Assessing the Reproducibility of Asthma Candidate Gene Associations, Using Genome-wide Data

Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 04/2009; 179(12):1084-90. DOI: 10.1164/rccm.200812-1860OC
Source: PubMed


Association studies have implicated many genes in asthma pathogenesis, with replicated associations between single-nucleotide polymorphisms (SNPs) and asthma reported for more than 30 genes. Genome-wide genotyping enables simultaneous evaluation of most of this variation, and facilitates more comprehensive analysis of other common genetic variation around these candidate genes for association with asthma.
To use available genome-wide genotypic data to assess the reproducibility of previously reported associations with asthma and to evaluate the contribution of additional common genetic variation surrounding these loci to asthma susceptibility.
Illumina Human Hap 550Kv3 BeadChip (Illumina, San Diego, CA) SNP arrays were genotyped in 422 nuclear families participating in the Childhood Asthma Management Program. Genes with at least one SNP demonstrating prior association with asthma in two or more populations were tested for evidence of association with asthma, using family-based association testing.
We identified 39 candidate genes from the literature, using prespecified criteria. Of the 160 SNPs previously genotyped in these 39 genes, 10 SNPs in 6 genes were significantly associated with asthma (including the first independent replication for asthma-associated integrin beta(3) [ITGB3]). Evaluation of 619 additional common variants included in the Illumina 550K array revealed additional evidence of asthma association for 15 genes, although none were significant after adjustment for multiple comparisons.
We replicated asthma associations for a minority of candidate genes. Pooling genome-wide association study results from multiple studies will increase the power to appreciate marginal effects of genes and further clarify which candidates are true "asthma genes."

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    • "In addition, GWAS have high sensitivity, which allows detection of signals localized to small regions of the chromosome containing only a single or a few genes, enabling us to identify the targeted genes. However, most GWAS have only managed to explain a small additional percentage of hereditability estimates, and exhibit poor reproducibility [5,6]. Several complementary strategies have been adopted to overcome these study limitations, including large-scale recruitment of cases and controls. "
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    ABSTRACT: To date, genome-wide association studies (GWAS) permit a comprehensive scan of the genome in an unbiased manner, with high sensitivity, and thereby have the potential to identify candidate genes for the prevalence or development of multifactorial diseases such as bronchial asthma. However, most studies have only managed to explain a small additional percentage of hereditability estimates, and often fail to show consistent results among studies despite large sample sizes. Epistasis is defined as the interaction between multiple different genes affecting phenotypes. By applying epistatic analysis to clinical genetic research, we can analyze interactions among more than 2 molecules (genes) considering the whole system of the human body, illuminating dynamic molecular mechanisms. An increasing number of genetic studies have investigated epistatic effects on the risk for development of asthma. The present review highlights a concept of epistasis to overcome traditional genetic studies in humans and provides an update of evidence on epistatic effects on asthma. Furthermore, we review concerns regarding recent trends in epistatic analyses from the perspective of clinical physicians. These concerns include biological plausibility of genes identified by computational statistics, and definition of the diagnostic label of 'physician-diagnosed asthma'. In terms of these issues, further application of epistatic analysis will prompt identification of susceptibility of diseases and lead to the development of a new generation of pharmacological strategies to treat asthma.
    Preview · Article · Jan 2014 · Medical science monitor: international medical journal of experimental and clinical research
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    • "It has been recently found that genetic variants in the vitamin D receptor (VDR) are variably associated with the risk of asthma development.22 VDR is also a critical molecule in calcium metabolism and bone turnover or other immune and inflammatory disorders.23 "
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    ABSTRACT: Humans have the ability to synthesize vitamin D during the action of ultraviolet (UV) radiation upon the skin. Apart from the regulation of calcium and phosphate metabolism, another critical role for vitamin D in immunity and respiratory health has been revealed, since vitamin D receptors have also been found in other body cells. The term "vitamin D insufficiency" has been used to describe low levels of serum 25-hydroxyvitamin D that may be associated with a wide range of pulmonary diseases, including viral and bacterial respiratory infection, asthma, chronic obstructive pulmonary disease, and cancer. This review focuses on the controversial relationship between vitamin D and asthma. Also, it has been found that different gene polymorphisms of the vitamin D receptor have variable associations with asthma. Other studies investigated the vitamin D receptor signaling pathway in vitro or in experimental animal models and showed either a beneficial or a negative effect of vitamin D in asthma. Furthermore, a range of epidemiological studies has also suggested that vitamin D insufficiency is associated with low lung function. In the future, clinical trials in different asthmatic groups, such as infants, children of school age, and ethnic minorities are needed to establish the role of vitamin D supplementation to prevent and/or treat asthma.
    Full-text · Article · Sep 2013 · Drug Design, Development and Therapy
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    • "Several studies have investigated the reproducibility of asthma candidate gene associations. One study by Rogers et al. (2009) investigated 160 associated SNPs from 39 genes from an Illumina 550k array in 422 families and successfully replicated 10 SNPs in six genes [12]. At the level of the gene they found additional support for association in 15 of the 39 genes but none were significant after adjustment for multiple comparisons. "
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    ABSTRACT: Background Asthma genetics has been extensively studied and many genes have been associated with the development or severity of this disease. In contrast, the genetic basis of allergic rhinitis (AR) has not been evaluated as extensively. It is well known that asthma is closely related with AR since a large proportion of individuals with asthma also present symptoms of AR, and patients with AR have a 5–6 fold increased risk of developing asthma. Thus, the relevance of asthma candidate genes as predisposing factors for AR is worth investigating. The present study was designed to investigate if SNPs in highly replicated asthma genes are associated with the occurrence of AR. Methods A total of 192 SNPs from 21 asthma candidate genes reported to be associated with asthma in 6 or more unrelated studies were genotyped in a Swedish population with 246 AR patients and 431 controls. Genotypes for 429 SNPs from the same set of genes were also extracted from a Singapore Chinese genome-wide dataset which consisted of 456 AR cases and 486 controls. All SNPs were subsequently analyzed for association with AR and their influence on allergic sensitization to common allergens. Results A limited number of potential associations were observed and the overall pattern of P-values corresponds well to the expectations in the absence of an effect. However, in the tests of allele effects in the Chinese population the number of significant P-values exceeds the expectations. The strongest signals were found for SNPs in NPSR1 and CTLA4. In these genes, a total of nine SNPs showed P-values <0.001 with corresponding Q-values <0.05. In the NPSR1 gene some P-values were lower than the Bonferroni correction level. Reanalysis after elimination of all patients with asthmatic symptoms excluded asthma as a confounding factor in our results. Weaker indications were found for IL13 and GSTP1 with respect to sensitization to birch pollen in the Swedish population. Conclusions Genetic variation in the majority of the highly replicated asthma genes were not associated to AR in our populations which suggest that asthma and AR could have less in common than previously anticipated. However, NPSR1 and CTLA4 can be genetic links between AR and asthma and associations of polymorphisms in NPSR1 with AR have not been reported previously.
    Full-text · Article · May 2013 · BMC Medical Genetics
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