Genetic variants and the risk of renal impairment in decompensated cirrhosis: a multi-ancestry genome-wide association study.
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Sanchez Lukas Otero, Clària Joan, Galvanin Clélia, Aguilar Ferran, Layese Richard, Serra Matteo, Jiménez-Gracia Laura, Nieto Paula, Castven Darko, Frankova Sona, Jirsa Milan, Tornai David, Curto-Vilalta Anna, Farias Alberto Queiroz, Papp Maria, Zitelli Patricia Momoyo, Caraceni Paolo, Zaccherini Giacomo, Goncalves Luciana L, Alessandria Carlo, Pereira Gustavo, Laleman Wim, Gadano Adrian C, Piano Salvatore, Mattos Angelo Z, Germanova Desislava, Lucidi Valério, Soret Daphnée, Wandji Line Carolle Ntandja, Uschner Frank Erhard, Torre Aldo, Vargas Victor, Mendes Liliana S C, Mookerjee Rajeshwar P, Benitez Carlos, Alvares-da-Silva Mario R, Remmelink Myriam, Bittencourt Paulo L, Albillos Agustin, Couto Claudia Alves, Bañares Rafael, Mendizabal Manuel, Degré Delphine, Toledo Claudio L, Janicko Martin, Mazo Daniel F, Barradas Mauricio Castillo, Bernal William, Miranda Adelina Zarela Lozano, Padilla-Machaca P Martín, Zipprich Alexander, Malé-Velázquez René, Moreno Christophe, Lyra André Castro, Carrilho Flair, Fernandez Javier, Trebicka Jonel, Jalan Rajiv, Angeli Paolo, Stefanescu Horia, Rautou Pierre-Emmanuel, Buch Stephan, Louvet Alexandre, Marquardt Jens U, Gustot Thierry, Heyn Holger, Nieto Juan C, Arroyo Vicente, Ganne-Carrié Nathalie, Sperl Jan, Moreau Richard, Mathurin Philippe, Nahon Pierre, Trépo Eric, CANONIC, PREDICT, ACLARA, ANRS CO12 CirVir, and CIRRAL study groups
Аннотация
METHODS: We performed a GWAS for serum creatinine levels in 3220 patients with decompensated cirrhosis across five cohorts (CANONIC [n=707], PREDICT [n=825], ACLARA [n=671], Bologna [n=272], and Brussels [n=745]); with 83% of patients having European and 17% having admixed American genetic ancestry. Findings were replicated in 1728 European patients with decompensated cirrhosis across four independent cohorts (Czech-Romanian [n=988], CirVir-CIRRAL [n=139], French-Belgian [n=294], and German [n=307]). Associations were evaluated in 3139 patients with compensated cirrhosis (EuroLiver [n=851], CirVir-CIRRAL [n=1142], and the UK Biobank [n=1146]) and 402 683 individuals from the UK Biobank with no history of cirrhosis, who served as a general population comparator. Single-cell and spatial transcriptomics mapped GWAS associations to cell types in the liver, blood, and kidney.
FINDINGS: We identified a genome-wide significant association at the SUSD1 locus (lead variant rs2099161[C→T]; trans-ancestry-discovery β=0·16 [95% CI 0·11 to 0·21], p=4·32 × 10-10; independent replication β=0·09 [0·03 to 0·16], p=5·34 × 10-3; combined meta-analysis β=0·13 [0·09 to 0·17], p=8·31 × 10-11; I2=0%). The effect was specific to decompensated cirrhosis, with no association in compensated cirrhosis (β= -0·0003 [-0·0460 to 0·0454], p=0·99) or the general population (β= -0·005 [-0·009 to -0·002], p=3·78 × 10-3). Each additional copy of the rs2099161(C) risk allele was associated with a higher risk of kidney failure at inclusion in the ACLARA, CANONIC, PREDICT, Bologna, Brussels, Czech-Romanian, and French-Belgian cohorts (n=4390, p=6·34 × 10-4). The risk was highest in CC homozygotes compared with patients with the TT genotype (odds ratio 1·60 [95% CI 1·21 to 2·11]). A similar pattern was observed for incident kidney failure at 1 week (CANONIC cohort n=638, p=0·035, CC vs TT genotypes 2·00 [1·10 to 3·65]), and terlipressin requirement (PREDICT, ACLARA, and Brussels cohorts, n=2161, p=0·027, CC vs TT genotypes 2·06 [1·08 to 3·93]). Transcriptomic analyses identified plasmacytoid dendritic cells as the primary SUSD1-expressing cell-type with elevated expression in patients with renal impairment across compartments. Patients with renal impairment showed increased abundance of plasmacytoid dendritic cells and type-I-interferon signalling in liver and kidney tissues.
INTERPRETATION: SUSD1 is a risk locus for renal impairment in decompensated cirrhosis, with genetic effects that appear context-dependent across cirrhosis stages and the general population. Our findings implicate the plasmacytoid dendritic cell-interferon axis as a candidate mechanism linking liver dysfunction to kidney injury.
FUNDING: European Foundation for the Study of Chronic Liver Failure and Horizon Europe.