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

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2021-09-01 Epub Date: 2021-03-25 DOI:10.1136/annrheumdis-2020-219727

Sarah Reid, Niklas Hagberg, Johanna K Sandling, Andrei Alexsson, Pascal Pucholt, Christopher Sjöwall, Karoline Lerang, Andreas Jönsen, Iva Gunnarsson, Ann-Christine Syvänen, Anne Margrethe Troldborg, Anne Voss, Anders A Bengtsson, Øyvind Molberg, Søren Jacobsen, Elisabet Svenungsson, Lars Rönnblom, Dag Leonard

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Abstract

Objective: To investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations.

Methods: Patients with SLE (n_{discovery cohort}=776, n_{replication 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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STAT4 rs11889341(T)风险等位基因与吸烟之间的相互作用会增加系统性红斑狼疮患者心肌梗死和肾炎的风险。

目的:探讨遗传因素对吸烟相关性系统性红斑狼疮(SLE)发病风险的影响。方法:采用200K免疫芯片单核苷酸多态性(SNP)阵列(Illumina)和定制阵列对SLE患者(未发现队列=776，未复制队列=836)进行基因分型。分析了60个与SLE相关的snp (p-8)。在体外刺激的健康对照(n=45)外周血单个核细胞中评估了信号换能器和转录激活子4 (STAT4)的激活。结果:在发现队列中，吸烟与心肌梗死(MI)相关(OR 1.96 (95% CI 1.09至3.55))，携带rs11889341 STAT4风险等位基因(OR 2.72 (95% CI 1.24至6.00))或两个风险等位基因(OR 8.27 (95% CI 1.48至46.27))的患者的影响更大。携带风险等位基因的吸烟者患肾炎的风险也增加(OR 1.47 (95% CI 1.06 - 2.03))。在重复队列中，携带风险等位基因的吸烟者患心肌梗死的风险较高，并且证实了STAT4风险等位基因与吸烟者肾炎之间的关联(OR分别为6.19 (95% CI 1.29 ~ 29.79)和1.84 (95% CI 1.05 ~ 3.29))。吸烟和STAT4风险等位基因之间的相互作用导致心肌梗死(OR 2.14 (95% CI 1.01至4.62))和肾炎(OR 1.53 (95% CI 1.08至2.17))的风险进一步增加，其中54%(心肌梗死)和34%(肾炎)的风险可归因于相互作用。吸烟者中白细胞介素-12诱导的CD8+ T细胞中STAT4磷酸化水平高于非吸烟者(平均几何荧光强度1063比565,p=0.0063)。最后，IL12A rs564799风险等位基因在两个队列中显示与心肌梗死相关(OR分别为1.53 (95% CI 1.01至2.31)和2.15 (95% CI 1.08至4.26)。结论:STAT4风险基因变异存在时吸烟似乎会增加SLE患者心肌梗死和肾炎的风险。我们的研究结果还强调了il - 12- stat4通路在sle心血管发病率中的作用。

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ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

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