Dense mapping of chromosome 12q13.12-q23.3 and linkage to asthma and atopy

Background: Asthma is a complex disease characterized by a high prevalence of allergic diathesis and the almost ubiquitous presence of upper airway disease (eg, rhinitis). Previously, we observed linkage of asthma among Afro-Caribbean families to markers in chromosome 12q, which contains a number of genes encoding for products closely related to allergic airway inflammation and disease. Objective: To identify susceptibility loci in chromosome 12q contributing to the genetics of upper and lower airway diseases and to expand the region to include genes encoding IFN-gamma (IFNG) and one of the signal transducers and activators of transcription (STAT6), we conducted further linkage studies among 33 multiplex families. Methods: We characterized 528 subjects from Barbados for asthma; 82% were characterized for allergic rhinitis. Two-point and multipoint linkage analysis of 22 microsatellite markers (spanning similar to 79 centimorgan) was performed. Results-Affected sib-pair analysis revealed significant evidence for linkage to asthma over approximately 30 cM (P < .05 to .002), with the best evidence for linkage at a CA repeat polymorphism in the first intron of IFNG in 12q21.1 (P = .002). Evidence of linkage to allergic rhinitis was observed in the same region (D12S313, P = 0.006, and IFNGCA, P = .01, respectively). Multipoint linkage analysis also provided evidence for linkage to asthma, with the best nonparametric link-age analysis score at D12S326 (nonparametric linkage score = 3.8, P = .0008). Modest evidence for linkage to allergic rhinitis was observed next to D12S326 at D12S1052 (P = .036). Conclusions: Our findings suggest that (1) one or more loci in the chromosome 12q13.12-q23.3 region are contributing to the expression of the clinical phenotype asthma and the strongest evidence for linkage is in a region near the gene encoding IFNG and (2) a susceptibility locus for both asthma and allergic rhinitis maps to this region.