Which genes increase the risk for Clostridium difficile (C diff) infection (CDI)?

Updated: Jul 25, 2019
  • Author: Faten N Aberra, MD, MSCE; Chief Editor: BS Anand, MD  more...
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Two genome-wide association studies (GWAS) found an association between a common polymorphism in the upstream promoter of the interleukin (IL)-8 gene and an increased risk for both the initial occurrence and the recurrence of CDI. [22, 23] Neutrophil recruitment to the intestine is thought to be coordinated by IL-8, and the polymorphism in the IL-8 promoter is thought to influence the manner in which neutrophils are recruited to the intestines when CDI is present. [22, 23]

An additional study looked more specifically at the regulation of the regenerating islet-derived genes (REG) in IBD. Interestingly, the study found that the activities of all REG genes were upregulated not only in IBD but also in patients with pseudomembranous colitis. [24] The implication from this study is that the function of the REG family of genes is more generalized in response to inflammation. These proteins are involved in injury, repair, and growth in the intestine. Also of interest is that REG proteins in the gut appear to be antimicrobial, with a function similar to lectin. [24]

Toxin A is an enterotoxin that is responsible for the major manifestations of colitis in humans. In a murine model deficient in the neurokinin-1 receptor, protection against inflammation from toxin A was demonstrated. [25] This protein, which is encoded by the NK1R gene, functions as the receptor for substance P. Downstream effects from this protective effect included decreased intestinal levels of tumor necrosis factor (TNF)-alpha and leukocyte myeloperoxidase. The overall suggestion from this study is that the substance P receptor is very important in the pathogenesis of inflammatory diarrhea. [25]

Further insight into the genetics of C difficile toxin A reveals that the main binding protein is gp96. [26] In addition, it has been found that C difficile has potent stimulatory activity for the Nod1 gene, and mice who were homozygous knockouts for Nod1 had increased lethality to CDI despite similar levels of intestinal damage relative to control the mice. [27] Those mice also had impaired clearance of bacteria and increased translocation of the bacteria. The implication of this study is that Nod1 regulates the susceptibility to C difficile. [27]

Ultimately, many of the genetic influences on CDI and the clinical course of C difficile colitis likely remain unknown. At this point, it is understood that subtle differences in the immune system may significantly influence the natural history of C difficile disease.

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