Abstract:
Rationale
ST2 (IL1RL1), is an IL1 family receptor that mediates important effectors of Th2 functions. Its soluble form (sST2) neutralizes its ligand, IL-33, by acting as a decoy receptor. Serum sST2 has been used as a biomarker for disease severity and outcome for multiple inflammatory and lung diseases, including atopic asthma. We undertook a targeted deep resequencing of ST2 gene in 241 samples of African ancestry to identify ST2variants controlling serum sST2 levels.
Methods
Serum sST2 concentration was measured by ELISA, and resequencing of ∼50kb (chr2:102922962-102973497) encompassing the ST2gene was performed using Illumina's HiSeq2000. Single-variant tests for all common variants (MAF≥5%) were performed using linear regression assuming an additive model on log serum total ST2 considering age, gender and the first two principal components on a pre-existing genome-wide association panel of ancestry informative markers to adjust for admixture.
Results
A total of 565 ST2 variants were identified, 192 of which had a MAF≥5% including 3 coding synonymous and 6 missense variants. In the sST2 level analysis, ten SNPs in strong linkage disequilibrium yielded p-value less than 10-3; a single common haplotype (frequency=65%) across all 10 SNPs yielded an overall p-value = 0.0002 and was negatively associated with sST2 levels (β = -0.09).
Conclusions
Sequencing ST2 gene revealed a novel haplotype influencing sST2 levels in individuals of African ancestry, including 5 variants mapping to intron 1 and 5 mapping to the 5’ region of ST2. Further work is ongoing to fully explore this association in an additional 400 subjects of African ancestry.
