Should family members of IBD patients be screened for CARD15/NOD2 mutations?

The familial occurrence of inflammatory bowel disease (IBD) is well known. Around 5.5%–22.5% of patients with IBD have another family member also affected with the disease.1–3 In fact, the most important risk factor for IBD is having a family member with the disease. The relative risk for a sibling of a CD patient to also become affected is 13–36, and for a sibling of a UC patient this risk is 7–17. Translating this into absolute numbers, hereby assuming an overall incidence in Europe and North America of 10 new cases per 100,000 for UC and 5– 6 new diagnoses per 100,000 for Crohn’s disease (CD), this gives a risk of only 2%–3% for a sibling of a CD patient and 0.5%–1% for a sibling of an ulcerative colitis (UC) patient.4 The greatest risk appears for children of whom both parents have IBD ( 30% at the age of 28 years).5 It is therefore not unexpected that patients are often worried that their healthy siblings or offspring would also get the same diagnosis. Patients with IBD and a familial history tend to get their disease at an earlier age than patients without a familial history and show an increased concordance in disease type (CD or UC) and probably also disease location. The severity of the disease, on the other hand, does not differ between familial or sporadic disease. Although the search for predictive markers that could identify family members at risk for IBD has been intensive, no such markers have been identified so far. The news of the identification of CARD15 (originally identified as NOD2 but officially renamed CARD15) as the first susceptibility gene for CD in 2001 was quickly spread both in the medical world as well as among patients and patient’s organizations.6–8 Since then gastroenterologists have often been asked by patients if their healthy relatives could be tested for the presence of CARD15 mutations. Over 30 nonconservative polymorphisms have been identified within the gene that are associated with CD but only 3 polymorphisms are common (Arg702Trp, Gly908Arg, and Leu1007insC) and account for 82% of the mutated alleles.9 CARD15 variants are found in the majority of the Caucasian CD patients and vary between 35%–45% with the exception of Scandinavian and Celtic populations, where the prevalence is much lower.10 In contrast to this, no CARD15 mutations are detected in the Asian and the African-American populations. CARD15 explains around 20% of the genetic predisposition to CD. When it comes to screening a population for a certain mutation or defect, this is only useful when the sensitivity is high enough and when preventive strategies (to slow down the onset of the disease or even prevent it) are available. In the case of CARD15/NOD2, only 40%–50% of patients with CD are mutation carriers. Moreover, 20% of healthy individuals also carry CARD15 variants. Hence, the absence of a mutation in an unaffected individual would not exclude the development of the disease, nor would the presence of a mutation necessarily lead to clinical symptoms. The same will inevitably be true for the other genes that are being identified in IBD. The only thing which can be said at this moment to answer the question if CARD15 genotyping in relatives is useful is that the relative risk to develop CD in the presence of 1 CARD15 mutation is 2–4, and that this risk increases to 20–40 in the case of 2 mutations (compound heterozygous or homozygous).11 However, healthy individuals with double mutations have also been reported. Even when the sensitivity of CARD15/NOD2 genotyping would be sufficiently high, preventive strategies or therapies to slow down the disease or prevent its onset are not (yet) available. It is only when such preventive actions become available that screening unaffected family members might be useful and even necessary. So far, the only advice clinicians can give to unaffected relatives of CD patients is to not smoke.