To improve the possibility to identify high risk patients in CD families we propose in alternative to the classical HLA classification (Fig. 4, panel A) a slight improved flow-chart (Fig. 4, panel B): 1) HLA genotyping: subjects belonging to the HLA risk groups 1 and 2 will be classified as at high CD risk; 2) subjects belonging to the HLA risk groups 3 and 4, will be further investigated for our SNPs combination (LPP, REL, RGS1) in order to calculate their BS (Fig. 4, panel B). The gene discussed is REL; the disease is Cowden disease.