rs12323963 (SHC4): HCV Genotype 3 and Brain eQTL

Key takeaways

• rs12323963 is located near the SHC4 gene and was included in a genome-wide association study of hepatitis C virus (HCV) genotype 3 outcomes in 1,759 patients.
• The alternate allele is associated with modestly increased SECISBP2L expression in brain cerebellar hemisphere tissue, per GTEx v11 data (n = 953 donors).
• The dominant genetic signals in that HCV cohort were at the IFNL4 locus, not SHC4; variant-level results for rs12323963 are not present in available study text.
• Current evidence for this variant is limited to a single tissue-expression association and should be considered preliminary.

What the research says A combined candidate gene and genome-wide analysis enrolling 1,759 patients chronically infected with HCV genotype 3 examined genetic determinants of pretreatment viral load, response to interferon (IFN)-based therapy, and response to direct-acting antiviral (DAA) therapy; the principal genetic factors identified were at the IFNL4 locus (a gene cluster encoding interferon-lambda proteins that modulate antiviral immunity), with the primary variant rs368234815 associating at an odds ratio (OR) of 1.5 for IFN-based sustained virologic response (SVR - no detectable virus after treatment), OR = 1.7 for DAA-based SVR, and a regression coefficient of −0.23 for pretreatment viremia; variant-specific results for rs12323963 are not present in the available study excerpt. Separately, GTEx v11 tissue expression data (953 donors) shows that the alternate allele at rs12323963 is associated with a modest increase in SECISBP2L (SECIS-binding protein 2-like) expression in brain cerebellar hemisphere tissue (slope +0.13, p = 3.3×10^-5) GTEx Portal.

Reported associations

• SECISBP2L expression - brain cerebellar hemisphere: The alternate allele is associated with increased SECISBP2L expression in this tissue (slope +0.13, p = 3.3×10^-5, n = 953 donors) GTEx Portal
• HCV genotype 3 outcomes (GWAS context): This locus was assessed in a genome-wide study of 1,759 HCV genotype 3 patients examining pretreatment viral load, IFN-based SVR, and DAA-based SVR; the dominant reported signal in that cohort was at the IFNL4 locus (rs368234815: OR = 1.5 for IFN-SVR, p = 2.3×10^-7; OR = 1.7 for DAA-SVR, p = 4.2×10^-4; viremia beta = −0.23, p = 8.8×10^-¹^0), and findings specific to rs12323963 are not documented in the available excerpt

Evidence quality The only association directly linked to rs12323963 in the available data is a cis-eQTL (a variant that influences the expression level of a nearby gene) from GTEx v11, showing increased SECISBP2L expression in brain cerebellar hemisphere tissue across 953 donors (slope +0.13, p = 3.3×10^-5, FDR < 0.05) GTEx Portal. Notably, this expression effect is on SECISBP2L rather than SHC4, the gene with which the variant is annotated, illustrating that regulatory variants can influence expression of genes beyond their immediately annotated neighbor. The single clinical study on file - a GWAS of HCV genotype 3 patients (n = 1,759) - reports IFN-based SVR (OR = 1.5, p = 2.3×10^-7 for rs368234815), DAA-based SVR (OR = 1.7, p = 4.2×10^-4), and viremia (beta = −0.23, p = 8.8×10^-¹^0) at the IFNL4 locus, but does not provide variant-level results for rs12323963 in the available excerpt. No replication data and no conflicting findings were available for this locus. Overall, evidence is preliminary.

Tissue-specific expression effects

• SECISBP2L: The alternate allele is associated with increased expression in brain cerebellar hemisphere tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.