rs10007975 (C4orf17): Liver Enzymes & Lipid Metabolism

Key takeaways

• rs10007975, near C4orf17 (chromosome 4 open reading frame 17), has been identified in genome-wide studies of liver enzymes and circulating metabolic traits involving hundreds of thousands of participants.
• The variant influences expression of MTTP (microsomal triglyceride transfer protein), the gene responsible for assembling VLDL particles that carry fat through the bloodstream, in tissues including arteries, testis, and brain.
• A metabolome-wide study of 249 blood-measured traits in approximately 450,000 people found this locus among nearly 30,000 genetic-metabolite associations.
• The variant also regulates TRMT10A, a tRNA-modifying enzyme, in skeletal muscle according to tissue gene-expression data.

What the research says A meta-analysis combining genome-wide association data from the UK Biobank (approximately 389,565 European-ancestry individuals) and BioBank Japan (approximately 162,255 individuals) identified 378 genome-wide significant loci at p < 5×10^-8 for serum concentrations of ALT (alanine aminotransferase), AST (aspartate aminotransferase), and ALP (alkaline phosphatase) - the standard clinical markers of liver cell injury and bile duct dysfunction - with associated variants implicating genes involved in diverse metabolic and liver-related pathology. A separate trans-ancestral genome-wide survey of 249 circulating metabolic phenotypes measured by proton NMR (nuclear magnetic resonance) spectroscopy, spanning 14 lipoprotein subclasses, amino acids, and ketone bodies across up to 450,000 UK Biobank participants from three ancestral groups, identified approximately 30,000 locus-metabolite associations at a metabolome-adjusted threshold of p < 2.0×10^-¹^0, with genetic effects described as largely consistent across sexes and major ancestral groups. Tissue gene-expression data from GTEx v11 (953 donors) confirm this variant acts as a cis-eQTL (a regulatory variant that shifts nearby gene expression levels) for MTTP and TRMT10A across multiple tissues GTEx Portal.

Reported associations

• Serum liver enzymes (ALT, AST, or ALP): This locus was identified among 378 genome-wide significant associations in a meta-analysis of serum liver enzyme concentrations from UK Biobank and BioBank Japan (combined n ≈ 551,820); associated variants implicated genes expressed across a wide range of liver cell types and involved in diverse metabolic and liver-related pathology.
• Circulating metabolic traits (lipoprotein and small-molecule profiles): The locus was detected in a trans-ancestral metabolome-GWAS of 249 NMR-measured metabolic phenotypes across approximately 450,000 UK Biobank participants spanning three ancestral groups, within a catalogue of approximately 30,000 locus-metabolite associations with effects largely consistent across sexes and ancestry.
• Age-related physical or cognitive decline: The locus appeared in a longitudinal genome-wide analysis of UK Biobank aging phenotypes that separately modelled baseline function (θ) and rate of decline (Δ) across physical domains (grip strength, forced expiratory volume) and cognitive domains (reaction time, fluid intelligence); that analysis found these two aging dimensions carry substantially different heritability levels - for example, 31.38% for baseline physical function versus 3.15% for physical decline - and distinct associated loci, with physical decline most influenced by telomere length and bone mineral density pathways.

Evidence quality The strongest evidence for this locus comes from the liver enzyme meta-analysis (combined n ≈ 551,820), which applied genome-wide significance correction (p < 5×10^-8), confirmed well-controlled population stratification (lambda-GC = 1.03 post-meta-analysis), and replicated associations across two independent biobanks spanning European and East Asian populations. The metabolome-wide association study (n ≈ 450,000) applied a more stringent metabolome-adjusted threshold (p < 2.0×10^-¹^0) and demonstrated consistent effects across ancestral groups and sexes, strengthening confidence. A functionally informed statistical method (FINDOR), which integrates coding, conserved, regulatory, and linkage-disequilibrium-related genomic annotations to improve detection power, was applied to the full UK Biobank (average n = 416,000) and detected on average 13% more genome-wide significant loci than standard analyses - a method that may have contributed to the detection or validation of this locus. The longitudinal aging analysis explicitly cautions that selective attrition - whereby less healthy participants drop out of follow-up - can bias two-wave estimates, and its findings should therefore be treated as more preliminary than the cross-sectional GWAS above. No study in this set reports a per-allele effect size (odds ratio or beta coefficient) specific to rs10007975 in isolation, and the variant's functional role within or near C4orf17 - as distinct from a regulatory effect on the adjacent MTTP locus - remains incompletely resolved.

Tissue-specific expression effects

• MTTP: The ALT allele of this variant is associated with increased MTTP expression in testis, brain cerebellum, aortic artery, and tibial artery, and with reduced MTTP expression in EBV-transformed lymphocytes, transverse colon, and left heart ventricle GTEx Portal.
• TRMT10A: The ALT allele is associated with increased TRMT10A expression in skeletal muscle GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.