NOD2 gene polymorphism rs2066844 associates with need for combined liver-intestine transplantation in children with short-gut syndrome.
OBJECTIVE
The nucleotide-binding oligomerization protein 2 (NOD2) gene single nucleotide polymorphisms (SNPs) associated with Crohn's disease were recently associated with severe rejection after small-bowel transplantation (SBTx). The purpose of this study was to re-test this association and explore whether deficient innate immunity suggested by the NOD2 SNPs predisposes to intestine failure requiring isolated SBTx or combined liver-intestine failure requiring combined liver-SBTx (LSBTx).


METHODS
Archived DNA from 85 children with primary isolated SBTx or LSBTx was genotyped with Taqman biallelic discrimination assays. To minimize confounding effects of racial differences in minor allele frequencies (MAFs), allelic associations were tested in 60 Caucasian recipients (discovery cohort). Replication was sought in an independent cohort of 39 Caucasian pediatric and adult SBTx patients.


RESULTS
MAF for rs2066845 and rs2066847 was similar to that seen in 538 healthy North American Caucasians. In the discovery cohort, MAF for rs2066844 was significantly higher in LSBTx (13.5 vs. 3.6%, P=0.0007, Fisher's exact test), but not in isolated SBTx recipients (2.2 vs. 3.6%, P=NS), when compared with 538 healthy Caucasians. In addition, among LSBTx recipients who received identical immunosuppression, the minor allele of rs2066844 associated with early rejection in linear regression analysis (P=0.028) (all but one of the risk alleles were found in rejectors), decreased survival (P=0.015, log-rank, Kaplan-Meier analysis), and a 20-fold greater hazard of septic death in proportional hazard analysis (P=0.030). Steroid-resistant (severe) rejection and graft loss were associated with isolated SBTx (P=0.036 and 0.082, respectively), but not with NOD2 SNPs. The association between rs2066844 and combined liver-intestine failure requiring LSBTx was significant in the replication cohort (P=0.014), and achieved greater significance in the combined cohort (P=0.00006).


CONCLUSIONS
The NOD2 SNP rs2066844 associates with combined liver and intestinal failure in subjects with short-gut syndrome, who require combined liver-intestine transplantation, and secondarily with early rejection and septic deaths.
Hillman Center for Pediatric Transplantation, University of Pittsburgh, Pittsburgh, Pennsylvania 15224, USA.
Mylarappa
M
Ningappa
Brandon W
BW
Higgs
Daniel E
DE
Weeks
Chethan
C
Ashokkumar
Richard H
RH
Duerr
Qing
Q
Sun
Kyle A
KA
Soltys
Geoffrey J
GJ
Bond
Kareem
K
Abu-Elmagd
George V
GV
Mazariegos
Feras
F
Alissa
Marcus
M
Rivera
Jeffrey
J
Rudolph
Robert
R
Squires
Hakon
H
Hakonarson
Rakesh
R
Sindhi
D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D016867:Immunocompromised Host; D007223:Infant; D007421:Intestine, Small / Q000637:transplantation*; D053208:Kaplan-Meier Estimate; D016031:Liver Transplantation / Q000009:adverse effects / Q000379:methods*; D008297:Male; D009102:Multiple Organ Failure / Q000517:prevention & control; D020380:Needs Assessment; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D012044:Regression Analysis; D012189:Retrospective Studies; D018570:Risk Assessment; D012778:Short Bowel Syndrome / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000601:surgery*; D016019:Survival Analysis
D053473:Nod2 Signaling Adaptor Protein