rs11709868 (HLMR1): Liver, lipid, and heart locus

Key takeaways

• The alternate allele at this locus reduces PAQR9 and PAQR9-AS1 expression in the liver, pointing to a hepatic role in adiponectin receptor signaling and lipid metabolism.
• The same allele increases PCOLCE2 expression in the aorta and heart left ventricle, tissues in which collagen remodeling shapes vascular mechanics.
• This locus sits within regions covered by a multi-ancestry lipid GWAS of approximately 1.65 million individuals across five ancestry groups and by a plasma metabolomics GWAS of roughly 20,000 individuals.
• Expression effects span from liver to heart to brain, indicating that this locus influences gene activity across multiple organ systems.

What the research says

A multi-ancestry genome-wide association meta-analysis of five blood lipid traits across approximately 1.65 million individuals spanning five ancestry groups identified 941 lipid-associated genomic regions at genome-wide significance (p < 5 x 10-8), including 355 novel regions, and demonstrated that ancestry diversity substantially improved fine-mapping of functional variants and polygenic score portability compared with expanding only European ancestry samples. A metabolomics GWAS in roughly 20,000 individuals across two independent cohorts identified 2,599 conditionally independent variant-metabolite associations across 330 genomic regions at a stringent threshold of p < 1.25 x 10-11, spanning metabolite classes including lipids, amino acids, xenobiotics, nucleotides, and cofactors. Tissue-specific eQTL data from GTEx v11 (953 donors, FDR < 0.05) show that the alternate allele at this locus alters expression of four nearby genes across cardiovascular, hepatic, and neural tissues GTEx Portal.

Reported associations

• Blood lipid levels (LDL-C, HDL-C, triglycerides, total cholesterol, non-HDL-C): This locus falls within regions covered by a multi-ancestry lipid GWAS (n approximately 1.65 million; five ancestry groups including approximately 99,000 African ancestry, 147,000 East Asian, 1.32 million European, 48,000 Hispanic, and 41,000 South Asian participants) that catalogued 941 lipid-associated regions and used trans-ancestry meta-regression to account for cross-population effect-size heterogeneity.
• Plasma metabolites: A metabolomics GWAS (n approximately 20,000; discovery in INTERVAL and EPIC-Norfolk cohorts with validation in 5,698 additional EPIC-Norfolk participants) linked 330 genomic regions to 646 plasma metabolites across multiple biochemical classes at p < 1.25 x 10-11, with rare variants (minor allele frequency 1% or lower) explaining 9.4% of identified associations.
• Coronary artery disease (polygenic lipid context): Polygenic LDL-C and triglyceride scores composed of genome-wide lipid-raising variants, evaluated in 135,638 individuals including 13,753 CAD cases from the FinnGen project, showed that the top 5% of the LDL-C polygenic score carried a CAD odds ratio of 1.36 (95% CI 1.24-1.49) vs. the lowest 95%, and the top 5% of the triglyceride score carried a CAD odds ratio of 1.31 (95% CI 1.19-1.43), with estimates only modestly attenuated after adjusting for a direct CAD polygenic score.
• Cross-population phenotypes: A genetic atlas spanning 220 phenotypes in BioBank Japan (n = 179,000) with meta-analysis including UK Biobank and FinnGen (combined n approximately 628,000) identified approximately 5,000 new loci across diseases, biomarkers, and medication usage, providing a multi-ancestry framework in which this region has been characterized.

Evidence quality

The studies providing context for this locus are among the largest human genetic investigations conducted to date. The lipid GWAS applied trans-ancestry meta-regression across approximately 1.65 million individuals, and 98% of ancestry-specific index variants remained significant after trans-ancestry meta-analysis. The metabolomics study used a threshold of p < 1.25 x 10-11 across two cohorts with independent replication. The polygenic CAD study examined 135,638 individuals with 13,753 cases; CAD risk estimates remained robust after adjustment for a direct CAD polygenic score, suggesting an effect path through lipid levels specifically. The cross-population atlas extended discovery to non-European populations and identified latent genetic components underlying disease classifications. The GTEx eQTL data (v11, 953 donors, FDR < 0.05) represent a current and well-validated reference for tissue-specific expression effects GTEx Portal. Note that the provided study text excerpts do not include explicit per-variant summary statistics for this specific SNP; association context is drawn from these studies having been curated alongside this locus rather than from named per-variant results in the excerpts.

Tissue-specific expression effects

• PCOLCE2: The alternate allele is linked to increased expression in the aorta (strongest reported signal), heart left ventricle, brain nucleus accumbens basal ganglia, and brain cortex, alongside reduced expression in testis GTEx Portal.
• PAQR9: The alternate allele is linked to reduced expression in the liver, pointing to a potential effect on hepatic progestin and adipoQ receptor signaling GTEx Portal.
• PAQR9-AS1: This long non-coding RNA antisense to PAQR9 also shows reduced liver expression with the alternate allele, moving in the same direction as its protein-coding neighbor GTEx Portal.
• RPL8P3: The alternate allele is linked to increased expression of this ribosomal protein pseudogene in the aorta GTEx Portal.

Lifestyle considerations

No lifestyle considerations on file for this variant.