A CARD9 Polymorphism Is Associated with Decreased Likelihood of Persistent Conjugated Hyperbilirubinemia in Intestinal Failure

Abstract

Recently, genetic associations have been described in intestinal transplants. Namely, Crohn's disease susceptibility gene NOD2 polymorphisms have been reported to be more prevalent in patients with graft failure following intestinal transplantation (IT). Therefore, we sought to determine if polymorphisms in the NOD2 signaling cascade, including NOD2, CARD9, RAC1 and ATG16L1 are associated with intestinal failure (IF) or its complications. We carried out a cross-sectional study of 59 children with IF and 500 healthy Caucasian controls. Using the Taqman platform we determined the prevalence of NOD2 as well as ATG16L1, RAC1 and CARD9 SNPs. NOD2 pathway polymorphisms were evaluated in relation to outcomes of episodes of sepsis, ICU admissions, hyperbilirubinemia and need for IT. We found that the minor allele of a CARD9 SNP was associated with protection from developing IF when compared to healthy controls and was also associated with decreased odds of sustained conjugated hyperbilirubinemia. Therefore, IF patients with CARD9 polymorphism are less likely to develop progressive liver disease and suggests that host innate immunity may play a role in IF associated liver disease.

Molecular and physiological roles of the adaptor protein CARD9 in immunity

“…Human CARD9 genetic mutations may result in protein structure modifications, lower expression, or function loss. CARD9 genetic mutations are associated with inflammatory responses, a susceptibility to fungal infection 45 , 46 , Crohn’s disease 47 , 48 , ulcerative colitis 49 , 50 , intestinal failure 51 , ankylosing spondylitis 52 , 53 , as well as the severity of pulmonary tuberculosis 54 .…”

“…The CARD9 mutations, rs4077515, were found to be protective against intestinal failure. One possibility was that this genetic mutations decreased the level of sustained conjugated hyperbilirubinemia and inhibited NOD 2 -dependent signal pathways 51 . The CARD9 mutations rs4077515 significantly decreased the ankylosing spondylitis risk in a HLA-B27-negative Iranian population, possibly by contributing to the CARD9-IL23 axis for the pathogenesis of inflammatory disorders 52 .…”

The CARD9 Polymorphisms rs4077515, rs10870077 and rs10781499 Are Uncoupled from Susceptibility to and Severity of Pulmonary Tuberculosis

“…While the selected CARD9 SNPs predispose to chronic inflammation in multifactorial inflammatory diseases [ 10 , 14 , 25 , 31 ], their roles in human infections driven by specific microbes, such as Mtb, as shown here, and Candida spp. [ 13 , 19 ], appears limited.…”

The interaction effect of rs4077515 and rs17019602 increases the susceptibility to IgA nephropathy

“…CARD9 is a nonredundant adapter protein which functions in the immune system. As an adaptor protein, CARD9 can coordinate innate and adaptive immune responses, mounting an IFN-γ gut response to pathogens appropriately [ 15 ] and stimulating T cells to differentiate into TH17 cells [ 16 ]. Previous researches have demonstrated that CARD9 was associated with some inflammatory diseases such as tuberculosis, [ 17 ] IBD, [ 18 ] CD [ 9 ] and rheumatoid arthritis [ 19 ].…”