Sequencing of the ST2 Gene Reveals a Haplotype That Determines Serum Total ST2 Levels in Individuals of African Ancestry

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.