The risks for myocardial infarction (MI) and lupus nephritis (LN) are increased among patients with systemic lupus erythematosus (SLE) who smoke and carry specific genetic risk factors, investigators report. 

In a cohort of 776 patients with SLE, ever-smokers (including those who currently smoked or had a history of smoking) had significant 2.0-fold increased odds of MI compared with never-smokers. The effect was more pronounced among smokers with 1 or 2 inherited rs11889341 risk alleles in the signal transducer and activator of transcription 4 (STAT4) gene, however. These patients had 2.7- and 8.3-fold increased odds of MI, respectively, compared with never-smokers, Lars Rönnblom, MD, of Uppsala University in Uppsala, Sweden, and colleagues reported in Annals of the Rheumatic Diseases. Smokers carrying the risk allele also had 1.5-fold increased odds of developing LN. In a replication cohort of 836 patients with SLE, smokers with the risk allele had 6.2- and 1.8-fold increased odds of MI and LN, respectively.

Interaction between the STAT4 risk allele and smoking multiplied the odds of MI and LN by 2.1- and 1.5-fold, respectively, with 54% and 34% of the increased risk, respectively, attributable to the interaction, Dr Rönnblom’s team reported. They confirmed that the probabilities of myocardial infarction and LN were independent from each other. 

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The interleukin-12-STAT4 pathway may be responsible for the cardiovascular comorbidities in SLE, according to the investigators. Smoking enhanced interleukin-12-induced phosphorylation of STAT4 in CD8+ T cells (mean geometric fluorescence intensity: 1063 vs 565 in nonsmokers). Patients with the interleukin-12A rs564799 risk allele had 1.5- and 2.2-fold increased odds of MI in the 2 cohorts, respectively. Patients with 2 risk alleles of both STAT4 and IL12A had significant 7.2-fold increased odds of MI compared with patients without this combination of risk alleles.

With respect to clinical implications, these findings suggest that genetic profiling of patients with SLE may be useful for predicting comorbidities of the disease, understanding the influence of environmental factors, and targeting smoking cessation interventions, according to Dr Rönnblom’s team.


Reid S, Hagberg N, Sandling JK, et al. Interaction between the STAT4 rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus. Published online March 25, 2021. Ann Rheum Dis. doi:10.1136/annrheumdis-2020-219727