Table 4 Childhood asthma and the 17q21 locus. Status: partially solved

Childhood asthma is the most common chronic childhood disorder with up to 50% of all children experiencing asthma-like symptoms before the age of 6 years, and 15% being diagnosed with persistent asthma during school-age [233]. Asthma is considered a heterogeneous syndrome consisting of several endophenotypes with distinct clinical features, divergent underlying molecular causes, and different prevention and treatment options [234]. There is a substantial genetic contribution to asthma susceptibility and studies have revealed more than 100 implicated genes.

Importantly, one of the first GWAS studies focusing on childhood onset asthma discovered a risk locus at 17q21, increasing the risk of asthma by 20% [235], which has since then been robustly replicated across different ethnicities in large meta-GWAS consortia [151, 152]. Thereafter, it was shown that genetic risk variants in the 17q21 locus up-regulate transcription of the ORMDL3 gene in EBV-transformed lymphoblastoid cell lines [235] and that rs12936231 is the functional SNP, which, via allele-specific changes in chromatin binding of the insulator protein CTCF, is responsible for ORMDL3 expression [236]. However, the mechanistic link between the ORMDL3 gene and asthma susceptibility was unknown.

Further studies showed that the ORMDL3 protein is expressed in airway epithelium cells [237] and that ORMDL3 and other related orm proteins in the endoplasmic reticulum have a major role in sphingolipid homeostasis via inhibition of serine palmitoyltransferase (SPT), which is the rate-limiting enzyme in de novo sphingolipid biosynthesis [238, 239]. This finding triggered the hypothesis that the ORMDL3 gene increases the risk of asthma through the sphingolipid metabolism [153], which has been confirmed in mouse studies showing that decreased sphingolipid biosynthesis in lung epithelial tissue [240] and SPT knockout [241] associate with airway hyper-reactivity via altered levels of ceramides, sphingosine-1-phosphate and sphingomyelins, subsequently affecting lung magnesium homeostasis.

Conclusion: Our understanding of the underlying biology of the initial GWAS discovery of 17q21 as a strong childhood asthma susceptibility locus has led to the recognition that the ORMDL3 protein, the SPT enzyme, and the sphingolipid metabolism are important players in airway reactivity and asthma pathogenesis, which may lead to novel therapeutics targeting this pathway. However, it is still unknown exactly how the sphingolipid homeostasis is regulated by expression of ORMDL3 and external environmental perturbants, but this presumably involves a network of multiple interconnected mechanisms that can be disentangled by metabolomics studies.