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Evidence for genetic association and interaction between the TYK2 and IRF5 genes in systemic lupus erythematosus.

https://arctichealth.org/en/permalink/ahliterature149961
Source
J Rheumatol. 2009 Aug;36(8):1631-8
Publication Type
Article
Date
Aug-2009
Author
Anna Hellquist
Tiina M Järvinen
Sari Koskenmies
Marco Zucchelli
Christina Orsmark-Pietras
Linda Berglind
Jaana Panelius
Taina Hasan
Heikki Julkunen
Mauro D'Amato
Ulpu Saarialho-Kere
Juha Kere
Author Affiliation
Department of Biosciences and Nutrition, Karolinska Institutet, Sweden.
Source
J Rheumatol. 2009 Aug;36(8):1631-8
Date
Aug-2009
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Antigens, CD - genetics
Apoptosis Regulatory Proteins - genetics
CTLA-4 Antigen
Child
Epistasis, Genetic - immunology
Female
Finland - epidemiology
Genetic Predisposition to Disease - epidemiology
Genotype
Humans
Interferon Regulatory Factors - genetics
Interferon Type I - immunology
Lupus Erythematosus, Systemic - epidemiology - genetics - immunology
Male
Middle Aged
Nod2 Signaling Adaptor Protein - genetics
Polymorphism, Single Nucleotide
Programmed Cell Death 1 Receptor
Receptors, IgG - genetics
Risk factors
TYK2 Kinase - genetics
Young Adult
Abstract
Several candidate genes have been implicated in susceptibility for systemic lupus erythematosus (SLE), a complex autoimmune disease. The proposed genes include members of the type I interferon (IFN) pathway and genes involved in immunological defense functions. Our aim was to systematically replicate 6 such genes, TYK2, IRF5, CTLA4, PDCD1, FCGR2A, and NOD2.
Single-nucleotide polymorphisms in TYK2, IRF5, CTLA4, PDCD1, FCGR2A, and NOD2 were genotyped in 277 SLE patients and 356 healthy controls from Finland, giving a power of 42%-70% for different genes at published allele frequencies.
Significant association was seen for rs2304256 (p = 0.0001) and rs12720270 (p = 0.0031) in TYK2 and rs10954213 (p = 0.0043) in IRF5 in our samples, but not for the other genes. We found evidence for genetic interaction (p = 0.014) between rs2304256 in TYK2 and rs10954213 in IRF5, both members of the type I IFN pathway, strengthening the role of the type I IFN pathway in the pathogenesis of SLE.
The IFN pathway genes IRF5 and TYK2 may act epistatically in increasing risk for SLE, but our lack of replication does not exclude effects of the other genes studied.
Notes
Comment In: J Rheumatol. 2010 Mar;37(3):676-7; author reply 67820197570
Comment In: J Rheumatol. 2011 Jan;38(1):177-821196586
PubMed ID
19567624 View in PubMed
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PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease.

https://arctichealth.org/en/permalink/ahliterature150812
Source
Inflamm Bowel Dis. 2009 Oct;15(10):1562-9
Publication Type
Article
Date
Oct-2009
Author
Marco Zucchelli
Leif Torkvist
Francesca Bresso
Jonas Halfvarson
Anna Hellquist
Francesca Anedda
Ghazaleh Assadi
Gunnar B Lindgren
Monika Svanfeldt
Martin Janson
Colin L Noble
Sven Pettersson
Maarit Lappalainen
Paulina Paavola-Sakki
Leena Halme
Martti Färkkilä
Ulla Turunen
Jack Satsangi
Kimmo Kontula
Robert Löfberg
Juha Kere
Mauro D'Amato
Author Affiliation
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Source
Inflamm Bowel Dis. 2009 Oct;15(10):1562-9
Date
Oct-2009
Language
English
Publication Type
Article
Keywords
Adult
Case-Control Studies
Cohort Studies
Colitis, Ulcerative - genetics
Crohn Disease - genetics
Female
Finland
Genotype
Humans
Male
Middle Aged
NF-kappa B - genetics - metabolism
Nod2 Signaling Adaptor Protein - genetics - metabolism
Polymorphism, Single Nucleotide - genetics
Sweden
Symporters - genetics
Abstract
Human polymorphisms affecting gut epithelial barrier and interactions with bacteria predispose to the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC). The intestinal transporter PepT1, encoded by the SLC15A1 gene, mediates intracellular uptake of bacterial products that can induce inflammation and NF-kappaB activation upon binding to NOD2, a protein often mutated in CD. Hence, we tested SLC15A1 polymorphisms for association with IBD.
Twelve SLC15A1 single nucleotide polymorphisms (SNPs) were genotyped in 1783 individuals from 2 cohorts of Swedish and Finnish IBD patients and controls. An in vitro system was set up to evaluate the potential impact of SLC15A1 polymorphism on PepT1 transporter function by quantification of NOD2-mediated activation of NF-kappaB.
The common allele (C) of a coding polymorphism (rs2297322, Ser117Asn) was associated with CD susceptibility both in Sweden and in Finland, but with genetic effects in opposite directions (risk and protection, respectively). The best evidence of association was found in both populations when the analysis was performed on individuals not carrying NOD2 common risk alleles (Sweden allelic P = 0.0007, OR 1.97, 95% confidence interval [CI] 1.34-2.92; Finland genotype P = 0.0013, OR 0.63, 95% CI 0.44-0.90). The PepT1 variant encoded by the C allele (PepT1-Ser117) was associated with reduced signaling downstream of NOD2 (P
PubMed ID
19462432 View in PubMed
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Polymorphisms of the ITGAM gene confer higher risk of discoid cutaneous than of systemic lupus erythematosus.

https://arctichealth.org/en/permalink/ahliterature138659
Source
PLoS One. 2010;5(12):e14212
Publication Type
Article
Date
2010
Author
Tiina M Järvinen
Anna Hellquist
Sari Koskenmies
Elisabet Einarsdottir
Jaana Panelius
Taina Hasan
Heikki Julkunen
Leonid Padyukov
Marika Kvarnström
Marie Wahren-Herlenius
Filippa Nyberg
Mauro D'Amato
Juha Kere
Ulpu Saarialho-Kere
Author Affiliation
Department of Dermatology, Institute of Clinical Medicine and Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Source
PLoS One. 2010;5(12):e14212
Date
2010
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Aged, 80 and over
Antigens, CD11b - genetics
Case-Control Studies
Child
Child, Preschool
Cohort Studies
Female
Finland
Genetic markers
Genetic Predisposition to Disease
Genotype
Humans
Infant
Lupus Erythematosus, Discoid - genetics
Lupus Erythematosus, Systemic - genetics
Male
Middle Aged
Odds Ratio
Polymorphism, Genetic
Risk
Sweden
Abstract
Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear.
To specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus. SLE patients were further subdivided by the presence or absence of discoid rash and renal involvement. In addition, 235 Finnish and Swedish patients positive for Ro/SSA-autoantibodies were included in a subphenotype analysis. Analysis of the ITGAM coding variant rs1143679 showed highly significant association to DLE in patients without signs of systemic disease (P-value ?=?4.73?10(-11), OR ?=?3.20, 95% CI ?=?2.23-4.57). Significant association was also detected to SLE patients (P-value ?=?8.29?10(-6), OR ?=?2.14, 95% CI ?=?1.52-3.00), and even stronger association was found when stratifying SLE patients by presence of discoid rash (P-value ?=?3.59?10(-8), OR ?=?3.76, 95% CI ?=?2.29-6.18).
We propose ITGAM as a novel susceptibility gene for cutaneous DLE. The risk effect is independent of systemic involvement and has an even stronger genetic influence on the risk of DLE than of SLE.
Notes
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PubMed ID
21151989 View in PubMed
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Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus.

https://arctichealth.org/en/permalink/ahliterature148515
Source
Exp Dermatol. 2010 Feb;19(2):123-31
Publication Type
Article
Date
Feb-2010
Author
Tiina M Järvinen
Anna Hellquist
Sari Koskenmies
Elisabet Einarsdottir
Lotta L E Koskinen
Leila Jeskanen
Linda Berglind
Jaana Panelius
Taina Hasan
Annamari Ranki
Juha Kere
Ulpu Saarialho-Kere
Author Affiliation
Department of Dermatology, Institute of Clinical Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Source
Exp Dermatol. 2010 Feb;19(2):123-31
Date
Feb-2010
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Aged, 80 and over
Antigens, CD - genetics
CTLA-4 Antigen
Case-Control Studies
Female
Finland
Genetic Predisposition to Disease
Genotype
Humans
Interferon Regulatory Factors - genetics
Lupus Erythematosus, Discoid - genetics
Male
Middle Aged
Polymorphism, Single Nucleotide
TYK2 Kinase - genetics
Up-Regulation
Young Adult
Abstract
Lupus erythematosus (LE) is a heterogeneous disease ranging from skin-restricted manifestations to a progressive multisystem disease. The specific skin lesions include chronic cutaneous, subacute cutaneous and acute cutaneous LE. Both genetic and environmental factors are involved in the development of LE. However, reports on the genetic background of cutaneous lupus erythematosus (CLE) forms, namely discoid (DLE) and subacute cutaneous lupus erythematosus (SCLE), are sparse. We investigated whether the known systemic LE (SLE) susceptibility genes also predispose to CLE. Altogether, 219 Finnish patients with DLE or SCLE and 356 healthy controls were recruited. Single nucleotide polymorphisms tagging reported risk genes were genotyped. Tyrosine kinase 2 (TYK2) rs2304256 was associated with increased risk of DLE (P = 0.012, OR = 1.47, 95% CI = 1.01-1.98). Expression of TYK2 was demonstrated by immunohistochemistry in macrophage-like cells and neutrophils and interferon regulatory factor 5 (IRF5) in macrophage- and fibroblast-like cells of DLE, SCLE and SLE skin. IRF5 rs10954213 showed association with DLE (P = 0.017, OR = 1.40, 95% CI = 1.06-1.86) and SCLE (P = 0.022, OR = 1.87, 95% CI = 1.09-3.21). A haplotype of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) showed association with DLE (P = 0.0065, OR = 2.51, 95% CI = 1.25-5.04). Our results show that the TYK2, IRF5 and CTLA4 genes previously associated with SLE also confer risk for DLE and SCLE, suggesting that different LE subphenotypes may share pathogenetic pathways.
PubMed ID
19758313 View in PubMed
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Variation in STAT4 is associated with systemic lupus erythematosus in a Finnish family cohort.

https://arctichealth.org/en/permalink/ahliterature148836
Source
Ann Rheum Dis. 2010 May;69(5):883-6
Publication Type
Article
Date
May-2010
Author
Anna Hellquist
Johanna K Sandling
Marco Zucchelli
Sari Koskenmies
Heikki Julkunen
Mauro D'Amato
Sophie Garnier
Ann-Christine Syvänen
Juha Kere
Author Affiliation
Department of Biosciences and Nutrition, Karolinska Institutet, Hälsovägen 7-9, S-14157 Huddinge, Sweden.
Source
Ann Rheum Dis. 2010 May;69(5):883-6
Date
May-2010
Language
English
Publication Type
Article
Keywords
Cohort Studies
Finland
Genetic markers
Genetic Predisposition to Disease
Haplotypes
Humans
Linkage Disequilibrium
Lupus Erythematosus, Systemic - genetics
Phenotype
Polymorphism, Single Nucleotide
STAT4 Transcription Factor - genetics
Abstract
To investigate whether 10 single nucleotide polymorphisms (SNPs) and haplotypes in the STAT4 gene, previously associated with systemic lupus erythematosus (SLE) in a Swedish case-control cohort, are also associated with SLE risk in a Finnish SLE family cohort.
Genotyping was performed in 192 Finnish families, with 237 affected subjects and their healthy relatives, using the SNPstream genotyping system.
Transmission disequilibrium test analysis provided the strongest signal of association for two linked SNPs: rs7582694 (p=0.002, OR=2.57) and rs10181656 (p=0.001, OR=2.53). Haplotype association analysis using a sliding window approach was also performed and showed that the strongest association signal originates from SNPs in intron 3 of STAT4.
The main association signal for STAT4 with SLE previously reported in Caucasians is the same in the Finnish population. This is the first study that confirms the association of STAT4 with SLE in a family cohort.
PubMed ID
19717398 View in PubMed
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