Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

CHI3L1 is a susceptibility gene for asthma, bronchial hyperresponsiveness, and reduced lung function, and elevated circulating YKL-40 levels are a biomarker for asthma and decline in lung function.

Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T(h)2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Ralpha and either gammac or IL-13Ralpha1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ralpha and IL-13Ralpha1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Ralpha1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Ralpha1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3. 38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.

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We present two extensions to linkage analysis for genetically complex traits. The first extension allows investigators to perform parametric (LOD-score) analysis of traits caused by imprinted genes-that is, of traits showing a parent-of-origin effect. By specification of two heterozygote penetrance parameters, paternal and maternal origin of the mutation can be treated differently in terms of probability of expression of the trait. Therefore, a single-disease-locus-imprinting model includes four penetrances instead of only three. In the second extension, parametric and nonparametric linkage analysis with two trait loci is formulated for a multimarker setting, optionally taking imprinting into account. We have implemented both methods into the program GENEHUNTER. The new tools, GENEHUNTER-IMPRINTING and GENEHUNTER-TWOLOCUS, were applied to human family data for sensitization to mite allergens. The data set comprises pedigrees from England, Germany, Italy, and Portugal. With single-disease-locus-imprinting MOD-score analysis, we find several regions that show at least suggestive evidence for linkage. Most prominently, a maximum LOD score of 4.76 is obtained near D8S511, for the English population, when a model that implies complete maternal imprinting is used. Parametric two-trait-locus analysis yields a maximum LOD score of 6.09 for the German population, occurring exactly at D4S430 and D18S452. The heterogeneity model specified for analysis alludes to complete maternal imprinting at both disease loci. Altogether, our results suggest that the two novel formulations of linkage analysis provide valuable tools for genetic mapping of multifactorial traits.