An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomes

Siawosh K. Eskandari; Mariana Gaya da Costa; Bernardo Faria; Vojtech Petr; Jamil R. Azzi; Stefan P. Berger; Marc A.J. Seelen; Jeffrey Damman; Felix Poppelaars

doi:10.1111/ajt.17212

An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomes

Siawosh K. Eskandari^*, Mariana Gaya da Costa, Bernardo Faria, Vojtech Petr, Jamil R. Azzi, Stefan P. Berger, Marc A.J. Seelen, Jeffrey Damman, Felix Poppelaars^*

^*Corresponding author for this work

Pathology

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Abstract

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.

Original language	English
Pages (from-to)	45-57
Number of pages	13
Journal	American Journal of Transplantation
Volume	22
Issue number	S4
DOIs	https://doi.org/10.1111/ajt.17212
Publication status	Published - Dec 2022

Bibliographical note

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.

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© 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.

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An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomesFinal published version, 5.2 MBLicence: CC BY-NC-ND

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@article{e4ef1c6f377b457ab799466b73e58cbb,

title = "An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomes",

abstract = "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.",

author = "Eskandari, {Siawosh K.} and {Gaya da Costa}, Mariana and Bernardo Faria and Vojtech Petr and Azzi, {Jamil R.} and Berger, {Stefan P.} and Seelen, {Marc A.J.} and Jeffrey Damman and Felix Poppelaars",

note = "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: {\textcopyright} 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.",

year = "2022",

month = dec,

doi = "10.1111/ajt.17212",

language = "English",

volume = "22",

pages = "45--57",

journal = "American Journal of Transplantation",

issn = "1600-6135",

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An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomes. / Eskandari, Siawosh K.; Gaya da Costa, Mariana; Faria, Bernardo et al.
In: American Journal of Transplantation, Vol. 22, No. S4, 12.2022, p. 45-57.

Research output: Contribution to journal › Article › Academic › peer-review

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

Y1 - 2022/12

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.

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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 -

An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomes

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