Genetic Factors Associated with Anti-Factor H Autoantibodies in Atypical Hemolytic Uremic Syndrome (aHUS)

Valoti, Elisabetta (2018). Genetic Factors Associated with Anti-Factor H Autoantibodies in Atypical Hemolytic Uremic Syndrome (aHUS). PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000da2d

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy characterized by renal failure and determined by genetic and acquired defects of alternative pathway (AP) of the complement system. Autoantibodies against factor H (anti-FHs), a regulator of the AP, were reported in 10% of patients, and are associated with the deficiency of factor H related 1 (FHR1), a FH homologous protein.

The aim of this thesis was to evaluate the contribution of genetics to the development of anti-FHs in aHUS.

Thirty patients affected by aHUS resulted positive for anti-FHs (9.8%) and FHR1 deficiency was present in 83.3% of them. A healthy control also showed anti-FHs in concomitance with FHR1 deficiency documenting that the lack of FHR1 strongly predisposed to anti-FH development also in healthy subjects although this condition was not sufficient for the disease manifestation.

The presence of infectious prodromal signs and an age at the disease onset around 8 years indicated that common infections may trigger the development of autoantibodies in subjects with at risk genetic background.

Likely pathogenetic variants in complement genes were observed in 37% of our patients with anti-FHs. At variance, common variants in complement genes did not seem to contribute to the disease, as documented by comparing patients with super controls, unaffected subjects carrying FHR1 deficiency.

Finally, I report that the HLA-DRB1*11:04 allele could be a predisposing genetic variant for anti-FH associated aHUS. Further works will be necessary to confirm this finding and to explore the presence of other genetic susceptibility factors that, in combination with the HLA-DRB1*11:04 allele and the FHR1 deficiency, could increase the risk for anti-FHs.

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