TY - JOUR
T1 - Local and not systemic factor H production dictates risk of age-related macular degeneration in liver transplant recipients
AU - Khandhadia, Sam
AU - Hakobyan, Svetlana
AU - Heng, Ling Z.
AU - Gibson, Jane
AU - Adams, David H.
AU - Alexander, Graeme J.
AU - Gibson, Jonathan M.
AU - Martin, Keith
AU - Menon, Geeta
AU - Nash, Kathryn
AU - Sivaprasad, Sobha
AU - Ennis, Sarah
AU - Cree, Angela J.
AU - Morgan, Paul
AU - Lotery, Andrew J.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - Age-related macular degeneration (AMD) is the commonest cause of blindness in the developed world, and is strongly associated with the Y402H polymorphism in the complement (C) factor H (CFH) gene. As liver is the primary site of C production, our hypothesis was that modification of liver CFH Y402H genotype through liver transplantation would influence the development of AMD. We recruited 223 Western European patients at least 55 years old, who had undergone LT at least 5 years previously. Recipient CFH Y402H genotype was obtained from DNA extracted from recipient blood samples. Donor CFH Y402H genotype was inferred from recipient plasma CFH Y402H protein allotype by previously described ELISA utilising variant-specific monoclonal antibodies. This approach was verified by genotyping donor tissue from a subgroup of patients (n = 49). We found that recipient AMD status was associated with recipient CFH Y402H genotype (p = 0.036) but not with donor CFH Y402H genotype (p = 0.626), after controlling for age, gender, smoking status, and body mass index. Compared to previously reported prevalence figures there was an increased prevalence of both AMD and recipient CFH Y402H risk allele frequency in LT patients. Plasma C protein levels (including C3 and C4, activation products C3a, C4a, C5a, TCC, and regulators C1 inhibitor and CFH) were similar in LT patients with and without AMD. We also compared LT patients with 30 randomly selected age matched healthy controls, without AMD or a history of LT. Plasma total CFH was higher in LT patients compared to controls, otherwise levels of all other C proteins were similar. AMD was associated with recipient CFH Y402H genotype, implying that local rather than systemic CFH protein or gene therapy may be more relevant for pathogenesis and a better target for therapy in AMD. The increased prevalence of AMD in LT patients may be explained by the observed increased frequency of the CFH 402H sequence variant
AB - Age-related macular degeneration (AMD) is the commonest cause of blindness in the developed world, and is strongly associated with the Y402H polymorphism in the complement (C) factor H (CFH) gene. As liver is the primary site of C production, our hypothesis was that modification of liver CFH Y402H genotype through liver transplantation would influence the development of AMD. We recruited 223 Western European patients at least 55 years old, who had undergone LT at least 5 years previously. Recipient CFH Y402H genotype was obtained from DNA extracted from recipient blood samples. Donor CFH Y402H genotype was inferred from recipient plasma CFH Y402H protein allotype by previously described ELISA utilising variant-specific monoclonal antibodies. This approach was verified by genotyping donor tissue from a subgroup of patients (n = 49). We found that recipient AMD status was associated with recipient CFH Y402H genotype (p = 0.036) but not with donor CFH Y402H genotype (p = 0.626), after controlling for age, gender, smoking status, and body mass index. Compared to previously reported prevalence figures there was an increased prevalence of both AMD and recipient CFH Y402H risk allele frequency in LT patients. Plasma C protein levels (including C3 and C4, activation products C3a, C4a, C5a, TCC, and regulators C1 inhibitor and CFH) were similar in LT patients with and without AMD. We also compared LT patients with 30 randomly selected age matched healthy controls, without AMD or a history of LT. Plasma total CFH was higher in LT patients compared to controls, otherwise levels of all other C proteins were similar. AMD was associated with recipient CFH Y402H genotype, implying that local rather than systemic CFH protein or gene therapy may be more relevant for pathogenesis and a better target for therapy in AMD. The increased prevalence of AMD in LT patients may be explained by the observed increased frequency of the CFH 402H sequence variant
U2 - 10.1016/j.imbio.2012.08.154
DO - 10.1016/j.imbio.2012.08.154
M3 - Conference abstract
SN - 0171-2985
VL - 217
SP - 1182
EP - 1183
JO - Immunobiology
JF - Immunobiology
IS - 11
M1 - 152
T2 - XXIV International Complement Workshop
Y2 - 10 October 2012 through 15 October 2012
ER -