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P662. BAX, a novel susceptibility gene for Crohn's disease

A. Fernandez1,2, R. Gonzalez3, V. Prieto1, J. Fernandez3, J. Martin3,4, M. San Maximo3,4, A. Alvarez1, C. Piñero1, Y. Jamanca1, J. Umaña1, A. Velasco1, A. Rodriguez1, 1Hospital Clínico de Salamanca, Gastroenterology, Salamanca, Spain, 2Salamanca, Gastroenterology, Salamanca, Spain, 3University of Salamanca, Medicine, Salamanca, Spain, 4University of Salamanca, Statistics, Salamanca, Spain

Background

Autophagy and apoptosis play a major role in Crohn's disease (CD). We present the first study in our population of polymorphisms (SNPs) involved in these scenarios (NOD2, ATG16L1, p53, BAX, BCL-2).

Methods

In 102 patients and 101 “ healthy” controls, following SNPs were studied: NOD2 (rs2066844); ATG16L1 (rs2241880); BAX (rs4645878); BCL-2 (rs2279115); p53 (Pro/Arg). After informed consent, DNA was obtained from peripheral blood. Polymorphisms were analyzed using TaqMan probes, after PCR amplification. p53 (rs1042522) was analyzed by PCR amplification and restriction endonuclease digestion. We analyzed whether these SNPs were associated with an increased risk of CD and its relationship with clinical variables. Interaction between genes was studied using CART (Classification And Regression Trees).

Results

Mean age at diagnosis 31.69±14.024 years, A2 predominance of Montreal (72.5%). Slight predominance of women (43.1% M, 56.9% F). In our study the most frequent genotypes were as shown in Table 1.

No associations were detected between polymorphisms and clinical variables. In the interaction gene–gene by CART individuals with CC-NOD2 genotype were all controls, while 88.7% of CT or TT genotypes were CD. BAX showed the greater association with NOD2: 90.9% of patients with genotype GG were controls and only one patient (9.1%) CD; in the GA-AA group, 97.1% were CD and only 3 controls. In individuals with an allelic composition CT/TT-NOD2, the risk of CD is 333.33 times higher in individuals with alleles AA/GA-BAX than in individuals with GG-BAX. Genotypes CT/TT-NOD2 and AA/GA-BAX, classified patients with CD with an accuracy of 98%. The model has a sensitivity of 99% and a specificity of 96.1%. PPV = 97.1%; NPV = 99%.

Table 1. Polymorphisms: comparison with control group (susceptibility)
PolymorphismHomozygote dominance in CDDominance in controlsAlleles CD/Controls
NOD2 (rs2066844)TT (98.8%)CC (100%)T (92.8% vs. 7.2%)
P53 (Pro/Arg)CC (HN=Pro/Pro) (67.6%)CG (61.3%)C (Pro) (52.5% vs. 47.5%)
ATG16L1 (rs2241880)GG (63.5%)AG (58.3%)G (53.7% vs. 46.3%
BAX (rs4645878)AA (95.7%)GG (98.6%)A (83.9% vs. 16.1%)
BCL2 (rs2279115):AA (65.8%)CC (56.9%)A (55.3% vs. 44.7%)

Conclusion

It is the first time that BAX is identified as a susceptibility gene for CD: 97.1% of patients with genotype AA/GA have the disease. Combination of genotypes CT/TT-NOD2 and AA/GA-BAX, classified patients with CD with an accuracy of 98%. It is necessary to extend the study to other populations and among family members.