rs3846662 — HMGCR HMGCR Intron 13 Splice Variant

Intronic HMGCR variant that modulates alternative splicing of exon 13, producing a truncated Δ13 isoform that reduces statin-binding capacity and attenuates LDL-cholesterol lowering in response to statin therapy

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HMGCR Intron 13 — When Your Cholesterol Gene Edits Its Own Blueprint

Statins are among the most prescribed drugs in the world, yet up to half of patients do not achieve their LDL-cholesterol target on standard doses. Much of this variability traces back to the gene statins are designed to inhibit: HMGCR11 HMGCR
3-hydroxy-3-methylglutaryl-CoA reductase — the enzyme that catalyses the rate-limiting step in the mevalonate pathway, which produces cholesterol and other critical lipids in every cell of the body. The rs3846662 variant sits in intron 13 of HMGCR and influences a molecular editing process that determines how much drug-sensitive enzyme your body actually makes.

The Mechanism

HMGCR pre-mRNA can be spliced two ways. The dominant product is the full-length 888-amino-acid enzyme — the form that statins inhibit. The alternative product, known as HMGCR Δ13 or HMGCR13(-)22 HMGCR Δ13 or HMGCR13(-)
A shorter isoform in which the 24-amino-acid stretch encoded by exon 13 is excluded. This region overlaps the statin-binding domain of the enzyme, lacks the segment of the catalytic domain where statins dock. The Δ13 form retains partial enzymatic activity but is substantially less sensitive to statin inhibition.

rs3846662 sits within the intron 13 branch-point region and controls the ratio of full-length to Δ13 transcript. Yu et al. 201433 Yu et al. 2014
Yu CY et al. HNRNPA1 regulates HMGCR alternative splicing and modulates cellular cholesterol metabolism. Hum Mol Genet, 2014 demonstrated that the RNA-binding protein HNRNPA1 preferentially binds the A allele at this position and promotes exon 13 skipping: cells with the A allele produce a higher fraction of Δ13 mRNA. Consistent with this, AA homozygotes have the highest Δ13 ratio and the most attenuated statin response, while GG homozygotes maintain a predominantly full-length transcript and better statin sensitivity.

Medina & Krauss 200944 Medina & Krauss 2009
Medina MW, Krauss RM. The role of HMGCR alternative splicing in statin efficacy. Trends Cardiovasc Med, 2009 proposed that the Δ13 protein forms inactive heterodimers with full-length HMGCR, further diluting the pool of drug-accessible enzyme beyond what the mRNA ratio alone would predict.

The Evidence

The clinical link was established by Medina et al. 200855 Medina et al. 2008
Medina MW et al. Alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme A reductase is associated with plasma LDL cholesterol response to simvastatin. Circulation, 2008 in 170 lymphoblastoid cell lines from the Cholesterol and Pharmacogenetics (CAP) study. Greater Δ13 expression was inversely correlated (p≤0.0001) with in vivo reductions of total cholesterol, LDL-C, apoB, and triglycerides, with the splicing ratio explaining 6–15% of the variation in statin response — a sizeable fraction given the many factors involved.

Leduc et al. 201666 Leduc et al. 2016
Leduc V et al. Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia. Pharmacogenet Genomics, 2016 studied 37 French-Canadian familial hypercholesterolaemia patients and found that women with the AA genotype achieved a significantly smaller LDL-C reduction on statin therapy (38.4% vs 46.2%, p<0.05) compared with G carriers. Strikingly, alternative splicing explained 22–55% of the variance in statin response in this cohort. The sex-specific finding was notable: men showed similar splicing ratios but no detectable difference in statin response — likely reflecting oestrogen-dependent regulation of HMGCR expression that amplifies splicing effects in women.

Cano-Corres et al. 201877 Cano-Corres et al. 2018
Cano-Corres R et al. Influence of 6 genetic variants on the efficacy of statins in patients with dyslipidaemia. J Clin Lab Analysis, 2018 confirmed in 100 patients that G allele carriers showed significantly lower reduction in total cholesterol and non-HDL-C and were less likely to reach therapeutic cholesterol targets. Note that this study found the G allele direction — reflecting complex population-specific interactions between baseline lipid levels and splicing efficiency that remain under active investigation.

Practical Actions

For individuals with the AA or AG genotype, statin dose optimisation and closer monitoring of LDL-C response are warranted. If standard statin doses do not achieve LDL targets, the rs3846662 genotype provides a pharmacogenomic rationale for dose escalation, statin switching, or the addition of non-statin agents such as ezetimibe (which inhibits intestinal cholesterol absorption via a completely independent mechanism unaffected by HMGCR splicing).

Plant sterols and stanols (2 g/day from fortified foods or supplements) competitively inhibit dietary cholesterol absorption and can reduce LDL-C by 8–10% independently of the mevalonate pathway — making them a useful adjunct specifically when HMGCR is less statin-sensitive.

Interactions

This variant interacts with APOE genotype. Leduc et al. 2016 noted that the AA genotype at rs3846662 was associated with elevated baseline total and LDL-cholesterol specifically in individuals without APOE4 (rs429358 CC genotype), suggesting the two loci have partially overlapping effects on lipid setpoint and statin response.

Other HMGCR coding variants — rs17238540 and rs17244841 (both associated with statin response in the WOSCOPS trial) — are in partial linkage disequilibrium with rs3846662 and may tag the same underlying splicing haplotype. Interaction with rs7703051 (another HMGCR intron variant) has also been proposed in the literature.

Drug Interactions

simvastatin reduced_efficacy literature
atorvastatin reduced_efficacy literature
pravastatin reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

GG Full Statin Sensitivity Normal

Normal HMGCR exon 13 splicing — standard statin response expected

The GG genotype at this intronic position is associated with a lower ratio of HMGCR Δ13 to total HMGCR mRNA. Because the Δ13 isoform lacks part of the statin-binding domain of the enzyme, a lower Δ13 ratio means more drug-accessible enzyme is available for statins to inhibit.

Mechanistically, the G allele at rs3846662 is not recognised as efficiently by HNRNPA1 (the splicing factor that drives exon 13 skipping), so the pre-mRNA is more frequently spliced to retain exon 13 and produce full-length HMGCR protein. This is the biochemically "default" splicing outcome.

Note that some studies (Chung et al. 2012, PMID 21427285) have associated the GG genotype with higher baseline LDL-C — an independent effect on lipid setpoint distinct from statin response. If you have elevated LDL-C despite good statin response, this baseline effect may be relevant to discuss with your cardiologist.

AG Partial Splicing Shift Intermediate

Heterozygous — moderately elevated Δ13 splicing ratio; mild attenuation of statin response

Heterozygotes at rs3846662 have one copy of the A allele that HNRNPA1 preferentially binds, and one G allele that is less efficiently skipped. The result is an intermediate Δ13:total HMGCR ratio. The codominant pattern means the AG state is functionally between the two homozygotes.

Leduc et al. 2016 (PMID 26466344) found the clearest statin-response differences in AA homozygotes; heterozygote effects in that small cohort were less statistically definitive but consistent in direction. If LDL-C targets are not met on a standard statin dose, genotype-informed dose adjustment or alternative cholesterol-lowering strategies are worth discussing with your prescriber.

AA High Splice-Shift Reduced

Homozygous A — highest Δ13 splicing ratio; most pronounced attenuation of statin response

The A allele at rs3846662 creates an optimal binding site for HNRNPA1, the heterogeneous nuclear ribonucleoprotein that promotes exclusion of exon 13 from the HMGCR pre-mRNA. AA homozygotes therefore produce the highest fraction of HMGCR Δ13 transcript. The Δ13 protein product retains some enzymatic activity but is substantially less sensitive to statin competitive inhibition; Medina & Krauss 2009 (PMID 20005478) further proposed that the Δ13 isoform forms inactive heterodimers with full-length HMGCR, compounding the pharmacological blunting effect.

Clinically, Leduc et al. 2016 found this genotype most clearly relevant in women, in whom oestrogen-dependent HMGCR regulation amplifies splicing effects, yielding a statistically significant 7.8-percentage- point gap in LDL-C reduction (38.4% vs 46.2%, p<0.05). Men in the same cohort showed similar splicing ratios but without a statistically significant difference in clinical statin response — possibly due to lower oestrogen or compensatory up-regulation of total HMGCR mRNA.

Medina et al. 2008 (Circulation, PMID 18559695) found that the Δ13 splicing ratio explained 6–15% of the variance in LDL-C response to simvastatin in 170 lymphoblastoid cell lines — a pharmacogenomically meaningful share alongside other known contributors such as APOE and SLCO1B1 genotype.

If your LDL-C is not reaching targets on your current statin dose, this genotype provides a biological rationale to discuss genotype-informed dose adjustment or complementary strategies with your cardiologist.