Association between endothelin-1 and systemic lupus erythematosus: insights from a case-control study

Abstract

Systemic lupus erythematosus (SLE) is a chronic rheumatic disorder. Endothelin-1, a vasoconstrictor, belongs to the endothelin family and is associated with vascular-related damages. To date, association between ET-1 and pathogenesis of SLE remains unclear. This case-control study was carried out by 314 SLE, 252 non-SLE diseases patients and 500 healthy controls. Serum ET-1, CCN3, IL-28B levels were detected by ELISA, and ET-1 gene polymorphisms (rs5369, rs5370, rs1476046, rs2070699, rs2071942, rs2071943, rs3087459, rs4145451, rs6458155, rs9369217) were genotyped with Kompetitive Allele-Specific PCR. SLE patients had high levels of ET-1, which were correlated with some clinical, laboratory features. Serum CCN3, IL-28B levels were higher in SLE patients, and ET-1 levels were positively correlated with the two cytokines. Rs5370, rs1476046, rs2070699, rs2071942, rs2071943, rs3087459, rs6458155 and rs2070699 were associated with SLE risk. Rs2070699 (T, TT) was related to SLE patients with alopecia. Rs5370 (T, TT, TG), rs1476046 (G,GA), rs2071942 (G,GA) and rs2071943 (G,GA) were associated with SLE patients with pericarditis, pyuria and fever manifestation, respectively. Rs3087459 (CC) and rs9369217 (TC) were related to SLE patients with positive anti-SSB antibody. Rs5369 (AA) was associated with IgG and CRP levels in SLE patients. In conclusion, elevated serum ET-1 in SLE patients may be a potential disease marker, and its gene polymorphisms were related to SLE susceptibility.

Figure 1

Comparison of ET-1 levels between SLE patients and healthy controls in the training cohort. (A) Serum ET-1 levels in 53 SLE patients and 80 healthy individuals were examined by ELISA. Each symbol stands for an independent sample. (B–D) ET-1 levels in SLE patients distributed according to alopecia, proteinuria and anti-Sm. (E) Difference of serum levels of ET-1 in SLE patients with less active disease and active disease. (F–G) Relationship between ET-1 levels and SLEDAI, ESR levels. (H) Receiver operating characteristic curve analysis of serum ET-1 as a biomarker for SLE.

Figure 2

ET-1 levels in SLE patients from validation cohort. (A) Comparison of serum ET-1 levels in SLE patients (N = 102) and diseases controls (N = 252, including 90 RA, 95 OA, 55 SS, 38 AS, 17 SSc) by ELISA. (B–F) Receiver operating characteristic curve analysis was used to assess potential of serum ET-1 in differentiating SLE from RA, OA, SS, AS, and SSc. (G) Analysis of difference in serum ET-1 between SLE and non-SLE patients. (H) Receiver operating characteristic curve analysis of serum ET-1 between SLE and non-SLE patients.

Figure 3

CCN3 and IL-28B levels in SLE patients and healthy controls. (A) Serum CCN3 levels were tested by ELISA in 53 SLE patients and 80 healthy controls. (B) Serum ET-1 in SLE patients distributed in accordance with thrombocytopenia. (C) Correlation between ET-1 and CCN3 levels in SLE patients. (D) Serum IL-28B levels were detected by ELISA in 53 SLE patients and 80 healthy controls. (E–G) Distribution of serum IL-28B in SLE patients with hematuria, proteinuria and cylindruria. (H) Difference of serum IL-28B in SLE patients with active disease and less active disease. (I–K) Relationship between IL-28B levels and SLEDAI score, ESR levels. (H) Correlation between ET-1 and IL-28B levels in SLE patients.

Figure 4

Linkage disequilibrium (LD) analysis for ten SNPs in ET-1 gene. The color and numerical value (D’) of each box represent the Te intensity of LD. Red and pink indicate significant linkage, light blue and white indicate no linkage. The value of D’ varies from 0 to 1, by which value of 1 represents the maximum link. Block 1 consists of rs6458155 and rs4145451. Block 2 consists of rs2071942, rs2071943 and rs5370.