A sequence variant on 17q21 is associated with age at onset and severity of asthma

Abstract

A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N¼4917 cases N¼34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR¼1.51, P¼6.89 . 10 À9 ) and adolescence (age: 14-17 years OR¼1.71, P¼5.47 . 10 À9 ). A weaker association was observed for onset between 6 and 13 years of age (OR¼1.17, P¼0.035), but none for adult-onset asthma (OR¼1.07, P¼0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P¼0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n¼743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.

Genetic variants on 17q21 are associated with asthma in a Han Chinese population

“…In this study, the most strongly associated SNPs were rs2305480 and rs8067378, which is consistent with recent studies (Flory et al, 2009;Bisgaard et al, 2009;Halapi et al, 2010). Additionally, Bouzigon et al (2008) reported a significant association between rs2305480 and asthma in a French population.…”

17q21 locus and ORMDL3: an increased risk for childhood asthma

“…A role of orm proteins in the regulation of sphingolipid synthesis has been well established in yeast for many years (24,28,(37)(38)(39) and has recently been demonstrated in human cells (40,41). ORMDL proteins act as negative regulators of sphingolipid synthesis by interacting with serine palmitoyl-coenzyme A transferase (SPT) (38).…”

The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma

“…The findings on the role of ORMDL3 in asthma were replicated in studies from different populations (26)(27)(28) (Table 1). Further analyses supported the conclusion that genetic elements regulating ORMDL3 expression (Table 2) may contribute to asthma development (7,13,22,25,(29)(30)(31)(32)(33)(34).…”