Insights into genetic susceptibility to asthma

Asthma is a common complex multifactorial disease in which genetic determinants play an important role (Box 11.3). Cookson and colleagues published research in 2007 that elegantly demonstrated the power of complimentary genome-wide association studies of disease susceptibility, and of gene expression (Dixon et al. 2007; Moffatt et al. 2007). The investigators carried out an initial genome-wide scan in family and case-control panels comprising a total of 994 individuals of British and German descent with childhood onset asthma and 1243 non-asthmatics (Moffatt et al. 2007). Analysis of 317 000 SNPs resolved that seven of 12 marker SNPs with a false discovery rate of less than 1% showed association with a 112 kb region at chromosome 17q21 (Fig. 11.7), the most strongly associated SNP being rs7216389 (c.236-1199G>A) (P = 9 X 10"). The associated markers (with P <106) spanned three haplotype blocks over 206 kb and showed low linkage disequilibrium, suggesting one or more causative variants may

Figure 11.6 Copy number variation in UGT2B17 for different human populations. Reprinted from American Journal of Human Genetics (Xue et al. 2008), copyright 2008, with permission from Elsevier .

Box 11.3 Asthma

Asthma is a common, chronic respiratory disease that is associated with significant morbidity and can be fatal. The condition is characterized by chronic airway inflammation and hyper-responsiveness. Symptoms include wheeze, breathlessness, chest tightness, and cough. Airflow obstruction is to a variable degree reversible, with effective bron-chodilator medications available. There are many known environmental factors influencing the development of asthma and the precipitation of acute attacks. There is a strong familial component to asthma and the disease has been subject to intensive investigation as a common multifactorial trait without a clear pattern of inheritance. Many linkage and candidate gene association studies have been performed with further evidence more recently from genome-wide association studies.

Linkage analysis and positional cloning has had significant successes, as seen with the identification of ADAM33 at chromosome 20p13 (Van Eerdewegh et al. 2002). Elsewhere genetic variation has been implicated in genes involved in innate immunity and immune regulation such as encoding pattern recognition receptors (CD14, TLR2) and cytokines (IL10, TGFB1), as well as in antigen presentation (HLA-DR, -DQ), Th2 differentiation, and functions integral to allergy and inflammation (GATA3, IL4, and IL13) together with genes involved in epithelial and mucosal cell biology and airway remodelling (Vercelli 2008). The list of associated genes and variants is extensive, and like many common multifactorial traits there have been difficulties in definitive replication of disease associations and resolution of specific functional variants.

be present at this locus; forward stepwise regression revealed three SNPs jointly showed strong association (P <1012). The association was replicated in further British and German cohorts (Moffatt et al. 2007).

In parallel with their genome-wide association study, the investigators established lymphoblastoid cell lines from 400 children of families with a proband who had asthma (Dixon et al. 2007). These cell lines were harvested for gene expression studies on initial culture after transformation, minimizing artefacts that may be associated with repeated passaging of such cell lines. Genome-wide SNP genotyping data on a total of 408 273 SNPs were generated and expression profiling for 54 675 transcripts (corresponding to 20 599 genes) was quantified. Of the 19 annotated genes in the disease associated region, gene expression data were available for 14.

Remarkably, the SNPs showing the strongest disease association were found to be highly associated with levels of ORMDL3 gene expression (correlation 0.67, P = 0.004) (Fig. 11.7C) (Dixon et al. 2007). ORMDL3 lies within the disease associated interval although the most strongly associated SNP from the disease association study (rs7216389) is within intron 1 of the neighbouring gene GSDML. This SNP shows a striking association with ORMDL3 expression (P <1022), and together the associated SNPs account for 29.5% of the variance observed in expression of ORMDL3 (Dixon et al. 2007). No difference was seen between lymphoblastoid cell lines established from individuals with and without asthma, indeed for all 54 675 transcripts analysed only ten differed significantly between the two groups.

The findings of the genome-wide association studies of disease association and gene expression implicate genetic diversity in a 206 kb interval of chromosome 17q21 within which ORMDL3 is a candidate gene for genetic susceptibility to childhood asthma. The initial findings have been replicated in a series of independent studies of asthma in a number of different populations, which have defined 17q21 as an asthma susceptibility locus. These have included a study of North American white asthmatics (Sleiman et al. 2008), a family-based study of a French Canadian population (Madore et al. 2008), a large case-control study from Scotland (Tavendale et al. 2008), a family-based study of Mexicans, and a case-control study of African Americans (Galanter et al. 2008). In the study by Tavendale and colleagues of 1054 asthmatics and 1465

Was this article helpful?

0 0

Post a comment