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

Medientyp: E-Artikel
Titel: Interaction between the STAT4 rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus
Beteiligte: Reid, Sarah; Hagberg, Niklas; Sandling, Johanna K; Alexsson, Andrei; Pucholt, Pascal; Sjöwall, Christopher; Lerang, Karoline; Jönsen, Andreas; Gunnarsson, Iva; Syvänen, Ann-Christine; Troldborg, Anne Margrethe; Voss, Anne; Bengtsson, Anders A; Molberg, Øyvind; Jacobsen, Søren; Svenungsson, Elisabet; Rönnblom, Lars; Leonard, Dag
Erschienen: BMJ, 2021
Erschienen in: Annals of the Rheumatic Diseases
Sprache: Englisch
DOI: 10.1136/annrheumdis-2020-219727
ISSN: 0003-4967; 1468-2060
Schlagwörter: General Biochemistry, Genetics and Molecular Biology ; Immunology ; Immunology and Allergy ; Rheumatology
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Beschreibung: <jats:sec><jats:title>Objective</jats:title><jats:p>To investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Patients with SLE (n<jats:sub>discovery cohort</jats:sub>=776, n<jats:sub>replication cohort</jats:sub>=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<jats:sup>−8</jats:sup>) were analysed. Signal transducer and activator of transcription 4 (STAT4) activation was assessed in <jats:italic>in vitro</jats:italic> stimulated peripheral blood mononuclear cells from healthy controls (n=45).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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 <jats:italic>STAT4</jats:italic> 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)).</jats:p><jats:p>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 <jats:italic>STAT4</jats:italic> 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).</jats:p><jats:p>The interaction between smoking and the <jats:italic>STAT4</jats:italic> 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).</jats:p><jats:p>Lastly, the <jats:italic>IL12A</jats:italic> 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).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Smoking in the presence of the <jats:italic>STAT4</jats:italic> 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.</jats:p></jats:sec>

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