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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Interaction between the STAT4 rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus

Reid, Sarah (författare): Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Reumatologi,Science for Life Laboratory, SciLifeLab

Hagberg, Niklas, 1977- (författare): Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Reumatologi,Science for Life Laboratory, SciLifeLab

Sandling, Johanna K. (författare): Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Science for Life Laboratory, SciLifeLab,Reumatologi

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Alexsson, Andrei (författare): 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

Pucholt, Pascal, Dr, 1985- (författare): Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Reumatologi,Science for Life Laboratory, SciLifeLab

Sjöwall, Christopher (författare): 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.

Lerang, Karoline (författare): Oslo university hospital,Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway.

Jönsen, Andreas (författare): 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.

Gunnarsson, Iva (författare): Karolinska Institutet,Karolinska Institute,Karolinska University Hospital,Karolinska Inst, Div Rheumatol, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.

Syvänen, Ann-Christine, 1950- (författare): Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Science for Life Laboratory, SciLifeLab,Reumatologi

Troldborg, Anne Margrethe (författare): Aarhus University Hospital,Aarhus University,Aarhus Univ Hosp, Dept Rheumatol, Aarhus, Denmark.;Aarhus Univ, Dept Biomed, Aarhus, Denmark.

Voss, Anne (författare): Odense University Hospital,Odense Univ Hosp, Dept Rheumatol, Odense, Denmark.

Bengtsson, Anders A. (författare): Lund University,Lunds universitet,Lund SLE Research Group,Forskargrupper vid Lunds universitet,Lund University Research Groups,Skåne University Hospital

Molberg, Øyvind (författare): Oslo university hospital,Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway.

Jacobsen, Søren (författare): Copenhagen University Hospital,University of Copenhagen,Rigshosp, Copenhagen Univ Hosp, Ctr Rheumatol & Spine Dis, Copenhagen, Denmark.;Univ Copenhagen, Inst Clin Med, Copenhagen, Denmark.

Svenungsson, Elisabet (författare): Karolinska Institutet,Karolinska Institute,Karolinska University Hospital,Karolinska Inst, Div Rheumatol, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.

Rönnblom, Lars (författare): Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Reumatologi,Science for Life Laboratory, SciLifeLab

Leonard, Dag, 1975- (författare): Uppsala universitet,Uppsala University,Uppsala Univ, Sweden,Reumatologi,Science for Life Laboratory, SciLifeLab

Molberg, O (författare)

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2021-03-25
2021
Engelska 7 s.
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 80:9, s. 1183-1189

Relaterad länk:: http://dx.doi.org/10... (free); visa fler...; https://ard.bmj.com/...; https://liu.diva-por... (primary) (Raw object); https://doi.org/10.1...; https://uu.diva-port... (primary) (Raw object); https://lup.lub.lu.s...; https://doi.org/10.1...; https://urn.kb.se/re...; https://urn.kb.se/re...; http://kipublication...; visa färre...

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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.

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Reumatologi och ...

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Av lärosätet: Lunds universitet; Linköpings universitet; Uppsala universitet; Karolinska Institutet

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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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