Prolactin and Dehydroepiandrosterone Levels in Women with Systemic Lupus Erythematosus: The Role of the Extrapituitary Prolactin Promoter Polymorphism at -1149G/T

Abstract

Systemic lupus erythematosus (SLE) has shown an association with high levels of prolactin, low levels of dehydroepiandrosterone (DHEA), and induction of inflammatory cytokines in the serum of patients with the disease. This preliminary study examined the relevance of a -1149G/T functional single-nucleotide polymorphism (SNP) (rs1341239) in the promoter of the extrapituitary prolactin gene in a cohort of African American and European American women with lupus. Examination of this SNP revealed that the -1149TT genotype was correlated with higher levels of prolactin in serum and prolactin gene expression (p = 0.0001) in peripheral blood mononuclear cells (PBMCs). Lower levels of DHEA in serum were demonstrated in lupus patients (p = 0.001); those with the -1149TT genotype had the lowest levels of DHEA. Furthermore, a small subset of women who were on DHEA therapy and had a TT genotype showed a significant decrease in prolactin gene expression and lower disease activity scores (SLEDAI). Lupus patients, particularly African Americans, had significantly higher levels of IL-6 (p = 0.0001) and TNF-α (p = 0.042). This study suggests that the -1149TT genotype may be a risk factor for lupus and may predict who could possibly benefit from DHEA therapy; therefore, these results should be validated in a larger cohort with all ethnic groups.

Figure 1

SLE disease activity index (SLEDAI) by population. African American (AAF-L) and European American (EAF-L) women with lupus have the highest SLEDAI scores compared to African American and European American men with lupus.

Figure 2

Prolactin expression and serum levels. Patients with lupus have significantly higher serum levels of prolactin (p = 0.0026) and expression at the mRNA level in PBMCs (p = 0.0017), although individual differences are shown among the patients.

Figure 3

Restriction fragment length polymorphism (RFLP) of prolactin −1149. RFLP analysis with ApoI digestion yields three fragment lengths to distinguish the three genotypes, GG, GT, and TT.

Figure 4

The genotype TT prolactin levels and expression. A significant number of lupus patients with the TT genotype demonstrated higher levels of prolactin expression (a) (p = 0.0485) and protein serum levels (b) (p = 0.0230). There were no significant differences in expression or serum levels in the other genotypes GT (c) and GG (d).

Figure 5

Serum levels of DHEA. (a) shows that lupus patients had a significant lower level of serum DHEA (p = 0.0001). (b) shows that the TT genotype had the lowest level of DHEA compared to GT or GG in lupus patients. Furthermore, (c) demonstrates that African American women with lupus and the TT genotype had the lowest level of DHEA. (d) shows that the serum DHEA level in TT genotype in African American women was significantly lower when compared to their normal age-matched nonlupus patients (p = 0.022).

Figure 6

SLEDAI score and DHEA therapy. (a) shows that lupus patients on DHEA therapy had lower SLEDAI scores than patients not on therapy. (b) demonstrate that those lupus patients with a TT genotype and on DHEA therapy had lower disease activity scores compared to those with GT and GG genotypes.

Figure 7

IL-6 serum levels in lupus and nonlupus patients. (a) shows that lupus patients have a significantly higher level of IL-6 compared to age-matched controls (p = 0.0001); however, (b) African American women with lupus have an increased level of IL-6 compared to European American women with lupus (p = 0.0272).

Figure 8

Tumor necrosis factor-alpha (TNF-α) serum levels. African American women with lupus (AAL) had the highest level of TNF-α compared to European American women with lupus (p = 0.0427).

Figure 9

17β-estradiol levels in serum. Estradiol levels in serum were significantly higher in lupus patients (a) (p = 0.0003). (b) However, women with lupus older (FO) than 50 had higher levels compared to women less than 50 (FY). (c) Lupus patients with the TT genotype had higher levels than women with the GG genotype.

Figure 10

Testosterone levels in serum. (a) No difference was found in testosterone between the small numbers of males with lupus in this study; however, we did notice a higher level of testosterone in a small number of women less than fifty years of age.