Linkage heterogeneity for the IBD1 locus in Crohn's disease pedigrees by disease onset and severity

Background & Aims: There is evidence for the IBD1 Crohn's disease'(CD) susc eptibility locus on chromosome 16 in several but not all populations studie d. Genetic and phenotypic heterogeneity may underlie ability to replicate I BD1. We determined if age and severity stratification could identify a clin ical subgroup at risk for IBD1. Methods: Linkage analysis at microsatellite s spanning chromosome 16 was performed in 2 groups of CD pedigrees: group 1 , 57 pedigrees with at least one affected relative classified as having "se vere" disease, by history of surgical resection or immunomodulator therapy, and with disease diagnosed before age 22; and group 2, 33 pedigrees with n o history of early-onset, severe CD. Results: Group 1 pedigrees demonstrate d genomewide significant linkage evidence for the IBD1 locus (nonparametric multipoint logarithm of the odds [Mlod], 3.84; P = 1.3 x 10(-5)) with link age evidence greater than all 90 pedigrees (Mlod, 2.12; P = 9.0 x 10(-4)). Group 2 pedigrees had near zero nonparametric 2-point and Mlod scores for t he IBD1 region. Heterogeneity between groups 1 and 2 was significant (P = 0 .002). Conclusions: Presence of early-onset, more severe CD identifies pedi grees at high risk for IBD1. These pedigrees will have move power to refine the IBD1 locus and identify the causative gene.