rs10159477 (HK1): VTE and Red Blood Cell Genetics

Key takeaways

• rs10159477 sits at the HK1 (hexokinase 1) locus, a gene encoding an enzyme essential for powering red blood cells through glucose metabolism.
• Large-scale genetic studies have linked this locus to venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, in a cross-ancestry study of over 81,000 cases from multiple ancestries.
• HK1 is among the genes known to underlie haemolytic anaemia, a condition where red blood cells are destroyed faster than they are made, as identified in a red blood cell study of over 135,000 individuals.
• In subcutaneous fat tissue, this variant is linked to reduced expression of a nearby gene, based on GTEx reference data.

What the research says A cross-ancestry GWAS meta-analysis of up to 81,669 VTE cases from 30 studies identified rs10159477 at the HK1 locus among 135 independent genomic loci significantly associated with VTE risk, with novel loci pointing to new pathways including hematology traits and platelet function PMID 35862144. In a separate red blood cell GWAS of up to 135,367 individuals of European and South Asian ancestry, the same locus was identified as hosting a candidate gene for haemolytic anaemia within 75 genome-wide significant red blood cell trait loci that collectively explain 4-9% of phenotypic variance per trait PMID 23222517. The two studies examine distinct phenotypes and report no conflicting findings; the biological pathway connecting this gene's red blood cell function to VTE risk is not fully characterised in the provided evidence.

Reported associations

• Venous thromboembolism: rs10159477 at the HK1 locus was among 135 independent loci reaching genome-wide significance (P<5.0x10-8) in a cross-ancestry meta-analysis of up to 81,669 VTE cases spanning European, African, and Hispanic ancestries, and was among 34 novel loci that replicated after correction for multiple testing PMID 35862144
• Red blood cell traits and haemolytic anaemia: HK1 was identified as a candidate gene underlying haemolytic anaemia within a GWAS of six red blood cell phenotypes (including haemoglobin concentration, mean cell volume, mean cell haemoglobin, mean cell haemoglobin concentration, packed cell volume, and red blood cell count) in up to 135,367 individuals; the gene has a recognised role in Mendelian red blood cell disorders PMID 23222517

Evidence quality The VTE association is supported by one of the largest VTE genetic studies conducted to date, drawing on 30 participating studies with independent replication across 12 separate populations at a genome-wide significance threshold of P<5.0x10-8 PMID 35862144. The red blood cell evidence comes from a meta-analysis with a discovery stage of 71,861 individuals and a replication stage of up to 63,506 individuals, using a conservative genome-wide threshold of P<1x10-8 that corrects both for the number of variants tested and for the six correlated traits studied; the 75 identified loci collectively explained 4-9% of variance per red blood cell trait PMID 23222517. Specific effect sizes for rs10159477 alone are not reported in the provided excerpts from either study; the 6-fold VTE risk increase cited in the VTE study reflects a polygenic risk score aggregating all 135 associated loci, not this single variant. HK1 carries biological credibility as a Mendelian disease gene for haemolytic anaemia, supporting the statistical signal at this locus. The two studies examine distinct traits and are not in conflict with each other.

Tissue-specific expression effects

• ENSG00000297237: In subcutaneous adipose (fat) tissue, the alternate allele at rs10159477 is associated with reduced expression of this gene (p=5.3e-5) GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.