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

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. <br></br><br></br> The aim of this thesis was to evaluate the contribution of genetics to the development of anti-FHs in aHUS. <br></br><br></br> 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. <br></br><br></br> 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. <br></br><br></br> 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. <br></br><br></br> Finally, I report that the <i>HLA-DRB1*11:04</i> 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 <i>HLA-DRB1*11:04</i> allele and the FHR1 deficiency, could increase the risk for anti-FHs.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

The Open University

Year dc:date.issued

2018

Author dc:creator

• Valoti, Elisabetta

Language dc:language

en