D3.388 - Association of HLA and cytokine production as risk factors for prostate cancer

This study  identifies risk antigens associated with benign prostatic hyperplasia (BPH) and prostate cancer (PCa), as well as the associations between HLA and cytokine production.

The distribution of HLA was studied using the standard microlymphocytotoxic test in 25 patients with BPH, 41 - with PCa and 350 healthy donors (172 men and 178 women). The etiologic fraction (attributive risk >0.1) was counted using the formula:  = x - y/ 1-y, where x is frequency of antigen in patients and y - frequency in healthy individuals. Levels of TNF-α, IL-18, MCP-1, IL-4, VEGF were measured by ELISA in 170 serum samples from the typed individuals.

Attributive risk (AR) of BPH was associated by A29, B38 (p=0.002; 0.006), while RR - by A25; AR of PCa - by A25, -29, B40, -44, -49 (p≤0.05), RR - by B8, -41. Disease-protective antigens were identified as A9, -10, B17 and A1, B5, -13, -15, respectively. Elevated levels of MCP-1 were found in the blood of HLA-A28+, B8+, and B41+ individuals; increased TNF-α levels were observed in B44+ and A10+ individuals also associated with an increase in IL-18 and decreased IL-4; VEGF was significantly higher in A9+-, A25+- and B8+- (p≤0.05). A25 is an AR PCa risk antigen and a relative risk factor for BPH. A25 is a component of the A10 antigen, which is a protector of BPH development in men (RR=0.28, p=0.023), as well as causing higher production of proinflammatory TNF-α and IL-18 and a tendency toward lower production of anti-inflammatory IL-4. The association of B44 and B41 with elevated production of TNF-α and MCP-1, and A25 and B8 with VEGF, which are associated with vascular invasion and metastases, represent additional risk factors for the development of PCa.

HLA antigens associated with the risk of developing BPH and PCa in men were identified, along with associative links to select cytokine production. A10 may contribute to changes in the balance of cytokines in the direction of pronounced inflammatory reactions, which protects against infections and prolonged inflammation of the prostate, and  BPH. The association of HLA-A25 with high elevated VEGF levels indicates that this antigen may serve not only as a predictor of PCa, but also as a potential marker of invasive course.