Abstract
IntroductionLiver X receptors are established sensors of lipid and cholesterol homeostasis. Recent studies have reported that these receptors are involved in the regulation of inflammation and immune responses. We attempted to identify single nucleotide polymorphisms (SNPs) of the NR1H3 gene associated with the susceptibility to systemic lupus erythematosus (SLE).MethodsSNPs were genotyped using SNaPSHOT assay in 300 Korean patients with SLE and 217 normal controls (NC), and in replication samples (160 SLE patients and 143 NC). Also, the functional effects of NR1H3 gene promoter polymorphisms were analyzed using a luciferase assay, real-time polymerase chain reaction, B cell proliferation assay and an electrophoretic mobility shift assay.ResultsWe identified five polymorphisms: -1851 T > C (rs3758673), -1830 T > C (rs3758674), -1003 G > A (new), -840 C > A (rs61896015) and -115 G > A (rs12221497). There was a significant and reproducible difference in the -1830 T > C, -1003 G > A and -115 G > A polymorphisms between the SLE and the NC. Luciferase activity of the structure containing -1830 C was less enhanced compared to the structure containing -1830 T in basal, GW3965 and T0901317 treated Hep3B cells (P = 0.009, P = 0.034 and P <0.001, respectively). Proliferation of the -1830 TC type was increased compared to the -1830 TT type in basal, GW3965 and T0901317 treated B cells from SLE patients (P = 0.011, P = 0.040 and P = 0.017, respectively). Transcription factor GATA-3 preferentially bound the -1830 T allele in the promoter.ConclusionsNR1H3 genetic polymorphisms may be associated with disease susceptibility and clinical manifestations of SLE. Specifically, -1830 T > C polymorphism within NR1H3 promoter region may be involved in regulation of NR1H3 expression.
Highlights
Liver X receptors are established sensors of lipid and cholesterol homeostasis
The antiinflammatory effect of Liver X receptor (LXR) was first described in a study that demonstrated that LXR activation attenuated Escherichia coli- or lipopolysaccharide (LPS)-induced expression of pro-inflammatory molecules including IL-6, inflammatory nitric oxide synthase and cyclooxygenase-2 in macrophages from wild type mice, but not LXR null mice [10]
In our luciferase assay and proliferation assay, LXR was activated by both T0901317 and GW3965 that has a similar tendency but the T0901317 effect was stronger than that of GW3965. These findings are consistent with the results of previous studies that have shown that activation of PXR targets may explain why T0901317 induces dramatic liver steatosis, while GW3965 has a milder effect [33]. These results suggest that the NR1H3 gene genetic polymorphisms may be associated with disease susceptibility and clinical manifestations of systemic lupus erythematosus (SLE)
Summary
Recent studies have reported that these receptors are involved in the regulation of inflammation and immune responses. We attempted to identify single nucleotide polymorphisms (SNPs) of the NR1H3 gene associated with the susceptibility to systemic lupus erythematosus (SLE). Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulation of the immune system involving the hyperactivity of T and B cells, elevated production of pathogenic autoantibodies, complement activation, and the formation of immune complexes causing multiorgan damage by deposition in host tissue [1]. Liver X receptor (LXR) alpha (NR1H3) and beta (NR1H2) can influence macrophage biology by modulation of lipid metabolism and by effects on innate immunity. A recent study found that LXRs mediate the regulation of Th17 cell differentiation and autoimmunity [13]. The possible association between LXRs genetic polymorphisms and SLE has not been addressed
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