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Risk of Preterm Birth Linked to Rare Variants in HSPA1L

NEW YORK (GenomeWeb) – Researchers have linked risk of preterm birth to variants in a gene belonging to a heat shock protein superfamily.

More than 15 million babies are born preterm — before 37 weeks — each year and 1 million die from complications related to preterm birth. While most spontaneous preterm births are idiopathic, some families have a history of recurrent preterm birth, suggesting there could be a genetic component.

An international team of researchers, including investigators from the direct-to-consumer genetic testing company 23andMe, sequenced the exomes of 17 Finnish mothers from seven multiplex families and 93 Danish sister-pairs who delivered babies preterm to identify rare variants and genes linked to the condition. As the team reported today in PLOS Genetics, women in both cohorts harbored likely damaging alleles in HSPA1L, which is involved in the glucocorticoid receptor signaling pathway.

"Overall, our data suggest the need for precise regulation of steroid signaling in mediating birth timing," senior author Louis Muglia from the University of Cincinnati College of Medicine and his colleagues wrote in their paper.

The researchers sequenced the exomes of the 17 Finnish mothers using the Illumina HiSeq 2500 instrument. After filtering, they identified 1,510 variants in 406 genes, which they traced to 64 pathways. Among the most significant affected pathways were the glucocorticoid receptor signaling, the estrogen receptor signaling, and the AMPK signaling pathways, which were all affected in the 10 mothers in this set with more than one pre-term birth.

In a family-based analysis, the researchers found the glucocorticoid receptor signaling pathway to be common to all five families, and the estrogen receptor signaling pathway to three. In particular, the team noted that several genes — including AR, HSPA1L, NCOA3, and NCOR2 — were also commonly affected in these families.

Similarly, in the set of 93 pairs of Danish sisters, who were sequenced on the Complete Genomics platform, the researchers uncovered an average of 807 rare variants in 593 genes shared by the sisters. Again, the glucocorticoid receptor signaling and estrogen receptor signaling pathways were significantly affected in a number of families. Additionally, the genes found in the discovery set — AR, HSPA1L, NCOA3 and NCOR2 — were also affected in between three and 12 families in this dataset.

In an independent pre-term GWAS dataset of more than 40,000 mothers of European ancestry from the 23andMe database, the researchers further linked a minor allele of HSPA1L to pre-term birth. HSPA1L variants from the Finnish and Danish cohorts, however, were not linked to the condition in two other, smaller GWAS datasets.

Though the four HSPA1L variants the researchers uncovered in their discovery and replication cohorts are all predicted to be damaging, they focused their analysis on the one also found in the 23andMe dataset. That variant leads to an amino acid change that adds a phosphorylation site next to an existing phosphorylation site. While the researchers said this doesn't lead to a change in protein structure, it appears to affect chemical bond lengths and could affect the binding efficiency of adenosine diphosphate.

This, the researchers said, could affect the chaperone activity of the HSPA1L protein and, in turn, affect the stability of the glucocorticoid receptor. They added that as glucocorticoids have anti-inflammatory and immunosuppressive roles, and that since sustaining a pregnancy relies on balancing different aspects of the immune system, alterations to glucocorticoid receptor signaling pathway could lead to an inadequate immune response and possibly to premature labor.