rs10846744 — SCARB1

Intronic SCARB1 variant associated with altered HDL-receptor function, subclinical atherosclerosis, and increased coronary heart disease risk

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SCARB1 — The HDL Docking Station Gene

When your HDL particles finish their journey through the bloodstream collecting excess cholesterol from tissues, they need somewhere to deliver it. That final destination is the liver, and the molecule that accepts the delivery is SR-BI11 SR-BI
Scavenger Receptor class B type I — a cell-surface receptor that extracts cholesterol esters directly from HDL into hepatocytes, the critical last step of reverse cholesterol transport. The SCARB1 gene encodes SR-BI, and rs10846744 — an intronic variant — influences how well this receptor functions. Carriers of the C allele show measurably higher rates of subclinical atherosclerosis and coronary heart disease, even in the presence of normal or elevated HDL cholesterol levels.

The Mechanism

rs10846744 lies within an intron of SCARB1 on chromosome 12 (GRCh38: 12:124,827,879). As a non-coding variant, it does not change the SR-BI amino acid sequence, but it likely affects gene expression, mRNA splicing efficiency, or protein levels — collectively altering the rate at which HDL cholesterol can be cleared from circulation into the liver. When SR-BI function is compromised, HDL particles accumulate in the bloodstream. This creates the HDL paradox22 HDL paradox
Normally, higher HDL is protective. But if HDL is high because the receptor that removes it isn't working well, the cholesterol isn't actually being delivered to the liver for excretion — it's stuck in transit: an elevated HDL reading accompanied by impaired reverse cholesterol transport and, paradoxically, increased cardiovascular risk.

The Evidence

The strongest evidence comes from a MESA cohort analysis33 MESA cohort analysis
Manichaikul et al. Association of SCARB1 variants with subclinical atherosclerosis and incident cardiovascular disease: the multi-ethnic study of atherosclerosis. ATVB, 2012 of 7,936 participants from four ethnic groups. The rs10846744 variant showed strong association with carotid intima-media thickness (cIMT) across all ethnicities (P=1.04×10⁻⁴), a validated marker of early atherosclerosis. In males specifically, the variant was significantly associated with incident cardiovascular disease events (P=0.01), with replication support in the Myocardial Infarction Genetics Consortium.

A subsequent multi-cohort study44 multi-cohort study
Manichaikul et al. Lp-PLA2, SCARB1 rs10846744 variant, and cardiovascular disease. PLoS One, 2018 using CARDIoGRAMplusC4D data (hundreds of thousands of participants) confirmed that the C allele associates with coronary artery disease (OR 1.05, 95% CI 1.02–1.07, P=1.4×10⁻⁴). The same study found associations with Lp-PLA2 activity, LDL particle number, and DHA levels in MESA participants.

A Chinese Han cohort study55 Chinese Han cohort study
Zeng et al. Influence of SCARB1 gene SNPs on serum lipid levels and susceptibility to coronary heart disease and cerebral infarction in a Chinese population. Gene, 2017 of 909 participants found the C allele significantly elevated CHD risk (OR 1.416, 95% CI 1.128–1.778, P=0.006). Notably, CC and CG carriers had higher HDL-cholesterol than GG carriers — illustrating the HDL paradox characteristic of SR-BI dysfunction.

Practical Actions

For C allele carriers, the impaired SR-BI function means the focus should shift from simply raising HDL cholesterol to optimizing HDL functionality and facilitating cholesterol clearance through alternative pathways. Omega-3 fatty acids (EPA and DHA) support HDL particle quality and enhance reverse cholesterol transport efficiency. Monitoring HDL function — not just HDL-C level — and tracking inflammatory markers such as Lp-PLA2 gives a more accurate cardiovascular risk picture than a standard lipid panel alone.

Interactions

rs10846744 is in the same gene as rs4238001 (an exonic SCARB1 variant), rs2278986 (another SCARB1 intronic SNP), and rs5888 (a synonymous coding variant). Combined analysis of multiple SCARB1 variants may capture more variance in SR-BI activity than any single SNP alone. SCARB1 also interacts with the APOE pathway (rs429358, rs7412): both genes govern how efficiently cholesterol is cleared from the bloodstream, so carriers of risk alleles in both genes may face compounded dysfunction in reverse cholesterol transport.

Nutrient Interactions

dietary fat altered_metabolism
omega-3 fatty acids altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal HDL Receptor Normal

Normal SR-BI function — standard reverse cholesterol transport

You carry two copies of the G allele (the common reference allele), found in approximately 71% of European-ancestry individuals but only about 13% of individuals of African ancestry. Your SCARB1 gene is expected to produce SR-BI at normal levels, supporting efficient uptake of cholesterol from HDL into hepatocytes — the final step of reverse cholesterol transport.

CG Reduced HDL Receptor Activity Intermediate

One risk copy — moderately impaired HDL clearance

The HDL paradox is the key concept here: because SR-BI is the receptor that extracts cholesterol from HDL for delivery to the liver, impaired SR-BI activity can cause HDL cholesterol to accumulate in the bloodstream rather than being cleared. This means a standard lipid panel showing "good" HDL levels may be misleading for CG carriers — the high HDL may reflect poor delivery, not efficient cholesterol management. The CARDIoGRAMplusC4D analysis (hundreds of thousands of participants) found an OR of 1.05 per C allele for coronary artery disease. This is a modest per-allele effect, but it is replicated across multiple large cohorts and ethnicities.

CC Significantly Reduced HDL Receptor Activity High Risk

Two risk copies — substantially impaired SR-BI function and elevated CHD risk

SR-BI dysfunction in CC homozygotes means HDL particles cycle through the bloodstream without efficiently offloading cholesterol esters to hepatocytes. Downstream consequences include elevated Lp-PLA2 activity (an inflammatory phospholipase marker of oxidized LDL and vascular inflammation), higher LDL particle number, and measurably thicker carotid artery walls. The cumulative evidence across MESA, CARDIoGRAM, and multiple ethnic cohorts consistently places CC homozygotes at the upper end of SCARB1-attributable cardiovascular risk. The additive inheritance pattern means two C copies confer approximately twice the per-allele effect seen in heterozygotes.