Variants of NOD1 and NOD2 genes display opposite associations with familial risk of crohn's disease and anti-saccharomyces cerevisiae antibody levels

Background: NOD2 is involved in Crohn's disease (CD), but the role of NOD1 remains unclear. Anti-Saccharomyces cerevisiae antibodies (ASCA) are higher in CD patients and some of their relatives. Using family-based analyses we investigated the relationships between NOD2 mutations, NOD1 +32656 variant, and both the risk of CD and ASCA levels. We compared allelic frequencies between families with multiple CD cases (multiplex), those with one case of CD (simplex), and control families, searching for a gradient of at risk alleles according to the prevalence of the disease among families. Methods: In all, 93 CD patients, 160 healthy relatives from 22 multiplex families, 22 CD patients and 81 healthy relatives from 22 simplex families, and 169 subjects from 27 control families were included in the study. ASCA levels were determined by enzyme-linked immunosorbent assay. NOD1 +32656, NOD2 R702W, G908R, and 1007fs were genotyped by polymerase chain reaction / restriction fragment length polymorphism. Results: In family-based analyses NOD2 mutations and the NOD1 wildtype allele were associated with CD in multiplex families, with a synergetic effect when risk alleles of both genes were transmitted. Lower ASCA levels were strongly associated with the NOD1 variant allele. Simplex families had a lower frequency of the "at risk" +32656 allele than multiplex families. Conclusions: The +32656 variant was associated with low ASCA level and low risk of CD in multiplex families. NOD2 and NOD1 variants displayed antagonist effects on the risk of CD and ASCA level. A gradient of NOD1, NOD2 at-risk alleles was associated with the variable prevalence of CD in families.