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Interaction between...
Interaction between the STAT4 rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus
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- Reid, Sarah (author)
- Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Reumatologi,Science for Life Laboratory, SciLifeLab
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- Hagberg, Niklas, 1977- (author)
- Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Reumatologi,Science for Life Laboratory, SciLifeLab
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- Sandling, Johanna K. (author)
- Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Science for Life Laboratory, SciLifeLab,Reumatologi
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- Alexsson, Andrei (author)
- Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Rheumatol, Lund, Sweden.,Reumatologi,Science for Life Laboratory, SciLifeLab
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- Pucholt, Pascal, Dr, 1985- (author)
- Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Reumatologi,Science for Life Laboratory, SciLifeLab
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- Sjöwall, Christopher (author)
- Linköpings universitet,Linköping University,Avdelningen för inflammation och infektion,Medicinska fakulteten,Region Östergötland, Reumatologiska kliniken i Östergötland,Linköping Univ, Div Inflammat & Infect, Dept Biomed & Clin Sci, Linköping, Sweden.
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- Lerang, Karoline (author)
- Oslo university hospital,Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway.
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- Jönsen, Andreas (author)
- Lund University,Lunds universitet,Lund SLE Research Group,Forskargrupper vid Lunds universitet,Lund University Research Groups,Skåne University Hospital,Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Rheumatol, Lund, Sweden.
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- Gunnarsson, Iva (author)
- Karolinska Institutet,Karolinska Institute,Karolinska University Hospital,Karolinska Inst, Div Rheumatol, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.
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- Syvänen, Ann-Christine, 1950- (author)
- Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Science for Life Laboratory, SciLifeLab,Reumatologi
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- Troldborg, Anne Margrethe (author)
- Aarhus University,Aarhus University Hospital,Aarhus Univ Hosp, Dept Rheumatol, Aarhus, Denmark.;Aarhus Univ, Dept Biomed, Aarhus, Denmark.
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- Voss, Anne (author)
- Odense University Hospital,Odense Univ Hosp, Dept Rheumatol, Odense, Denmark.
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- Bengtsson, Anders A. (author)
- Lund University,Lunds universitet,Lund SLE Research Group,Forskargrupper vid Lunds universitet,Lund University Research Groups,Skåne University Hospital
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- Molberg, Øyvind (author)
- Oslo university hospital,Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway.
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- Jacobsen, Søren (author)
- University of Copenhagen,Copenhagen University Hospital,Rigshosp, Copenhagen Univ Hosp, Ctr Rheumatol & Spine Dis, Copenhagen, Denmark.;Univ Copenhagen, Inst Clin Med, Copenhagen, Denmark.
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- Svenungsson, Elisabet (author)
- Karolinska Institutet,Karolinska Institute,Karolinska University Hospital,Karolinska Inst, Div Rheumatol, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.
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- Rönnblom, Lars (author)
- Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Reumatologi,Science for Life Laboratory, SciLifeLab
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- Leonard, Dag, 1975- (author)
- Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Reumatologi,Science for Life Laboratory, SciLifeLab
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Molberg, O (author)
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(creator_code:org_t)
- 2021-03-25
- 2021
- English 7 s.
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 80:9, s. 1183-1189
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Abstract
Subject headings
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- Objective: To investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations. Methods: Patients with SLE (ndiscovery cohort=776, nreplication cohort=836) were genotyped using the 200K Immunochip single nucleotide polymorphisms (SNP) Array (Illumina) and a custom array. Sixty SNPs with SLE association (p<5.0×10-8) were analysed. Signal transducer and activator of transcription 4 (STAT4) activation was assessed in in vitro stimulated peripheral blood mononuclear cells from healthy controls (n=45). Results: In the discovery cohort, smoking was associated with myocardial infarction (MI) (OR 1.96 (95% CI 1.09 to 3.55)), with a greater effect in patients carrying any rs11889341 STAT4 risk allele (OR 2.72 (95% CI 1.24 to 6.00)) or two risk alleles (OR 8.27 (95% CI 1.48 to 46.27)). Smokers carrying the risk allele also displayed an increased risk of nephritis (OR 1.47 (95% CI 1.06 to 2.03)). In the replication cohort, the high risk of MI in smokers carrying the risk allele and the association between the STAT4 risk allele and nephritis in smokers were confirmed (OR 6.19 (95% CI 1.29 to 29.79) and 1.84 (95% CI 1.05 to 3.29), respectively). The interaction between smoking and the STAT4 risk allele resulted in further increase in the risk of MI (OR 2.14 (95% CI 1.01 to 4.62)) and nephritis (OR 1.53 (95% CI 1.08 to 2.17)), with 54% (MI) and 34% (nephritis) of the risk attributable to the interaction. Levels of interleukin-12-induced phosphorylation of STAT4 in CD8+ T cells were higher in smokers than in non-smokers (mean geometric fluorescence intensity 1063 vs 565, p=0.0063). Lastly, the IL12A rs564799 risk allele displayed association with MI in both cohorts (OR 1.53 (95% CI 1.01 to 2.31) and 2.15 (95% CI 1.08 to 4.26), respectively). Conclusions: Smoking in the presence of the STAT4 risk gene variant appears to increase the risk of MI and nephritis in SLE. Our results also highlight the role of the IL12-STAT4 pathway in SLE-cardiovascular morbidity.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
Keyword
- cardiovascular diseases
- genetic
- lupus erythematosus
- lupus nephritis
- polymorphism
- smoking
- systemic
Publication and Content Type
- art (subject category)
- ref (subject category)
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Reid, Sarah
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Hagberg, Niklas, ...
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Sandling, Johann ...
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Alexsson, Andrei
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Pucholt, Pascal, ...
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Sjöwall, Christo ...
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Lerang, Karoline
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Jönsen, Andreas
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Gunnarsson, Iva
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Syvänen, Ann-Chr ...
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Troldborg, Anne ...
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Voss, Anne
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Bengtsson, Ander ...
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Molberg, Øyvind
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Jacobsen, Søren
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Svenungsson, Eli ...
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Rönnblom, Lars
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Leonard, Dag, 19 ...
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Molberg, O
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Rheumatology and ...
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Annals of the Rh ...
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Lund University
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Linköping University
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Uppsala University
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Karolinska Institutet