Sanchez LO, Clària J, Galvanin C, Aguilar F, Layese R, Serra M, Jiménez-Gracia L, Nieto P, Castven D, Frankova S, Jirsa M, Tornai D, Curto-Vilalta A, Farias AQ, Papp M, Zitelli PM, Caraceni P, Zaccherini G, Goncalves LL, Alessandria C, Pereira G, Laleman W, Gadano AC, Piano S, Mattos AZ, Germanova D, Lucidi V, Soret D, Wandji LCN, Uschner FE, Torre A, Vargas V, Mendes LSC, Mookerjee RP, Benitez C, Alvares-da-Silva MR, Remmelink M, Bittencourt PL, Albillos A, Couto CA, Bañares R, Mendizabal M, Degré D, Toledo CL, Janicko M, Mazo DF, Barradas MC, Bernal W, Miranda AZL, Padilla-Machaca PM, Zipprich A, Malé-Velázquez R, Moreno C, Lyra AC, Carrilho F, Fernandez J, Trebicka J, Jalan R, Angeli P, Stefanescu H, Rautou PE, Buch S, Louvet A, Marquardt JU, Gustot T, Heyn H, Nieto JC, Arroyo V, Ganne-Carrié N, Sperl J, Moreau R, Mathurin P, Nahon P, Trépo E, CANONIC, PREDICT, ACLARA, ANRS CO12 CirVir, and CIRRAL study groups.
Lancet Gastroenterol Hepatol. 2026 Dec;11(12):1065-1080.
Background: Renal impairment is a major complication of decompensated cirrhosis and a key driver of mortality. Despite its clinical significance, the genetic architecture of susceptibility to renal impairment in this context remains largely unexplored. We conducted a multi-ancestry genome-wide association study (GWAS) to identify genetic loci associated with renal impairment in decompensated cirrhosis.
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.
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