Research and references GcMAF

2011 Polymorphism in vitamin D-binding protein as a genetic risk factor in the pathogenesis of endometriosis (PDF)
K Faserl, G Golderer, L Kremser, H Lindner, B Sarg, L Wildt, B Seeber.

• Abstract. Previous studies have implicated a deficiency in the inflammatory response in women who develop endometriosis. The specific immunological deficits have not been completely elucidated. Objective. Our objective was to identify differences in protein expression in serum that might shed light on the pathophysiology of endometriosis. Method. This cross-sectional study of women undergoing laparoscopy between 2003 and 2005 took place at a university medical center. Patients included consenting women age 18–49 yr undergoing surgery for pain and/or infertility or elective tubal ligation. Blood was collected preoperatively. Main Outcome Measure. Proteomic analysis of serum was done using two-dimensional difference gel electrophoresis. Results. We found 25 protein spots with a significant difference in abundance between women with endometriosis and controls, including acute-phase proteins and complement components. The abundance of vitamin D-binding protein was higher in all endometriosis pools by a factor of approximately 3 compared with the control pool. Analysis of specific allele products using nano-scalec liquid chromatography-electrospray ionization-mass spectrometry indicated that it was the GC*2 allele product that was in greater concentration in serum pools, as well as in single validation samples, in women with endometriosis. In contrast to the GC*1 allele product, which is readily converted to a potent macrophage factor (Gc protein-derived macrophage activating factor), the GC*2 allele product undergoes practically no such conversion. Conclusions. We speculate that the inability to sufficiently activate macrophages’ phagocytotic function in those carrying the GC*2 polymorphism (more prevalent in endometriosis) may allow endometriotic tissues to implant in the peritoneal cavity. Future studies evaluating specific vitamin D-binding protein polymorphisms as a risk factor for endometriosis in larger populations of women are warranted.
• Author’s comments:Endometriosis is a common disease of reproductive age women. It affects about 10% of all women and upwards of 40% of women with infertility. Women with endometriosis may have an impairment of their immune systems and inflammatory responses, allowing for the development of endometriotic lesions.

  Our most impressive discovery is the differential abundance of a specific allele product of DBP, GC*2. The expression of the GC*2 allele product was 3-fold higher in all endometriosis pools compared with the control pool.

  Besides acting as a transporter for vitamin D metabolites, DBP is the most potent activator for macrophages in the form of Gc protein-derived macrophage-activating factor (GcMAF). The GC*1 allele products are glycosylated at a total rate of 10–30%, whereas the GC*2 allele product is glycosylated at a rate of 1–5%. Thus, the form of DBP encoded by the GC*1 allele is much more readily converted to GcMAF, whereas that encoded by GC*2 is converted hardly at all.

  Those with only GC*2 allele products, disproportionally represented in the endometriosis group, have a much reduced capability to convert DBP to GcMAF, the critical macrophage activator.

  Based on the findings of our study, we speculate that the immune defect may lie, at least in part, in the inability to sufficiently activate macrophages’ phagocytotic function in those carrying the GC*2 allele of DBP.

  The activation of macrophages via targeted immunotherapy in affected women might form the basis of a novel treatment strategy for endometriosis.