Article Text

PDF

Letter
Association of Crohn's disease-associated NOD2 variants with intestinal failure requiring small bowel transplantation and clinical outcomes
  1. M Janse1,2,
  2. R K Weersma1,
  3. D L Sudan3,
  4. E A M Festen1,2,
  5. C Wijmenga2,
  6. G Dijkstra1,
  7. D Mercer4
  1. 1Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
  2. 2Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
  3. 3Department of Abdominal Transplant Surgery, Duke University Medical Center, Durham, USA
  4. 4Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA
  1. Correspondence to Dr RK Weersma, Department of Gastroenterology and Hepatology, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands; R.K.Weersma{at}int.umcg.nl

Statistics from Altmetric.com

In the past decade intestinal transplantation has evolved to a viable option in the treatment of short bowel syndrome, especially for patients who have developed life-threatening complications attributable to their intestinal failure and/or long-term total parental nutrition therapy.1 Technical improvements, novel immunosuppressive agents and increased clinical experience have contributed to an improvement in intestineal transplant graft and patient survival. One-year graft and patient survival are nowadays both estimated at 80%.2 3

Despite these recent advances, rejection resulting in failure of the graft still remains a problem causing significant patient morbidity and mortality. Identifying involved pathogenetic mechanisms might make it possible to predict or eventually prevent intestinal graft failure or rejection.

We would like to respond to the interesting study by Fishbein et al recently published in this journal.4 The authors point out the clinical and pathological resemblance of intestinal allograft rejection and Crohn's disease. On the basis of this resemblance Fishbein et al genotyped 34 recipients and 34 donors of small bowel transplants for the three Crohn's disease-associated NOD2 polymorphisms: R702W, 3020insC and G908R. The authors conclude that the prevalence of NOD2 mutations in the recipients compared to the donors of small intestinal transplants is higher (35% and 8.6%, respectively) and are also associated with graft failure after small bowel transplantation.

Since the cohort in the study of Fishbein et al was small, we set out to study their findings in a larger cohort of small bowel transplant recipients and donors. Our study population consisted of 99 recipients of either a small bowel transplant, combined small bowel/liver transplant, or a multivisceral transplant, and 71 donors. There were 55 matched donor–recipient couples. All patients were transplanted at the Nebraska Medical Center, Omaha, Nebraska. Eighty-six patients were transplanted between February 2003 and July 2007 and 13 patients between 1996 and December 2002. Clinical characteristics of both recipients and donors are shown in table 1.

Table 1

Recipient and donor demographic (A) and clinical (B) characteristics

All donors and recipients were genotyped for the three Crohn's disease-associated NOD2 polymorphisms.

The results are depicted in table 2. Comparing allele frequencies of R702W, G908R and 3020insC in recipients and donors, there is no significant difference between the two groups (table 2).

Table 2

NOD2 allele frequencies in small bowel transplant recipients and donors from the Nebraska Medical Center, Omaha, Nebraska

We then evaluated NOD2 mutation status in recipients for association with the clinical outcomes: rejection, graft failure and patient survival. In recipients without any NOD2 mutation 30/87 experienced an initial rejection episode, 8/87 experienced graft failure, and 23/87 died within 3 years after transplantation. In recipients with a NOD2 mutation these numbers were 3/8, 2/8 and 3/8, respectively (log-rank analysis: p=0.681; p=0.097 and p=0.391 respectively). NOD2 status of the donor was also not significantly associated with these clinical endpoints (p=0.235; p=0.806 and p=0.704, respectively; N=55).

In our cohort, which is three times as large as the one in the original study by Fishbein et al, we could not reproduce their findings regarding the increased occurrence of NOD2 in small bowel transplant recipients or an association with intestinal allograft rejection. Although their hypothesis regarding NOD2 being a critical immunological risk factor for intestinal allograft rejection is intriguing, it is conceivable that the identified genetic association constitutes a false positive finding, due to the small sample size. However, the small number of recipients carrying one or more NOD2 variants in our cohort prevented a definite conclusion on clinical endpoints. Therefore an even larger cohort than ours would be necessary to definitely prove or rule out a possible association.

References

View Abstract

Footnotes

  • Funding RW is supported by a clinical fellow grant from the Netherlands Organization for Scientific Research (NWO). CW is supported by a VICI grant from the Netherlands Organization for Scientific Research (NWO). GD is supported by a clinical fellow grant from the Netherlands Organization for Scientific Research (NWO). Other Funders: Netherlands Organization for Scientific Research (NWO).

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the University of Nebraska Medical Center, Omaha, Nebraska, USA.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Linked Articles

  • PostScript
    Thomas M Fishbein Michael Zasloff