A recent meta-analysis has identified rare exonic variants that play a role in eczema susceptibility.
Eczema is a chronic inflammatory skin disease with one in 10 individuals developing it during their lifetime. It is often associated with immunoglobulin E (IgE)-mediated allergies. Like other complex human diseases, eczema is associated with a substantial heritable contribution to disease risk. There have been several large genome-wide association studies (GWAS) over the past few years that have uncovered a total of 32 susceptibility loci for eczema. However, despite increases in sample size, the reported significant variants have only explained a fraction of the estimated heritability of eczema.
It has been suggested that some of this missing heritability may be explained by rare risk variants that are not well captured on SNP arrays designed to study common variants. There is increasing evidence that rare variants not only contribute to disease risk in Mendelian diseases, but also contribute in complex diseases as well.
Meta-GWAS on rare variants in eczema
In a recent study, researchers performed a meta-analysis on 21 populations including 20,016 eczema cases and 380,433 controls. Rare variants were then imputed with high accuracy using large population-based reference panels.
The team uncovered disease-associated exonic variants in the genes encoding dual specificity phosphatase 1 (DUSP1), neurogenic locus notch homolog protein 4 (NOTCH4) and solute carrier family 9 member A4 (SLC9A4). For DUSP1 and NOTCH4, the researchers found missense variants that were located within functional domains.
They also extended the GWAS to common variants, where they found another five new eczema-associated loci. These included variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB. Interestingly, the team found that rare variants were significantly up-regulated in the skin, whereas common variants pointed to immune cell function.
Overall, the researchers estimate that over 20% of the single nucleotide variant-based heritability in eczema is attributable to rare and low-frequency variants. In addition, the variants identified within functional protein domains could point to promising drug targets for novel therapeutic approaches to eczema.
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