rs10846744 — SCARB1

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.