Common variants in NLRP2 and NLRP3 genes are strong prognostic factors for the outcome of HLA-identical sibling allogeneic stem cell transplantation.
The inflammasomes are macromolecular cytosolic complexes involved in the production of interleukin-1beta (IL-1beta) and IL-18 in response to several pathogen-derived stimuli. Such interleukins have been implicated in the origin of severe allogeneic stem cell transplant (allo-SCT) complications. We analyzed the relationship between the interindividual variability in inflammasome protein-encoding genes in donors and patients and clinical outcome after allo-SCT. Fourteen common genetic variants in 5 genes of the inflammasome, namely, NLRP1, NLRP2, NLRP3, CARD8, and CASP5, were genotyped in 133 human leukocyte antigen-identical sibling pairs undergoing allo-SCT. In the multivariate analysis, donor variants in NLRP2 and NLRP3 were the most important prognostic factors for the clinical outcome after allo-SCT. Thus, donor TT genotype at rs10925027 in NLRP3 was associated with disease relapse (odds ratio (OR) = 6.3, P = 1 x 10(-7)), and donor GG genotype at rs1043684 in NLRP2 was associated with nonrelapse mortality (OR = 4.4, P = 6 x 10(-4)) and overall survival (OR = 3.1, P = .001). In addition, patient AA genotype at rs5862 in NLRP1 was associated with nonrelapse mortality (OR = 2.8, P = .005) and overall survival (OR = 2.0, P = .009). These results suggest that inflammasome genetic variants are important prognostic factors for the outcome of allo-SCT. If validated in larger studies, including unrelated allo-SCT, NLRPs genotype would become an important factor in donor selection.
Granell
Miquel
M
Hematology Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain.
Urbano-Ispizua
Alvaro
A
Pons
Aina
A
Aróstegui
Juan Ignacio
JI
Gel
Bernat
B
Navarro
Alfons
A
Jansa
Sonia
S
Artells
Rosa
R
Gaya
Anna
A
Talarn
Carme
C
Fernández-Avilés
Francesc
F
Martínez
Carmen
C
Rovira
Montserrat
M
Carreras
Enric
E
Rozman
Ciril
C
Juan
Manel
M
Yagüe
Jordi
J
Montserrat
Emili
E
Monzó
Mariano
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006680:HLA Antigens; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D006801:Humans; D020382:Interleukin-18; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011237:Predictive Value of Tests; D012008:Recurrence; D012189:Retrospective Studies; D035781:Siblings; D033581:Stem Cell Transplantation; D015996:Survival Rate; D014184:Transplantation, Homologous
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D002352:Carrier Proteins; D006680:HLA Antigens; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; C427903:NLRP1 protein, human; C495732:NLRP2 protein, human; C453881:NLRP3 protein, human; D009363:Neoplasm Proteins; C099217:CASP5 protein, human; D020169:Caspases