Liver X receptors alpha gene (NR1H3) promoter polymorphisms are associated with systemic lupus erythematosus in Koreans.

Abstract

INTRODUCTION: Liver 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). METHODS: SNPs 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. RESULTS: We 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. CONCLUSIONS: NR1H3 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.