Abstract
Background: Very recently, a sub-analysis of genome-wide association
scans revealed that the non-coding single nucleotide polymorphism (SNP)
rs12212067 in the FOXO3A gene is associated with a milder course of
Crohn's disease (CD) (Cell 2013; 155: 57-69). The aim of our study was
to evaluate the clinical value of the SNP rs12212067 in predicting the
severity of CD by correlating CD patient genotype status with the most
relevant complications of CD such as stenoses, fistulas, and CD-related
surgery.
Methodology/Principal Findings: We genotyped 550 CD patients for
rs12212067 (FOXO3A) and the three common CD-associated NOD2 mutations
rs2066844, rs2066847, and rs2066847 and performed genotype-phenotype
analyses.
Results: No significant phenotypic differences were found between the
wild-type genotype TT of the FOXO3A SNP rs12212067 and the minor
genotypes TG and GG independently from NOD2 variants. The allele
frequency of the minor G allele was 12.7%. Age at diagnosis, disease
duration, body mass index, surgery rate, stenoses, fistula, need for
immunosuppressive therapy, and disease course were not significantly
different. In contrast, the NOD2 mutant p. Leu1007fsX1008 (rs2066847)
was highly associated with penetrating CD (p = 0.01), the development of
fistulas (p = 0.01) and stenoses (p = 0.01), and ileal disease
localization (p = 0.03). Importantly, the NOD2 SNP rs2066847 was a
strong separator between an aggressive and a mild course of CD (p = 2.99
x 10(-5)), while the FOXO3A SNP rs12212067 did not separate between mild
and aggressive CD behavior in our cohort (p = 0.35). 96.2% of the
homozygous NOD2 p. Leu1007fsX1008 carriers had an aggressive disease
behavior compared to 69.3% of the patients with the NOD2 wildtype
genotype (p = 0.007).
Conclusion/Significance: In clinical practice, the NOD2 variant p.
Leu1007fsX1008 (rs2066847), in particular in homozygous form, is a much
stronger marker for a severe clinical phenotype than the FOXO3A
rs12212067 SNP for a mild disease course on an individual patient level
despite its important impact on the inflammatory response of monocytes.