Penetrance of NOD2/CARD15 genetic variants in the general population

Background: In case-control studies of Europeans, heterozygosity for Arg702Trp(rs2066844), Gly908Arg(rs2066845) and Leu1007fsinsC(rs5743293) on the NOD2/CARD15 gene is associated with a 2-fold greater risk of Crohn disease, whereas homozygosity or compound heterozygosity is associated with a 17-fold greater risk. However, the importance of these genetic variants if identified in particular individuals within the general population is unknown. We undertook this study to estimate the penetrance of these variants in the general population. Methods: We genotyped 43 596 individuals from the Danish general population followed between January 1976 and July 2007 Using a logistic regression model, we estimated the risk of Crohn disease in relation to variants of the NOD2/CARD15 gene in the general population. Penetrance was calculated as the fraction of participants in whom Crohn disease was diagnosed before age 50 years. Results: In the general population, 89% of participants were noncarriers of the genetic variants of interest (n = 38 594), 11% were heterozygotes (n = 4838), and 0.4% were compound heterozygtes or homozygotes (n = 164). or Crohn disease, multifactorially adjusted odds ratios were 1.2 (95% confidence interval [Cl] 0.8-1.9) for heterozygotes and 3.3 (95% Cl 0.8-13.6) for compound heterozygotes and homozygotes combined, relative to noncarriers. Only h compound heterozygotes received a diagnosis of Crohn disease, and this disease was not diagnosed in any of the homo c zygotes. The penetrance at age 50 years of NOD2/CARD15 genetic variants of Crohn disease was 0.30% (95% CI 0.29%-0.31%) for heterozygotes and 1.5% (95% CI 1.4%-1.6%) for compound heterzygotes and homozygotes. Interpretation: The penetrance of NOD2/CARD15 genetic variants in relation to risk of Crohn disease for this Danish population was lower than might have been expected from previous European case-control studies. This should be considered when advising healthy individuals in whom these genetic variants are identified.