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Alterations in KLRB1 gene expression and a Scandinavian multiple sclerosis association study of the KLRB1 SNP rs4763655.

https://arctichealth.org/en/permalink/ahliterature134204
Source
Eur J Hum Genet. 2011 Oct;19(10):1100-3
Publication Type
Article
Date
Oct-2011
Author
Helle Bach Søndergaard
Finn Sellebjerg
Jan Hillert
Tomas Olsson
Ingrid Kockum
Magdalena Lindén
Inger-Lise Mero
Kjell-Morten Myhr
Elisabeth G Celius
Hanne F Harbo
Jeppe Romme Christensen
Lars Börnsen
Per Soelberg Sørensen
Annette Bang Oturai
Author Affiliation
Department of Neurology, Danish Multiple Sclerosis Center, University Hospital Rigshospitalet, Copenhagen, Denmark. hbs@rh.dk
Source
Eur J Hum Genet. 2011 Oct;19(10):1100-3
Date
Oct-2011
Language
English
Publication Type
Article
Keywords
Case-Control Studies
Female
Gene Expression Regulation
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Multiple Sclerosis - epidemiology - genetics
NK Cell Lectin-Like Receptor Subfamily B - genetics - metabolism
Polymorphism, Single Nucleotide
Scandinavia - epidemiology
Abstract
Multiple sclerosis (MS) is a complex autoimmune disease affecting genetically susceptible individuals. A genome-wide association study performed by the International MS Genetics Consortium identified several putative susceptibility genes; among these, the KLRB1 gene is represented by the single-nucleotide polymorphism rs4763655. We could confirm a marginally significant association between rs4763655 and MS (P=0.046, odds ratio=1.06 (1.00-1.13)) in a large Scandinavian case-control study of 5367 MS patients and 4485 controls. The expression of KLRB1 in blood from MS patients was higher compared with healthy controls (P
Notes
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PubMed ID
21610746 View in PubMed
Less detail

Association analysis of the LAG3 and CD4 genes in multiple sclerosis in two independent populations.

https://arctichealth.org/en/permalink/ahliterature167185
Source
J Neuroimmunol. 2006 Nov;180(1-2):193-8
Publication Type
Article
Date
Nov-2006
Author
Frida Lundmark
Hanne F Harbo
Elisabeth G Celius
Janna Saarela
Pameli Datta
Annette Oturai
Cecilia M Lindgren
Thomas Masterman
Hugh Salter
Jan Hillert
Author Affiliation
Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden. frida.lundmark@ki.se
Source
J Neuroimmunol. 2006 Nov;180(1-2):193-8
Date
Nov-2006
Language
English
Publication Type
Article
Keywords
Adult
Antigens, CD - genetics - immunology
Antigens, CD4 - genetics - immunology
Biological Markers - metabolism
Case-Control Studies
Cohort Studies
DNA Mutational Analysis
Denmark - epidemiology
European Continental Ancestry Group - genetics
Female
Finland - epidemiology
Gene Frequency - genetics
Genetic Markers - genetics - immunology
Genetic Predisposition to Disease - genetics
Genetic Testing
Humans
Linkage Disequilibrium
Male
Middle Aged
Multiple Sclerosis - epidemiology - genetics - immunology
Norway - epidemiology
Polymorphism, Single Nucleotide - genetics
Predictive value of tests
Sweden - epidemiology
Abstract
We have investigated the genetic involvement of the CD4 and the LAG3 genes, two appealing candidates for MS due to their suggested role in MS pathology. We genotyped a Swedish case-control material consisting of 920 MS patients and 778 controls in an initial study of CD4, three SNPs showed a significant association with MS. An independent material consisting of 1720 Nordic MS patients and 1416 controls were used for confirmation of associated markers in CD4 and to do a confirmative study of the LAG3 gene from previous findings. The result, including a total of 2640 MS patients and 2194 controls shows no significant association with CD4 and LAG3 and MS. We conclude that these genes are of minor importance in regard of genetic predisposition to the MS.
PubMed ID
17020785 View in PubMed
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Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients.

https://arctichealth.org/en/permalink/ahliterature145176
Source
Respir Res. 2010;11:25
Publication Type
Article
Date
2010
Author
Johan Grunewald
Boel Brynedal
Pernilla Darlington
Magnus Nisell
Kerstin Cederlund
Jan Hillert
Anders Eklund
Author Affiliation
Department of Medicine, Division of Respiratory Medicine, Karolinska University Hospital Solna, Sweden. johan.grunewald@ki.se
Source
Respir Res. 2010;11:25
Date
2010
Language
English
Publication Type
Article
Keywords
Adult
Aged
Female
Gene Frequency
Genetic Predisposition to Disease - epidemiology - genetics
HLA-DR Antigens - genetics
HLA-DRB1 Chains
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide - genetics
Prevalence
Risk Assessment - methods
Risk factors
Sarcoidosis, Pulmonary - epidemiology - genetics
Sweden - epidemiology
Young Adult
Abstract
A strong genetic influence by the MHC class II region has been reported in sarcoidosis, however in many studies with different results. This may possibly be caused by actual differences between distinct ethnic groups, too small sample sizes, or because of lack of accurate clinical subgrouping.
In this study we HLA typed a large patient population (n = 754) recruited from one single centre. Patients were sub-grouped into those with L?fgren's syndrome (LS) (n = 302) and those without (non-L?fgren's) (n = 452), and the majority of them were clinically classified into those with recovery within two years (resolving) and those with signs of disease for more than two years (non-resolving). PCR was used for determination of HLA-DRB1 alleles. Swedish healthy blood donors (n = 1366) served as controls.
There was a dramatic difference in the distribution of HLA alleles in LS compared to non-LS patients (p = 4 x 10(-36)). Most notably, DRB1*01, DRB1*03 and DRB1*14, clearly differed in LS and non-LS patients. In relation to disease course, DRB1*07, DRB1*14 and DRB1*15 generally associated with, while DRB1*01 and DRB1*03 protected against, a non-resolving disease. Interestingly, the clinical influence of DRB1*03 (good prognosis) dominated over that of DRB1*15 (bad prognosis).
We found several significant differences between LS and non-LS patients and we therefore suggest that genetic association studies in sarcoidosis should include a careful clinical characterisation and sub-grouping of patients, in order to reveal true genetic associations. This may be particularly accurate to do in the heterogeneous non-LS group of patients.
Notes
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PubMed ID
20187937 View in PubMed
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HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis.

https://arctichealth.org/en/permalink/ahliterature162294
Source
PLoS One. 2007;2(7):e664
Publication Type
Article
Date
2007
Author
Boel Brynedal
Kristina Duvefelt
Gudrun Jonasdottir
Izaura M Roos
Eva Akesson
Juni Palmgren
Jan Hillert
Author Affiliation
Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. boel.brynedal@ki.se
Source
PLoS One. 2007;2(7):e664
Date
2007
Language
English
Publication Type
Article
Keywords
DNA Primers - genetics
Gene Frequency
Genetic Linkage
Genetic Predisposition to Disease
HLA-A Antigens - genetics - immunology
HLA-DQ Antigens - genetics
HLA-DR Antigens - genetics - immunology
HLA-DRB1 Chains
Humans
Linkage Disequilibrium
Middle Aged
Multiple Sclerosis - epidemiology - genetics - immunology
Polymorphism, Single Nucleotide
Reference Values
Regression Analysis
Risk factors
Sweden
Abstract
A recent high-density linkage screen confirmed that the HLA complex contains the strongest genetic factor for the risk of multiple sclerosis (MS). In parallel, a linkage disequilibrium analysis using 650 single nucleotide polymorphisms (SNP) markers of the HLA complex mapped the entire genetic effect to the HLA-DR-DQ subregion, reflected by the well-established risk haplotype HLA-DRB1*15,DQB1*06. Contrary to this, in a cohort of 1,084 MS patients and 1,347 controls, we show that the HLA-A gene confers an HLA-DRB1 independent influence on the risk of MS (P = 8.4x10(-10)). This supports the opposing view, that genes in the HLA class I region indeed exert an additional influence on the risk of MS, and confirms that the class I allele HLA-A*02 is negatively associated with the risk of MS (OR = 0.63, P = 7x10(-12)) not explained by linkage disequilibrium with class II. The combination of HLA-A and HLA-DRB1 alleles, as represented by HLA-A*02 and HLA-DRB1*15, was found to influence the risk of MS 23-fold. These findings imply complex autoimmune mechanisms involving both the regulatory and the effector arms of the immune system in the triggering of MS.
Notes
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PubMed ID
17653284 View in PubMed
Less detail

Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles.

https://arctichealth.org/en/permalink/ahliterature115733
Source
PLoS One. 2013;8(3):e58352
Publication Type
Article
Date
2013
Author
Inger-Lise Mero
Marte W Gustavsen
Hanne S Sæther
Siri T Flåm
Pål Berg-Hansen
Helle B Søndergaard
Poul Erik H Jensen
Tone Berge
Anja Bjølgerud
Aslaug Muggerud
Jan H Aarseth
Kjell-Morten Myhr
Elisabeth G Celius
Finn Sellebjerg
Jan Hillert
Lars Alfredsson
Tomas Olsson
Annette Bang Oturai
Ingrid Kockum
Benedicte A Lie
Bettina Kulle Andreassen
Hanne F Harbo
Author Affiliation
Department of Neurology, Oslo University Hospital, Ullevål, and Department of Medical Genetics, University of Oslo, Oslo, Norway.
Source
PLoS One. 2013;8(3):e58352
Date
2013
Language
English
Publication Type
Article
Keywords
Adult
Alleles
Case-Control Studies
Denmark
Female
Gene Frequency
Genome-Wide Association Study
Genotype
HLA-DRB1 Chains - genetics
Humans
Male
Multiple Sclerosis - cerebrospinal fluid - epidemiology - genetics
Norway
Oligoclonal Bands - cerebrospinal fluid - genetics
Polymorphism, Single Nucleotide
Sweden
Abstract
The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n?=?2781) and OCB negative (n?=?292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p?=?5.7×10(-15)) and rs3817963 (p?=?5.7×10(-10)) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p?=?8.83×10(-7)). In HLA-DRB1 analyses HLA-DRB1*15:01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04:04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01:01 and HLA-DRB1*07:01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.
Notes
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PubMed ID
23472185 View in PubMed
Less detail

PDE4D and ALOX5AP genetic variants and risk for Ischemic Cerebrovascular Disease in Sweden.

https://arctichealth.org/en/permalink/ahliterature162265
Source
J Neurol Sci. 2007 Dec 15;263(1-2):113-7
Publication Type
Article
Date
Dec-15-2007
Author
Konstantinos Kostulas
Solveig Gretarsdottir
Vasilios Kostulas
Andrei Manolescu
Anna Helgadottir
Gudmar Thorleifsson
Larus J Gudmundsson
Unnur Thorsteinsdottir
Jeffrey R Gulcher
Kari Stefansson
Jan Hillert
Author Affiliation
Department of Neurology, Neuro-angiological Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Huddinge, Sweden. konstantinos.kostulas@karolinska.se
Source
J Neurol Sci. 2007 Dec 15;263(1-2):113-7
Date
Dec-15-2007
Language
English
Publication Type
Article
Keywords
5-Lipoxygenase-Activating Proteins
Aged
Aged, 80 and over
Carrier Proteins - genetics
Cerebrovascular Disorders - genetics
Cyclic Nucleotide Phosphodiesterases, Type 3 - genetics
Female
Gene Frequency
Genetic Variation - genetics
Genotype
Humans
Linkage Disequilibrium
Male
Membrane Proteins - genetics
Microsatellite Repeats - genetics
Middle Aged
Odds Ratio
Polymorphism, Single Nucleotide - genetics
Risk factors
Sweden
Abstract
Genetic variants in Phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP) have been shown to confer risk of Ischemic Cerebrovascular Disease (ICVD) in Iceland. We investigated whether these variants associate with ICVD in Sweden.
Previously published PDE4D and ALOX5AP gene variants were genotyped for cases (685) and controls (751). In PDE4D this consisted of SNP41, SNP45 and microsatellite AC008818-1 and in ALOX5AP four SNPs that define the HapA haplotype.
The PDE4D SNPs, showed a non-significant risk in the ICVD group which increased for the Large Artery Atherosclerosis subtype (SNP45: RR=1.43, P=0.063, SNP41: RR=1.57, P=0.018). The SNP haplotype GA (SNP45, SNP41) showed an increased risk for LAA (RR=1.58, P=0.016) and the combined LAA and Cardioembolism (CE) (RR=1.34, P=0.031) subgroups. As the SNPs are in strong LD, this haplotype corresponds to the complement of the protective haplotype in the Icelandic study. No allele of the microsatellite marker, showed association to stroke or any subtype and nor did the Icelandic PDE4D at-risk haplotype (GA0). We did not confirm the association between ALOX5AP HapA haplotype and ICVD, but a non-significant risk was observed in the LAA subtype.
Our PDE4D findings although non-significant considering the number of markers and phenotypes tested, are consistent with the association observed in the original study, with a trend observed in the whole ICVD group, which was strengthened in the stroke subtype LAA and the combined group of LAA and CE stroke. This supports the notion that PDE4D contributes to the risk of developing stroke.
PubMed ID
17655870 View in PubMed
Less detail

Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis.

https://arctichealth.org/en/permalink/ahliterature137236
Source
Brain. 2011 Mar;134(Pt 3):653-64
Publication Type
Article
Date
Mar-2011
Author
Anna Karin Hedström
Emilie Sundqvist
Maria Bäärnhielm
Nina Nordin
Jan Hillert
Ingrid Kockum
Tomas Olsson
Lars Alfredsson
Author Affiliation
Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden. anna.hedstrom@ki.se
Source
Brain. 2011 Mar;134(Pt 3):653-64
Date
Mar-2011
Language
English
Publication Type
Article
Keywords
Case-Control Studies
Community Health Planning
Confidence Intervals
Gene Frequency
Genetic Predisposition to Disease
Genotype
HLA-A Antigens - genetics
HLA-DR Antigens - genetics
HLA-DRB1 Chains
Humans
Incidence
Logistic Models
Models, Genetic
Multiple Sclerosis - epidemiology - etiology - genetics
Odds Ratio
Retrospective Studies
Risk factors
Smoking - adverse effects
Sweden - epidemiology
Abstract
Both genetic and environmental factors display low or modest associations with multiple sclerosis. Hypothetically, gene-environment interactions may exert much stronger effects. In this study, we investigated potential interactions between genetic risk factors and smoking in relation to risk of developing multiple sclerosis. A population-based case-control study involving incident cases of multiple sclerosis (843 cases, 1209 controls) was performed in Sweden. Cases and controls were classified according to their smoking status and human leukocyte antigen DRB1 as well as human leukocyte antigen A genotypes. Subjects with different genotypes and smoking habits were compared with regard to incidence of multiple sclerosis, by calculating odds ratios with 95% confidence intervals employing logistic regression. The potential interaction between different genotypes, as well as between genotype and smoking, was evaluated by calculating attributable proportion due to interaction. A significant interaction between two genetic risk factors, carriage of human leukocyte antigen DRB1*15 and absence of human leukocyte antigen A*02, was observed among smokers whereas such an interaction was absent among non-smokers. There were considerable differences in odds ratios between the various groups. Compared with non-smokers with neither of the genetic risk factors, the odds ratio was 13.5 (8.1-22.6) for smokers with both genetic risk factors. The odds ratio for smokers without genetic risk was 1.4 (0.9-2.1) and the odds ratio for non-smokers with both genetic risk factors was 4.9 (3.6-6.6). Among those with both genetic risk factors, smoking increased the risk by a factor of 2.8 in comparison with a factor of 1.4 among those without the genetic risk factors. The risk of developing multiple sclerosis associated with human leukocyte antigen genotypes may be strongly influenced by smoking status. The findings are consistent with our hypothesis that priming of the immune response in the lungs may subsequently lead to multiple sclerosis in genetically susceptible people.
Notes
Comment In: Brain. 2011 Mar;134(Pt 3):638-4021310724
Comment In: J Neurol. 2011 May;258(5):954-721512740
PubMed ID
21303861 View in PubMed
Less detail

Two HLA class I genes independently associated with multiple sclerosis.

https://arctichealth.org/en/permalink/ahliterature141784
Source
J Neuroimmunol. 2010 Sep 14;226(1-2):172-6
Publication Type
Article
Date
Sep-14-2010
Author
Jenny Link
Aslaug R Lorentzen
Ingrid Kockum
Kristina Duvefelt
Benedicte A Lie
Elisabeth G Celius
Hanne F Harbo
Jan Hillert
Boel Brynedal
Author Affiliation
Karolinska Institutet, Department of Clinical Neuroscience, CMM L8:00, SE-17176 Stockholm, Sweden. jenny.link@ki.se
Source
J Neuroimmunol. 2010 Sep 14;226(1-2):172-6
Date
Sep-14-2010
Language
English
Publication Type
Article
Keywords
Cohort Studies
Female
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study - methods
HLA-A2 Antigen - genetics
HLA-C Antigens - genetics
HLA-DR Antigens - genetics
HLA-DRB1 Chains
Humans
Logistic Models
Male
Middle Aged
Multiple Sclerosis - genetics
Norway
Risk factors
Sweden
Abstract
The risk of multiple sclerosis (MS) is influenced by HLA-DRB1, while protective effects have been proposed for HLA-A*02 and HLA-C*05. Our aim was to further understand the role of HLA class I in MS through a comprehensive investigation.
1529 MS patients and 1814 controls from Sweden and Norway were genotyped for HLA-DRB1, HLA-A, and HLA-C. Simultaneous analysis of all alleles while adjusting for confounding was achieved using logistic regression.
We observed independent effects of all three genes. We confirm the HLA-A*02 (OR=0.73, p=9.2 x 10(-4)) association and report a novel effect of HLA-C*08 (OR=1.85, p=0.0093).
The HLA class I region contains two factors modulating MS risk, characterized by independent associations with HLA-A and HLA-C.
PubMed ID
20678810 View in PubMed
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Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis.

https://arctichealth.org/en/permalink/ahliterature162230
Source
Nat Genet. 2007 Sep;39(9):1108-13
Publication Type
Article
Date
Sep-2007
Author
Frida Lundmark
Kristina Duvefelt
Ellen Iacobaeus
Ingrid Kockum
Erik Wallström
Mohsen Khademi
Annette Oturai
Lars P Ryder
Janna Saarela
Hanne F Harbo
Elisabeth G Celius
Hugh Salter
Tomas Olsson
Jan Hillert
Author Affiliation
Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital-Huddinge, SE-141 86 Stockholm, Sweden.
Source
Nat Genet. 2007 Sep;39(9):1108-13
Date
Sep-2007
Language
English
Publication Type
Article
Keywords
Adult
Case-Control Studies
Denmark
Female
Finland
Gene Expression
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation
Genotype
Humans
Interleukin-7 - genetics
Leukocytes, Mononuclear - cytology - metabolism
Linkage Disequilibrium
Logistic Models
Male
Middle Aged
Multiple Sclerosis - cerebrospinal fluid - genetics
Norway
Polymorphism, Single Nucleotide
RNA, Messenger - genetics - metabolism
Receptors, Interleukin-7 - genetics
Reverse Transcriptase Polymerase Chain Reaction
Risk factors
Sweden
Abstract
Multiple sclerosis is a chronic, often disabling, disease of the central nervous system affecting more than 1 in 1,000 people in most western countries. The inflammatory lesions typical of multiple sclerosis show autoimmune features and depend partly on genetic factors. Of these genetic factors, only the HLA gene complex has been repeatedly confirmed to be associated with multiple sclerosis, despite considerable efforts. Polymorphisms in a number of non-HLA genes have been reported to be associated with multiple sclerosis, but so far confirmation has been difficult. Here, we report compelling evidence that polymorphisms in IL7R, which encodes the interleukin 7 receptor alpha chain (IL7Ralpha), indeed contribute to the non-HLA genetic risk in multiple sclerosis, demonstrating a role for this pathway in the pathophysiology of this disease. In addition, we report altered expression of the genes encoding IL7Ralpha and its ligand, IL7, in the cerebrospinal fluid compartment of individuals with multiple sclerosis.
Notes
Comment In: Nat Genet. 2007 Sep;39(9):1053-417728770
PubMed ID
17660816 View in PubMed
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