Genetic variants modulating CRIPTO serum levels identified by genome-wide association study in Cilento isolates

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• Cripto (Epidermal Growth Factor-Cripto, FRL-1, Cryptic) is crucial for embryonic development and cancer progression.
• It functions as a GPI-anchored protein, interacting with signaling pathways like TGF-β, Wnt, and MAPK.
• Re-expression of Cripto in adult tissues is linked to cancer, with elevated serum levels observed in patients.

Purpose of the Study:

• To investigate the population-level variability of serum Cripto levels.
• To identify genetic factors contributing to this variability using a genome-wide association study (GWAS).

Main Methods:

• Conducted a GWAS on serum Cripto levels in isolated Italian populations (n=1,054).
• Replicated associated genetic loci in an independent sample (n=535).
• Performed pathway analysis and functional analysis of associated genetic variants.

Main Results:

• Identified significant single nucleotide polymorphisms (SNPs) associated with serum Cripto levels on chromosome 3p22.1-3p21.3, within the CRIPTO gene region.
• Six CRIPTO-associated loci were replicated, collectively explaining over 87% of the variance in serum Cripto levels.
• A causal variant in the 5'UTR of the CRIPTO gene was identified, modulating Cripto expression via AP-1 transcriptional regulation.

Conclusions:

• Serum Cripto levels exhibit significant heritability, primarily driven by variants within the CRIPTO gene locus.
• These findings highlight the clinical relevance of serum Cripto levels and their genetic underpinnings.
• The identified causal variant offers a molecular mechanism for Cripto expression regulation.