Association of TNFd and IL-10 polymorphisms with mortality in unrelated hematopoietic stem cell transplantation.
BACKGROUND
Non-HLA immunogenetic polymorphisms may influence outcome of hematopoietic stem cell transplantation (HSCT). In this study, we have determined the role of TNFa, TNFd, IL-10, IL-1, IL-1Ra, and IL-4R polymorphisms in patients transplanted with HSC of an unrelated donor.


METHODS
The allelic variants of four SNPs (IL-10-1082, IL-1beta-511, IL-4R-3223, IL-4R-1902) and four microsatellites (TNFa, TNFd, IL-10-1064, IL-1Ra) were determined in 131 unrelated patient/donor pairs typed for HLA-A/B/C/DR/DQ (four digits).


RESULTS
The allelic distribution of the polymorphisms was similar to that previously reported in Caucasoid populations. Patient and donor TNFd and patient IL-10-1064 polymorphisms correlated with mortality in univariate analysis. Patients with TNFd1/d2/d3 genotypes had 3-year survival rates of 65%. A gradual decrease in survival rates was observed for patients with TNFd3/d3 genotypes (50%, p=n.s.), TNFd4 (46%, P=0.08), and TNFd5 (33%, P=0.03). A multivariate analysis of 10/10 matched patients revealed that the following patient genotypes correlated with lower survival: TNFd3/d3 (RR 4.08, P=0.026) TNFd4 (RR 3.78, P=0.032) and TNFd5 (RR 6.69, P=0.021) all compared to TNFd1/d2/d3 genotypes. Patient IL-10 (12, 14, 15) microsatellite alleles correlated with lower 3-year survival (28%) when compared to IL-10 (<12) (56%, P=0.052) and to Il-10 (13) alleles (60%, P=0.0023). In multivariate analysis this correlation remained significant only in recipients of HSCT of 10/10 HLA matched donors (RR=2.96, P=0.038).


CONCLUSIONS
The data demonstrate a significant correlation of the TNFd and IL-10-1064 microsatellite polymorphisms with mortality after unrelated HSCT. They support the hypothesis that simple genomic tests, in addition to precise HLA matching, may contribute to determine prognosis in patients undergoing unrelated HSCT.
Bettens
Florence
F
Transplantation Immunology Unit/LNRH, University Hospital, Geneva, Switzerland.
Passweg
Jakob
J
Gratwohl
Alois
A
Chalandon
Yves
Y
Helg
Claudine
C
Chapuis
Bernard
B
Schanz
Urs
U
Libura
Jolanta
J
Roosnek
Eddy
E
Tiercy
Jean-Marie
JM
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D016753:Interleukin-10 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011336:Probability; D033581:Stem Cell Transplantation / Q000401:mortality*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D017931:DNA Primers; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10