rs11881940 — HNRNPUL1
Intronic variant in HNRNPUL1, an RNA-processing gene highly expressed in macrophages and immune cells, associated with elevated early-onset coronary heart disease risk; the common A allele is the risk allele
Details
- Gene
- HNRNPUL1
- Chromosome
- 19
- Risk allele
- A
- Clinical
- Risk Factor
- Evidence
- Moderate
Population Frequency
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HNRNPUL1 — RNA Processing, Macrophages, and Early-Onset Coronary Risk
Deep inside chromosome 19 lies a variant that, for most of human history, has gone entirely unnoticed — yet it sits in a gene that orchestrates how immune cells process and deploy genetic information during inflammation. HNRNPUL1 (heterogeneous nuclear ribonucleoprotein U-like 1) is an RNA-binding protein expressed at especially high levels in macrophages, monocytes, and the immune cells that patrol arterial walls. The rs11881940 variant is intronic — it doesn't change any protein sequence — but the A allele, carried by [roughly 72% of Europeans as homozygotes | the minor T allele reaches only 11.8% frequency in Europeans and is extremely rare in African and South Asian populations], was one of the first variants outside the canonical cardiovascular pathways to show replicable association with early-onset myocardial infarction.
The Mechanism
HNRNPUL1 belongs to the heterogeneous nuclear ribonucleoprotein family — a class of proteins that bind pre-mRNA in the nucleus and direct its splicing, stability, and transport. Studies in zebrafish with HNRNPUL1 loss-of-function mutations found that the gene governs the splicing of at least 76 other transcripts and the expression of over 1,500 downstream genes, including pathways regulating ubiquitination, cell cycle, and protein turnover. [| Lalonde et al. 2022 (PMC9073674): HNRNPUL1 zebrafish mutants show 76 splicing changes and 1,575 differentially expressed genes]
The [Human Protein Atlas | proteinatlas.org/ENSG00000105323-HNRNPUL1] shows that HNRNPUL1 is particularly enriched in immune tissues: bone marrow, thymus, lymph nodes, and tonsil show the highest RNA expression, and single-cell data reveal especially high expression in monocyte progenitors (198.8 nCPM), innate lymphoid cells (209.3 nCPM), and macrophages (104 nCPM). It is also expressed in heart muscle (70.9 nTPM) and blood vessels (85.9 nTPM). This expression profile positions HNRNPUL1 squarely within the cellular machinery that governs how macrophages respond to pro-inflammatory signals in arterial walls — the same macrophages that form foam cells and atherosclerotic plaques.
The rs11881940 A-allele is intronic and does not produce an amino acid change. Its functional effect likely operates through altered pre-mRNA splicing of HNRNPUL1 itself or nearby transcripts, modifying the levels of functionally relevant RNA isoforms in immune and vascular cells. A separate GWAS identified that an eQTL near the CYP2F1 locus (rs12459996) influences HNRNPUL1 expression in blood, supporting the idea that HNRNPUL1 expression levels — not protein structure — are the mechanism by which variants in this region affect cardiovascular risk.
The Evidence
The original discovery study by Shiffman et al. 200611 Shiffman et al. 2006
Shiffman D et al. Gene variants of VAMP8
and HNRPUL1 are associated with early-onset myocardial infarction. Arterioscler Thromb Vasc Biol.
2006;26(7):1613-8 used a gene-centric association
approach across cardiovascular candidate genes. The HNRNPUL1 A-allele emerged with OR 1.92
(95% CI 1.28–2.86, P=0.0043) for early-onset myocardial infarction — a striking effect size
for a common intronic variant.
Independent replication came from van der Net et al. 200822 van der Net et al. 2008
van der Net JB et al. Replication
study of 10 genetic polymorphisms associated with coronary heart disease in a specific high-risk
population with familial hypercholesterolemia. Eur Heart J. 2008;29(18):2195-201,
who genotyped 2,145 Dutch familial hypercholesterolemia (FH) patients — individuals already at
extreme CHD risk — and confirmed HR 1.27 (95% CI 1.07–1.51, P=0.007) for coronary events.
Among the ten polymorphisms tested, rs11881940 was one of only four to replicate. Critically,
the association held after adjustment for hypertension, diabetes, BMI, and lipid levels,
indicating the risk is not simply mediated by traditional risk factors. Within the FH cohort,
the genotype distribution was TT 2.3%, AT 26.0%, AA 71.7% — meaning most patients carried the
risk genotype.
A 2020 GWAS for alcohol-related liver cirrhosis also identified HNRNPUL1 as a susceptibility locus (via a nearby SNP rs15052), further supporting the gene's role in tissue-damage and inflammatory responses beyond the heart. [| Innes et al. 2020: MARC1 and HNRNPUL1 variants associated with alcohol-related cirrhosis risk]
The evidence level is rated moderate: there are two consistent human studies with replication,
a plausible immune-cell expression mechanism, and no contradicting large-scale null results.
However, the variant has not yet appeared as a genome-wide significant hit in the multi-million
participant CAD meta-analyses (CARDIoGRAM, MVP), which use broader case definitions that may
dilute the early-onset specific signal.
Practical Actions
Because the A-allele risk is specifically observed in early-onset MI — defined as myocardial infarction before age 55 in men and 65 in women — the most directly evidence-grounded action is earlier and more structured coronary risk assessment. For AT heterozygotes, the modest elevated HR (approximately 1.15–1.27 in replication) supports awareness and regular lipid and inflammatory marker monitoring. For AA homozygotes, who carry the highest burden and are the majority of the population, the 27–61% increased CHD hazard (dose-response from heterozygosity to homozygosity in the van der Net cohort) justifies earlier cardiovascular risk stratification.
High-sensitivity CRP (hs-CRP) is a practical biomarker for the macrophage-driven inflammatory mechanism this variant is associated with. Coronary artery calcium (CAC) scoring provides direct anatomical assessment of subclinical atherosclerosis and is particularly informative for asymptomatic individuals with genetic risk factors but intermediate Framingham scores.
Interactions
The replication cohort in van der Net 2008 consisted of familial hypercholesterolemia patients, which suggests the HNRNPUL1 A-allele may amplify risk when combined with already-elevated LDL — the combination of high cholesterol substrate with pro-inflammatory macrophage activity being particularly atherogenic. There is currently no published compound genotype analysis, but pathway logic supports heightened vigilance in individuals who carry the HNRNPUL1 A-allele together with high LDL-driving variants (e.g. LDLR, APOB, PCSK9 risk variants).
Genotype Interpretations
What each possible genotype means for this variant:
Rare protective genotype — lowest HNRNPUL1-associated coronary risk
The TT genotype is the rarest of the three genotypes globally (approximately 2% frequency), reflecting that the T allele is a derived, less-common variant that may have arisen relatively recently in human evolution. In the Shiffman 2006 discovery study, the T allele was the lower-risk allele (OR for A-allele vs T-allele reference = 1.92). In the van der Net 2008 FH replication cohort, TT homozygotes anchored the low-risk reference against which AT carriers had ~27% higher CHD hazard and AA homozygotes had ~61% higher CHD hazard. The T allele's functional role likely relates to altered splicing or expression of HNRNPUL1 in macrophages and vascular immune cells — the exact mechanism remains to be characterized at the molecular level.
One A allele — moderately elevated coronary heart disease risk from HNRNPUL1 locus
The HNRNPUL1 AT genotype places you at intermediate risk on the dose-response gradient observed for the A allele. In the gene-centric discovery study by Shiffman et al. (2006), the A allele showed OR 1.92 for early-onset myocardial infarction — an effect driven by AA homozygotes predominantly, but with AT carriers contributing a stepped intermediate effect in the replication cohort. The variant is intronic: it does not change the HNRNPUL1 protein sequence but is thought to influence expression or splicing efficiency of HNRNPUL1 and neighboring transcripts in macrophages and vascular immune cells. HNRNPUL1 is highly expressed in monocyte progenitors and macrophages — the cells that infiltrate arterial walls and form atherosclerotic plaques.
Because this variant's risk signal was specifically found in early-onset MI cohorts and replicated in a high-risk (familial hypercholesterolemia) population, its relevance may be greatest in people with other cardiovascular risk factors. In isolation, the AT genotype represents a modest additive risk that warrants proactive monitoring rather than immediate intervention.
Two A alleles — the most common genotype, associated with meaningfully elevated early-onset coronary risk
As an AA homozygote at rs11881940, you carry the maximum dose of the HNRNPUL1 risk allele. This intronic variant does not change protein structure but is believed to affect gene expression or mRNA splicing in HNRNPUL1 — a gene that is especially highly expressed in macrophages, monocyte progenitors, and immune cells that patrol arterial walls and mediate atherosclerotic plaque formation.
The functional pathway is plausible: HNRNPUL1 controls the splicing of dozens of other transcripts and regulates hundreds of genes involved in protein turnover and inflammation (Lalonde et al. 2022, PMC9073674). Altered HNRNPUL1 activity in macrophages could shift the balance of pro-inflammatory signaling in exactly the cell type that drives foam cell accumulation and plaque instability. The gene's high expression in immune tissues (bone marrow, thymus, lymph nodes) and macrophages specifically underscores this mechanism.
The evidence is rated moderate: the discovery was gene-centric (not a full GWAS), and
the variant has not yet reached genome-wide significance in the million-participant CAD
meta-analyses. However, two independent studies with consistent direction, independent
replication in a different population, and a biologically coherent mechanism cross the
threshold for actionable awareness.
Because the original discovery was specifically in early-onset MI cohorts (men under 55, women under 65), the risk is most pronounced for people who have a family history of premature coronary artery disease or who have multiple cardiovascular risk factors. The replication in FH patients also suggests that elevated LDL amplifies the A-allele risk considerably.