TY - JOUR
T1 - An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomes
AU - Eskandari, Siawosh K.
AU - Gaya da Costa, Mariana
AU - Faria, Bernardo
AU - Petr, Vojtech
AU - Azzi, Jamil R.
AU - Berger, Stefan P.
AU - Seelen, Marc A.J.
AU - Damman, Jeffrey
AU - Poppelaars, Felix
N1 - Funding Information:
The authors thank the members of the REGaTTA cohort (REnal GeneTics TrAnsplantation; University Medical Center Groningen, University of Groningen, Groningen, the Netherlands): S.J.L. Bakker, J. van den Born, M.H. de Borst, H. van Goor, J.L. Hillebrands, B.G. Hepkema, G.J. Navis, and H. Snieder.
Publisher Copyright:
© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Of all kidney transplants, half are still lost in the first decade after transplantation. Here, using genetics, we probed whether interleukin 6 (IL-6) could be a target in kidney transplantation to improve graft survival. Additionally, we investigated if a genetic risk score (GRS) based on IL6 and IL10 variants could improve prognostication of graft loss. In a prospective cohort study, DNA of 1271 donor-recipient kidney transplant pairs was analyzed for the presence of IL6, IL6R, IL10, IL10RA, and IL10RB variants. These polymorphisms and their GRS were then associated with 15-year death-censored allograft survival. The C|C-genotype of the IL6 polymorphism in donor kidneys and the combined C|C-genotype in donor-recipient pairs were both associated with a reduced risk of graft loss (p =.043 and p =.042, respectively). Additionally, the GRS based on IL6, IL6R, IL10, IL10RA, and IL10RB variants was independently associated with the risk of graft loss (HR 1.53, 95%-CI [1.32–1.84]; p <.001). Notably, the GRS improved risk stratification and prediction of graft loss beyond the level of contemporary clinical markers. Our findings reveal the merits of a polygenic IL-6-based risk score strengthened with IL-10- polymorphisms for the prognostication and risk stratification of late graft failure in kidney transplantation.
AB - Of all kidney transplants, half are still lost in the first decade after transplantation. Here, using genetics, we probed whether interleukin 6 (IL-6) could be a target in kidney transplantation to improve graft survival. Additionally, we investigated if a genetic risk score (GRS) based on IL6 and IL10 variants could improve prognostication of graft loss. In a prospective cohort study, DNA of 1271 donor-recipient kidney transplant pairs was analyzed for the presence of IL6, IL6R, IL10, IL10RA, and IL10RB variants. These polymorphisms and their GRS were then associated with 15-year death-censored allograft survival. The C|C-genotype of the IL6 polymorphism in donor kidneys and the combined C|C-genotype in donor-recipient pairs were both associated with a reduced risk of graft loss (p =.043 and p =.042, respectively). Additionally, the GRS based on IL6, IL6R, IL10, IL10RA, and IL10RB variants was independently associated with the risk of graft loss (HR 1.53, 95%-CI [1.32–1.84]; p <.001). Notably, the GRS improved risk stratification and prediction of graft loss beyond the level of contemporary clinical markers. Our findings reveal the merits of a polygenic IL-6-based risk score strengthened with IL-10- polymorphisms for the prognostication and risk stratification of late graft failure in kidney transplantation.
KW - interleukins
KW - kidney transplantation
KW - long-term graft survival
KW - polymorphisms
U2 - 10.1111/ajt.17212
DO - 10.1111/ajt.17212
M3 - Article
C2 - 36453708
AN - SCOPUS:85143098276
SN - 1600-6135
VL - 22
SP - 45
EP - 57
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - S4
ER -