Black Death protective gene mutation shows ambiguous role in type 1 diabetes, its complications, and common viral infections

Aims Because ERAP2 is implicated in infections and autoimmune diseases, we hypothesize that the rs9939609 ERAP2 polymorphism, with allele frequencies observed in human samples from both before and after the Black Death, may influence type 1 diabetes (T1D), its complications, and common viral infections. Methods We examined 400 patients with T1D and 300 healthy, age-matched controls. The analysis focused on the ERAP2 polymorphism in relation to T1D complications and comorbidities, the history of common childhood viral infections, and the inflammatory status of T1D patients. Results The T allele is linked to a decreased risk of developing diabetes, modulates its complications in a differential manner, and has diverse effects on the inflammatory status of T1D patients. Our results also indicate statistically significant differences in the correlation of monocyte subsets, the quantitative status of CD4 + CD25 high FOXP3 + regulatory T cells, and susceptibility to common childhood viral infections between different ERAP2 variants. Conclusions Our findings suggest that the rs2549794 ERAP2 polymorphism may serve as a genetic marker for susceptibility to T1D complications and comorbidities, further emphasizing the role of ERAP2-mediated pathways in their etiology. These results also provide new evidence supporting the hypothesis of balancing selection at this locus, driven by autoimmune and infectious diseases.