Taken together, our results uncovered a mechanistic insight of a noncoding functional variant acting as an allele-specific distal enhancer to directly modulate IRF5 expression, which might obligate in understanding of complex genetic architectures of SLE and SSc pathogenesis.
This meta-analysis confirms that the IRF5rs2004640 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.
We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively).
It has become clear that IRF5 contributes to the pathogenesis of many inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus.
Studies of IRF5 expression and function in genotyped healthy donors will address the question of whether IRF5 dysregulation in SLE is driven by genetic or non-genetic factors.
The current study suggested that individuals carrying rs2004640 T allele correlated with a high risk of SLE, and the IRF5rs2004640 polymorphism was associated with SLE susceptibility.
However, IRF5 and TNFAIP3 gene alleles, established risk factors for SLE in populations of European and Asian ancestry, are not significantly associated with SLE in this cohort.
Therefore, IRF5 is an important therapeutic target of SLE, and selective suppression of its activity and expression may potentially lead to the development of new therapies.
Here, we evaluated the major SLE risk haplotype of IRF5 on the functional attributes of freshly isolated B cells from human subjects who do not have evidence of SLE or other forms of autoimmunity.
Genome-wide association studies have implied the association of IRF5 with several autoimmune diseases, including systemic lupus erythematosus (SLE), Sjogren's syndrome, inflammatory bowel disease and multiple sclerosis.
Subjects and methods Typing of interferon regulatory factor 5rs10954213, rs2004640 and rs2280714 polymorphisms were done using polymerase chain reaction-restriction fragment length polymorphism for 100 children with SLE and 100 matched healthy controls.
This study demonstrates the association of IRF5 with an increased susceptibility for SLE in the population of Crete and emphasizes the association of the Neanderthal-derived IRF5 haplotype with SLE susceptibility.
<i>IRF5</i> genetic risk has been widely replicated in systemic lupus erythematosus (SLE), and loss of <i>Irf5</i> ameliorates disease in murine lupus models, in part, through the lack of pathogenic autoantibody secretion.
Interferon regulatory factor-5 (IRF5), a transcription factor critical for the induction of innate immune responses, contributes to the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE) in humans and mice.
The IRF5-TNPO3 region showed the strongest association and largest OR for SLE (rs10488631: genomic control-adjusted P [Pgcadj ] = 2.61 × 10(-29), OR 2.12 [95% CI 1.88-2.39]), followed by HLA class II on the DQA2-DQB1 loci (rs9275572: Pgcadj = 1.11 × 10(-16), OR 1.62 [95% CI 1.46-1.80] and rs9271366: Pgcadj = 6.46 × 10(-12), OR 2.06 [95% CI 1.71-2.50]).
The IRF5rs2070197 polymorphism was identified as risk factors for SLE in Caucasian populations (OR 1.82, 95 % CI 1.70-1.96), but it had no effects (monomorphic) in Asians.