Histograms representing the proportion of individual African ancestry estimates based on 95 AIMs for REACH (A), BASS (B), and overall case-controls (C).

<p>Histograms representing the proportion of individual African ancestry estimates based on 95 AIMs for REACH (A), BASS (B), and overall case-controls (C).</p

Association of African ancestry and asthma using logistic regression models.^a

a<p>Multiple logistic regression models included age, gender and the study site. The African ancestry was introduced as a proportion in the range 0–1.</p

Differences in African ancestry estimates (%, mean±SD) among case-control samples.

a<p>Mean difference between asthmatics and non-asthmatics.</p>b<p>t-test. Sample sizes in parenthesis.</p

Association of demographic, socioeconomic, clinical and genetic factors with asthma exacerbations in CHIRAH study.

a<p>Use at each time point of the model.</p>b<p>Basal forced expiratory volume in one second.</p

Assessing the Validity of Asthma Associations for Eight Candidate Genes and Age at Diagnosis Effects

<div><p>Background</p><p>Before the advent of genome-wide association studies (GWAS), <i>ADAM33, ADRB2, CD14, MS4A2</i> (alias <i>FCER1B</i>), <i>IL13, IL4, IL4R</i>, and <i>TNF</i> constituted the most replicated non-<i>HLA</i> candidate genes with asthma and related traits. However, except for the <i>IL13-IL4</i> region, none of these genes have been found in close proximity of genome-wide significant hits among GWAS for asthma or related traits. Here we aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis.</p><p>Methodology/Principal Findings</p><p>We systematically evaluated 286 common single nucleotide polymorphisms (SNPs) of these 8 genes in a sample of 1,865 unrelated Spanish individuals (606 asthmatics and 1,259 controls). We found that variants at <i>MS4A2</i>, <i>IL4R</i> and <i>ADAM33</i> genes demonstrated varying association effects with the age at diagnosis of asthma, with 10 SNPs showing study-wise significance after the multiple comparison adjustment. In addition, <i>in silico</i> replication with GWAS data supported the association of <i>IL4R</i>.</p><p>Conclusions/Significance</p><p>Our results support the important role of <i>MS4A2</i>, <i>IL4R</i> and <i>ADAM33</i> genes in asthma and/or atopy susceptibility. However, additional studies in larger samples sets are needed to firmly implicate these genes in asthma susceptibility, and also to identify the causal variation underlying the associations found.</p></div

<i>P</i>-values of association by chromosome position with A) asthma ≤14years for <i>ADAM33</i>, B) asthma ≤39 years for <i>MS4A2</i> and, C) asthma ≤39 years for <i>IL4R</i>.

<p><b><i>P</i>-values are expressed in –log₁₀ scale.</b> The SNP number shown on the plot denotes the result for the most significant SNP for each gene and the results for the remaining were color coded to reflect their LD with this SNP based on pairwise <i>r</i>² values from the 1KGP. Estimated recombination rates (from 1KGP) were also plotted on the right axis to reflect the local LD structure.</p

Association summary of the 10 SNPs that resulted significantly associated with asthma after adjustments for the multiple comparisons.

<p>tSNPs are underlined.</p>a<p>According to NCBI build 36.3.</p>b<p>Computed for allele 1.</p>c<p>SNPs associated in previous studies.</p