ABSTRACT
Heterogeneity of results of linkage and association studies for complex trait susceptibility loci is not uncommon, and can result through a variety of mechanisms, including true genetic or phenotypic differences across populations and issues relating to study design (i.e., ascertainment scheme, sample size, population substructure). Epigenetic effects, including allelic imprinting, can also introduce important heterogeneity across studies, and may contribute to observed inconsistencies in linkage and association results. Because there is evidence that maternal history of allergic disease (compared to paternal history) has more influence over subsequent allergic phenotypes in offspring,345-347 this latter possibility of genetic imprinting of genes related to atopy has received considerable attention, particularly with regard to chromosome 11q13. Using statistical models that consider allelic parent-of-origin effects, several groups have demonstrated strengthened evidence of either linkage or association with FCER1B when considering maternally derived alleles.312,319,344,348-350 In certain instances, maternally derived effects were detected without evidence of primary association. Although an intriguing possible mechanism, there is no molecular evidence that chromosome 11q13 demonstrates imprinting, and the observed associations may simply reflect post-hoc analysis and
There is contradictory evidence to support an association between each of the 10 genes discussed above (IL4, IL4RA, IL10, IL13, ADRB2, CD14, TNFA, LTA, HLA-DRB1, and FCERIB) and asthma and/or asthma-related phenotypes, suggesting that none of these genes is a major susceptibility gene for asthma. However, the relatively high number of positive association studies, and the fact that potentially functional SNPs in eight of these genes (IL4, IL4RA, IL10, IL13, ADRB2, CD14, TNFA, and HLA-DRB1) are associated with asthma and/or asthma-related phenotypes, suggests that these genes are either true susceptibility genes for asthma-related phenotypes with minor to moderate effect, or that they are in LD with genes that influence asthmarelated phenotypes.
