Quantitative Trait Loci on Chromosome 21 have Pleiotropic Effects on %FEV1 and Allergen Polysensitization; asthma related traits in the EGEA study

To investigate whether the 21q21 region may contain a quantitative trait locus (QTL) with pleiotropic effect on % predicted FEV1 (forced expiratory volume in 1 second) and SPTQ (number of positive skin test responses to 11 allergens), in 295 EGEA families ascertained through asthmatic probands, we conducted a bivariate linkage analysis using two approaches: (1) a bivariate variance components (VC) analysis and (2) A combined principal components (CPC) analysis, with 13 microsatellites covering the whole chromosome 21. To identify the genetic variants associated with these traits, we performed family-based association analysis (FBAT) for the second principal component (PC2) using two microsatellites and 27 SNPs belonging to three candidate genes, located in the vicinity of the linkage peak. Univariate linkage analyses showed suggestive evidence of linkage to %FEV1 and SPTQ at two positions. Bivariate VC linkage analysis of these phenotypes led to an increase in linkage signals as compared to univariate analysis at the same positions. The peaks obtained by the CPC led to similar results as the full bivariate VC approach; evidence for linkage mainly coming from PC2. The strongest association signal, using single marker analysis for PC2, was obtained with D21S1252 (p=0.003 for global test; p=0.004 for allele 2 and p=0.001 for allele 11) and rs2834213 of IFNGR2 (p=0.003), these two loci being 3 Mb apart. Multi-marker analysis further strengthened this finding. These results indicate that at least two genetic factors may be involved in SPTQ and %FEV1 variability but further genotyping is needed to better understand these findings.