Expressive

rs10937275 (ST6GAL1): Drug-Induced Liver Injury Risk

Key takeaways

  • rs10937275 in ST6GAL1 amplifies flucloxacillin liver injury risk roughly 4-fold, but only in people who also carry the HLA-B*5701 immune variant.
  • This is a gene-gene interaction: the variant shows no significant independent effect and only modifies risk within the HLA-B*5701 carrier group.
  • ST6GAL1 encodes an enzyme that adds sialic acid sugar groups to cell-surface proteins, playing a role in immune recognition.
  • GTEx data links the ALT allele to increased ST6GAL1 expression across multiple tissues, with the strongest effect in the pancreas.
  • The evidence is preliminary: it comes from a single small study of 51 cases, with no independent replication of this modifier signal.

Key takeaways

  • rs10937275 in ST6GAL1 amplifies flucloxacillin liver injury risk roughly 4-fold, but only in people who also carry the HLA-B*5701 immune variant.
  • This is a gene-gene interaction: the variant shows no significant independent effect and only modifies risk within the HLA-B*5701 carrier group.
  • ST6GAL1 encodes an enzyme that adds sialic acid sugar groups to cell-surface proteins, playing a role in immune recognition.
  • GTEx data links the ALT allele to increased ST6GAL1 expression across multiple tissues, with the strongest effect in the pancreas.
  • The evidence is preliminary: it comes from a single small study of 51 cases, with no independent replication of this modifier signal.

What the research says A genome-wide association study (GWAS - a scan of genetic variants across the whole genome to find those linked to a trait) of flucloxacillin drug-induced liver injury (DILI - serious liver damage triggered by this antibiotic) found that rs10937275, located in ST6GAL1 (ST6 beta-galactoside alpha-2,6-sialyltransferase 1, an enzyme that attaches sialic acid sugar molecules to proteins on the cell surface), reached genome-wide significance specifically within cases who also carried the HLA-B5701 allele, with an odds ratio (OR) of 4.1 and P = 1.4 × 10^-8 PMID 19781057. The dominant risk factor in that same analysis was HLA-B5701 itself (OR = 80.6, P = 9.0 × 10^-¹^9), placing this locus as a secondary modifier that compounds an already extreme genetic risk rather than an independent susceptibility factor PMID 19781057.

Reported associations

  • Flucloxacillin drug-induced liver injury (HLA-B*5701 carriers only): In a stratified analysis restricted to HLA-B*5701-positive individuals, this variant was associated with approximately 4-fold increased odds of DILI (OR = 4.1, P = 1.4 × 10^-8; discovery sample: 51 DILI cases, 282 matched controls) PMID 19781057

Evidence quality This variant's association with flucloxacillin DILI rests on a single GWAS with 51 discovery cases and 282 controls - a small sample by contemporary standards PMID 19781057. The signal emerged from a subgroup analysis limited to HLA-B5701 carriers, reducing the effective sample further and limiting statistical precision. Replication was conducted for the primary HLA-B5701 finding in a second cohort of 23 additional cases, but independent replication of this modifier effect specifically is not described in the provided sources PMID 19781057. The evidence should be regarded as preliminary. No conflicting findings appear in the available studies.

Tissue-specific expression effects

  • ST6GAL1: The ALT allele is associated with increased expression in the pancreas (strongest signal), brain anterior cingulate cortex (BA24), tibial artery, thyroid, lung, aorta, and heart left ventricle GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Lifestyle context

Concrete actions anchored to the cited research. We do not prescribe, we describe.

Drug interactions

  • flucloxacillin sensitivity and liver injury risk High

    rs10937275 is associated with 4-fold increased flucloxacillin-induced liver injury risk, particularly in HLA-B*5701 carriers

    Discuss rs10937275 status with physician before prescribing flucloxacillin

Frequently asked questions

What is ST6GAL1 and what does it do?

ST6GAL1 is an enzyme that attaches sialic acid sugar molecules to proteins on the surface of cells. This chemical modification affects how the immune system recognizes cells and is involved in cell-to-cell communication.

Is rs10937275 linked to liver disease?

One genome-wide association study found rs10937275 to be significantly associated with liver injury caused by the antibiotic flucloxacillin, but only in individuals who also carry the HLA-B*5701 gene variant. The evidence is preliminary and comes from a small discovery cohort of 51 cases.

What is drug-induced liver injury (DILI)?

Drug-induced liver injury is serious liver damage triggered by a medication. Flucloxacillin, an antibiotic commonly used for staph infections, is a known though uncommon cause. Certain genetic variants appear to sharply raise the risk of this reaction.

What role does HLA-B*5701 play alongside rs10937275?

HLA-B*5701 is the primary genetic risk factor for flucloxacillin liver injury, associated with approximately 80-fold higher odds. The rs10937275 variant was found significant only within people who already carry HLA-B*5701, suggesting it acts as a secondary modifier rather than a stand-alone risk factor.

What does GTEx data show about rs10937275?

GTEx eQTL data shows the ALT allele of rs10937275 is linked to higher ST6GAL1 expression in several tissues including the pancreas, lung, heart, thyroid, and arteries. These are expression-level observations and do not directly measure disease risk.