Association of polymorphisms in the human interferon-gamma and interleukin-10 gene with acute and chronic kidney transplant outcome: the cytokine effect on transplantation.
BACKGROUND
Our group has previously described five different size alleles of an interferon (IFN)-gamma microsatellite. Analyzing this polymorphism, this study correlated high IFN-gamma production with a 12 CA repeat allele (allele 2). Further, our group has described interleukin (IL)-10 polymorphism defining in vitro high and low IL-10 producer status.


METHODS
Samples from 88 of 115 consecutive cadaveric renal transplants were used to define polymorphism of both IFN-gamma and IL-10. Patients were separated into high and low genotypes based on the previously reported association between certain genotypes and in vitro production. Graft survival, acute rejection, and serum creatinine at 5 years were analyzed for comparison between groups.


RESULTS
The genotype associated with high IFN-gamma production was found in 70 patients. The incidence of acute rejection was 54.3% in the high IFN-gamma genotype group, compared with 44.4% in the low IFN-gamma group. Requirement for antithymocyte globulin therapy was greater in the high IFN-gamma group (odds ratio [OR]=2.5). Among HLA-DR-mismatched patients, IFN-gamma genotype was more strongly associated with rejection (OR=2.86). In the cyclosporine monotherapy subgroup, patients with high IFN-gamma genotype had a 61% incidence of rejection compared with only 20% in the low IFN-gamma genotype patients (OR=3.06). Graft survival was similar between the two groups. When the analysis was controlled for the presence of delayed graft function, 40.5% of the high IFN-gamma genotype patients had serum creatinine levels above 200 micromol/L compared with only 14.3% of the low IFN-gamma genotype recipients at 5 years after transplantation (P=0.05). The high IL-10 genotype was shown to be associated with better graft function at 5 years (75 vs. 50%, P=0.09).


CONCLUSIONS
In this study we have shown that high producer genotype for IFN-gamma may have an influence on acute rejection of kidney transplants, particularly in patients on cyclosporine monotherapy. It is also associated with worse long-term graft function. On the contrary high IL-10 production may have a long-term protective effect.
Asderakis
A
A
Renal Transplant Unit, Manchester Royal Infirmary, United Kingdom. arcat@msn.com
Sankaran
D
D
Dyer
P
P
Johnson
R W
RW
Pravica
V
V
Sinnott
P J
PJ
Roberts
I
I
Hutchinson
I V
IV
D000208:Acute Disease; D000328:Adult; D000483:Alleles; D016207:Cytokines / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006084:Graft Rejection / Q000453:epidemiology / Q000235:genetics / Q000628:therapy; D006684:HLA-DR Antigens / Q000032:analysis; D006650:Histocompatibility Testing; D006801:Humans; D007165:Immunosuppression Therapy; D015994:Incidence; D007371:Interferon-gamma / Q000235:genetics*; D016753:Interleukin-10 / Q000235:genetics*; D007668:Kidney / Q000503:physiopathology; D016030:Kidney Transplantation; D011110:Polymorphism, Genetic; D012016:Reference Values; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
D016207:Cytokines; D006684:HLA-DR Antigens; D016753:Interleukin-10; D007371:Interferon-gamma