyopathy. A pronounced peripheral axonal neuropathy was with certainty demonstrated in one patient only, who also was operated for a magnetic resonance confirmed spinal stenosis, however, without any effect on his neurological symptoms. Five of the patients had carpal tunnel syndrome. The first reported case is now deceased from cardiac failure. One patient has had a sequential heart and liver transplantation. One gene carrier had no symptoms or findings of disease on latest evaluation at the age of 44. In conclusion: the Swedish TTRHis88Arg patients all have a common Swedish founder. Cardiomyopathy with heart failure, as well as carpal tunnel syndrome and spinal stenosis were early signs of disease; but peripheral neuropathy was present in one patient before symptoms of cardiomyopathy so the phenotypical presentation of this mutation is variable.

Keywords
Amyloidosis-hereditary, Cardiomyopathy, Genealogy, Neuropathy, Transthyretin
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-106370 (URN)10.1016/j.ejmg.2015.02.005 (DOI)000353995500003 ()25721874 (PubMedID)
Available from: 2015-07-15 Created: 2015-07-14 Last updated: 2018-06-07Bibliographically approved
Varga, T. V., Sonestedt, E., Shungin, D., Koivula, R. W., Hallmans, G., Andersson Escher, S., . . . Franks, P. W. (2014). Genetic determinants of long-term changes in blood lipid concentrations: 10-year follow-up of the GLACIER study. PLOS Genetics, 10(6), e1004388
Open this publication in new window or tab >>Genetic determinants of long-term changes in blood lipid concentrations: 10-year follow-up of the GLACIER study
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2014 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 6, p. e1004388-Article in journal (Refereed) Published
Abstract [en]

Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (beta = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0x10(-11) for TC; beta = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0x10(-5) for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (beta = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0x10(-5)), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (beta = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1x10(-4)) and apolipoprotein A-I (APOA1) rs6589564 (beta = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4x10(-8)), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P <= 0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.

Place, publisher, year, edition, pages
Public library science, 2014
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-91861 (URN)10.1371/journal.pgen.1004388 (DOI)000338847700010 ()
Available from: 2014-08-26 Created: 2014-08-18 Last updated: 2018-06-07Bibliographically approved
Crosby, J., Peloso, G. M., Auer, P. L., Crosslin, D. R., Stitziel, N. O., Lange, L. A., . . . Kathiresan, S. (2014). Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease. New England Journal of Medicine, 371(1), 22-31
Open this publication in new window or tab >>Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease
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2014 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 1, p. 22-31Article in journal (Refereed) Published
Abstract [en]

Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G -> A and IVS3+1G -> T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1x10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8x10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4x10(-6)). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-104169 (URN)10.1056/NEJMoa1307095 (DOI)000338265700006 ()
Available from: 2015-06-18 Created: 2015-06-08 Last updated: 2018-06-07Bibliographically approved
Kriström, B., Zdunek, A.-M., Rydh, A., Jonsson, H., Sehlin, P. & Andersson Escher, S. (2009). A novel mutation in the LIM homeobox 3 gene is responsible for combined pituitary hormone deficiency, hearing impairment, and vertebral malformations.. Journal of Clinical Endocrinology and Metabolism, 94(4), 1154-1161
Open this publication in new window or tab >>A novel mutation in the LIM homeobox 3 gene is responsible for combined pituitary hormone deficiency, hearing impairment, and vertebral malformations.
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2009 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, no 4, p. 1154-1161Article in journal (Refereed) Published
Abstract [en]

CONTEXT: The LIM homeobox 3 (LHX3) LIM-homeodomain transcription factor gene, found in both man and mouse, is required for development of the pituitary and motor neurons, and is also expressed in the auditory system. OBJECTIVE: The objective of this study was to determine the cause of, and further explore, the phenotype in six patients (aged 6 months to 22 yr) with combined pituitary hormone deficiency (CPHD), restricted neck rotation, scoliosis, and congenital hearing impairment. Three of the patients also have mild autistic-like behavior. DESIGN: Because patients with CPHD and restricted neck rotation have previously been shown to have mutations in the LHX3 gene, a candidate gene approach was applied, and the gene was sequenced. Neck anatomy was explored by computed tomography and magnetic resonance imaging, including three-dimensional reformatting. RESULTS: A novel, recessive, splice-acceptor site mutation was found. The predicted protein encoded by the mutated gene lacks the homeodomain and carboxyl terminus of the normal, functional protein. Genealogical studies revealed a common gene source for all six families dating back to the 17th century. Anatomical abnormalities in the occipito-atlantoaxial joints in combination with a basilar impression of the dens axis were found in all patients assessed. CONCLUSIONS: This study extends both the mutations known to be responsible for LHX3-associated syndromes and their possible phenotypical consequences. Previously reported traits include CPHD and restricted neck rotation; patients examined in the present study also show a severe hearing defect. In addition, the existence of cervical vertebral malformations are revealed, responsible for the rigid neck and the development of scoliosis.

Keywords
Hormone Deficiency, Hearing Impairment, Vertebral Malformations
National Category
Medical and Health Sciences
Research subject
Pediatrics
Identifiers
urn:nbn:se:umu:diva-34983 (URN)10.1210/jc.2008-0325 (DOI)19126629 (PubMedID)
Available from: 2010-06-29 Created: 2010-06-29 Last updated: 2019-04-01Bibliographically approved
Nilsson-Ardnor, S., Janunger, T., Wiklund, P.-G., Lackovic, K., Nilsson, A. K., Lindgren, P., . . . Holmberg, D. (2007). Genome-wide linkage scan of common stroke in families from northern Sweden.. Stroke, 38(1), 34-40
Open this publication in new window or tab >>Genome-wide linkage scan of common stroke in families from northern Sweden.
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2007 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 38, no 1, p. 34-40Article in journal (Other academic) Published
Keywords
Aged, Chromosome Mapping/*methods, Chromosomes; Human; Pair 13/genetics, Chromosomes; Human; Pair 18/genetics, Chromosomes; Human; Pair 5/genetics, DNA Mutational Analysis, Female, Gene Frequency/genetics, Genetic Predisposition to Disease/epidemiology/*genetics, Genetic Screening, Genetic Variation/genetics, Genome; Human/*genetics, Humans, Male, Middle Aged, Stroke/epidemiology/*genetics, Sweden/epidemiology
Identifiers
urn:nbn:se:umu:diva-11537 (URN)10.1161/01.STR.0000251643.37454.16 (DOI)17122438 (PubMedID)
Available from: 2009-01-13 Created: 2009-01-13 Last updated: 2018-06-09Bibliographically approved
Einarsdottir, E., Egerbladh, I., Beckman, L., Holmberg, D. & Andersson Escher, S. (2007). The genetic population structure of northern Sweden and its implications for mapping genetic diseases.. Hereditas, 144(5), 171-180
Open this publication in new window or tab >>The genetic population structure of northern Sweden and its implications for mapping genetic diseases.
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2007 (English)In: Hereditas, ISSN 1601-5223, Vol. 144, no 5, p. 171-180Article in journal (Refereed) Published
Abstract [en]

The northern Swedish population has a history of admixture of three ethnic groups and a dramatic population growth from a relatively small founder population. This has resulted in founder effects that together with unique resources for genealogical analyses provide excellent conditions for genetic mapping of monogenic diseases. Several recent examples of successful mapping of genetic factors underlying susceptibility to complex diseases have suggested that the population of northern Sweden may also be an important tool for efficient mapping of more complex phenotypes. A potential factor contributing to these effects may be population sub-isolates within the large river valleys, constituting a central geographic characteristic of this region. We here provide evidence that marriage patterns as well as the distribution of gene frequencies in a set of marker loci are compatible with this notion. The possible implications of this population structure on linkage- and association based strategies for identifying genes contributing risk to complex diseases are discussed.

Identifiers
urn:nbn:se:umu:diva-24653 (URN)10.1111/j.2007.0018-0661.02007.x (DOI)18031350 (PubMedID)
Available from: 2009-07-08 Created: 2009-07-08 Last updated: 2018-06-08
Einarsdottir, E., Mayans, S., Ruikka, K., Andersson Escher, S., Lindgren, P., Ågren, Å., . . . Holmberg, D. (2006). Linkage but not association of calpain-10 to type 2 diabetes replicated in northern Sweden. Diabetes, 55(6), 1879-1883
Open this publication in new window or tab >>Linkage but not association of calpain-10 to type 2 diabetes replicated in northern Sweden
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2006 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, no 6, p. 1879-1883Article in journal (Refereed) Published
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-15417 (URN)10.2337/db05-1495 (DOI)000238053400043 ()16731857 (PubMedID)
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2018-06-09Bibliographically approved
Andersson Escher, S., Ekenstedt, J., Elberg, K. & Saura, A. (2006). The Drosophilidae (Diptera) of Estonia. Entomologica Fennica, 17, 13-20
Open this publication in new window or tab >>The Drosophilidae (Diptera) of Estonia
2006 (English)In: Entomologica Fennica, Vol. 17, p. 13-20Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-18047 (URN)
Available from: 2007-11-26 Created: 2007-11-26 Last updated: 2018-06-09Bibliographically approved
Nilsson-Ardnor, S., Wiklund, P.-G., Lindgren, P., Nilsson, A. K., Janunger, T., Andersson Escher, S., . . . Holmberg, D. (2005). Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population.. Stroke, 36(8), 1666-1671
Open this publication in new window or tab >>Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population.
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2005 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 36, no 8, p. 1666-1671Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: Recent Icelandic studies have demonstrated linkage for common forms of stroke to chromosome 5q12 and association between phosphodiesterase4D (PDE4D) and ischemic stroke. Using a candidate region approach, we wanted to test the validity of these findings in a different population from northern Sweden. METHODS: A total of 56 families with 117 affected individuals were included in the linkage study. Genotyping was performed with polymorphic microsatellite markers with an average distance of 4.5 cM on chromosome 5. In the association study, 275 cases of first-ever stroke were included together with 550 matched community controls. Polymorphisms were tested individually for association of PDE4D to stroke. RESULTS: Maximum allele-sharing lod score in favor of linkage was observed at marker locus D5S424 (lod score=2.06; P=0.0010). Conditional logistic regression calculations revealed no significant association of ischemic stroke to the defined at-risk allele in PDE4D (odds ratio, 1.1; 95% confidence interval, 0.84 to 1.45). A protective effect may though be implied for 2 of the polymorphisms analyzed in PDE4D. CONCLUSIONS: Using a candidate region approach in a set of stroke families from northern Sweden, we have replicated linkage of stroke susceptibility to the PDE4D gene region on chromosome 5q. Association studies in an independent nested case-control sample from the same geographically located population suggested that different alleles confer susceptibility/protection to stroke in the Icelandic and the northern Swedish populations.

Keywords
3';5'-Cyclic-Nucleotide Phosphodiesterase/*genetics, Algorithms, Alleles, Case-Control Studies, Cerebrovascular Accident/genetics, Chromosome Mapping, Chromosomes; Human; Pair 5, Diabetes Complications/genetics, Exons, Family Health, Gene Frequency/*genetics, Genetic Markers, Genetic Predisposition to Disease, Genotype, Humans, Iceland, Ischemia, Linkage (Genetics), Linkage Disequilibrium, Lod Score, Microsatellite Repeats, Models; Statistical, Odds Ratio, Polymorphism; Genetic, Regression Analysis, Risk Factors, Sweden
Identifiers
urn:nbn:se:umu:diva-14817 (URN)10.1161/01.STR.0000174188.04716.8d (DOI)16020760 (PubMedID)
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2018-06-09Bibliographically approved
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