rs4888378 — CFDP1

Intronic CFDP1 locus variant that regulates BCAR1 expression in vascular tissue via FOXA binding; the A allele reduces BCAR1 levels and is associated with lower carotid intima-media thickness progression and reduced coronary artery disease risk, with the protective effect strongest in women

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The BCAR1-CFDP1 Locus — A Vascular Wall Regulator Tied to Coronary Risk

The rs4888378 variant sits within an intron of CFDP1 (Craniofacial Development Protein 1) on chromosome 16q23, but the functionally relevant gene it controls is a neighbor: BCAR1 (Breast Cancer Anti-Estrogen Resistance 111 Breast Cancer Anti-Estrogen Resistance 1
a scaffold protein originally characterised in drug-resistant breast cancer but now recognised as a regulator of endothelial cell migration and vascular smooth muscle remodelling). GWAS analysis identified this locus as one of 64 novel genome-wide-significant loci for coronary artery disease in a study spanning over 82,000 subjects, with the G allele conferring risk (P=6×10⁻¹⁵).

The Mechanism

The rs4888378 position falls within a regulatory element that binds the transcription factor FOXA (Forkhead Box A)22 FOXA (Forkhead Box A)
a pioneer transcription factor that opens chromatin and activates gene expression in liver, vascular, and epithelial tissues. Electrophoretic mobility shift assays show allele-specific protein binding at this exact nucleotide: the A allele weakens FOXA recruitment, while the G allele supports it. The consequence is a large change in BCAR1 expression — luciferase reporter assays showed the A allele reduces BCAR1 promoter activity by 35% to 92% relative to the G allele (P values: 0.0057 and 4.0×10⁻²²).

BCAR1 (also called p130Cas) is a scaffold protein with 15 phosphorylation sites for Src family kinases. In vascular tissue it promotes endothelial cell migration, smooth muscle cell proliferation after arterial injury, and integrin-mediated signalling pathways that drive plaque development. Higher BCAR1 expression — the state produced by the G allele — accelerates the cellular programmes that thicken arterial walls and build atherosclerotic burden.

The Evidence

The initial GWAS discovery by Gertow et al. 201233 Gertow et al. 2012
Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk. Circ Cardiovasc Genet 2012 identified rs4888378 as the lead SNP for maximum carotid IMT in 3,430 Swedish subjects (IMPROVE study; discovery P=6.75×10⁻⁷), replicated in 11,590 subjects across five European cohorts. In two independent case-control samples totalling 13,591 and 82,297 subjects of European ancestry, the A allele was associated with lower coronary artery disease risk (OR 0.83, 95% CI 0.77–0.90, P=6.53×10⁻⁶; and OR 0.95, 95% CI 0.92–0.98, P=1.83×10⁻⁴). These are additive per-allele effects — each copy of the A allele lowers CAD risk incrementally.

The follow-up functional study by Boardman-Pretty et al. 201544 Boardman-Pretty et al. 2015
Functional Analysis of a Carotid Intima-Media Thickness Locus Implicates BCAR1 and Suggests a Causal Variant. Circ Cardiovasc Genet 2015 narrowed 214 candidate regulatory variants in strong LD with rs4888378 to six by layering ENCODE regulatory annotations, then confirmed allele-specific FOXA binding and expression effects at rs4888378 itself. Crucially, the protective effect on IMT progression was sex-stratified: in the PLIC cohort, the AA genotype associated with slower IMT progression in women (P=0.04) but not in men, and meta-analysis across five cohorts confirmed the A allele's protective beta was significant only in women (β=-0.0047, P=1.63×10⁻⁴ versus P=0.068 in men). The sex-differential mechanism is not fully understood but may relate to oestrogen's interaction with FOXA-regulated vascular gene programmes.

The large-scale coronary artery disease signal was confirmed in a 2018 genome-wide study by van der Harst & Verweij55 van der Harst & Verweij
Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease. Circ Res 2018, reaching genome-wide significance (P=6×10⁻¹⁵) — establishing this locus as a robust, replicated determinant of atherosclerotic burden, not just an initial association.

Practical Actions

The rs4888378 locus acts on the rate of subclinical atherosclerosis accumulation over decades. The G allele raises vascular BCAR1 expression, accelerating endothelial and smooth muscle remodelling processes. For GG carriers the most useful focus is on biomarkers that detect subclinical atherosclerosis before clinical events — carotid IMT measurement and coronary artery calcium scoring quantify exactly the burden that this locus influences. Controlling modifiable atherosclerosis drivers (LDL cholesterol, blood pressure, smoking, glycaemia) becomes proportionally more important when the genetic background is already pro-atherogenic. For women carrying risk genotypes, the evidence of sex-specific vulnerability at this locus strengthens the case for proactive vascular risk monitoring.

Interactions

This locus sits in a genomic cluster with TMEM170A and BCAR1 itself. The three genes share regulatory architecture, and expression quantitative trait loci analysis confirms BCAR1 as the vascular-relevant effector. CFDP1 and TMEM170A are expressed in the region but did not show the same vascular eQTL pattern in the Boardman-Pretty functional study. No epistatic interactions with other SNPs have been formally characterised for this locus, but co-occurring risk variants in lipid pathways (APOE, PCSK9, LPA) and blood pressure pathways would be expected to compound atherosclerotic burden additively.

Genotype Interpretations

What each possible genotype means for this variant.

AA Beneficial

Protective genotype associated with lower carotid atherosclerosis and reduced coronary artery disease risk

You carry two copies of the A allele at rs4888378, the genotype associated with the lowest BCAR1 vascular expression at this locus. About 23% of people globally share this genotype. The A allele weakens FOXA transcription factor binding at this regulatory element, reducing BCAR1 expression by 35–92% relative to the G allele. In the IMPROVE study and subsequent replication cohorts, each A allele was associated with reduced coronary artery disease risk (OR 0.83 per copy in the largest dataset). Functional studies confirmed slower carotid IMT progression in AA individuals, particularly in women.

AG Intermediate

One copy of the coronary risk allele — moderately elevated atherosclerosis susceptibility

You carry one A and one G allele at rs4888378, the most common genotype found in approximately 50% of people globally. Each G allele adds to BCAR1 expression in vascular tissue through FOXA-mediated regulatory activation. The risk is additive: AG carriers have intermediate coronary artery disease risk between the protective AA and the higher-risk GG genotype. The BCAR1 scaffold protein promotes endothelial cell migration and smooth muscle remodelling processes that contribute to atherosclerotic plaque development. For women, sex-stratified analysis suggests the A allele provides measurable protection that is partially diluted in heterozygotes.

GG High Risk

Two copies of the coronary risk allele — elevated BCAR1 vascular expression and increased atherosclerosis susceptibility

The rs4888378 G allele acts through an elegant regulatory mechanism: it maintains FOXA transcription factor binding at a vascular enhancer within the CFDP1 intron. FOXA is a pioneer factor that opens chromatin and activates downstream target genes. When bound at this locus, it drives BCAR1 expression — and BCAR1's 15 Src-kinase phosphorylation sites make it a powerful amplifier of integrin-mediated signalling in vascular cells. Higher BCAR1 levels translate to enhanced endothelial cell migration during injury responses, more aggressive smooth muscle proliferation, and a pro-atherogenic cellular environment.

The signal at this locus is robust: it was identified at array-wide significance in discovery, replicated across five independent European cohorts, and reached genome-wide significance (P=6×10⁻¹⁵) in the largest CAD GWAS meta-analysis to date. The effect per allele is modest (OR ~0.90–0.95 per protective A allele carried), which is typical for common coronary disease variants — meaning GG homozygotes carry meaningfully elevated lifetime atherosclerotic susceptibility that compounds with other genetic and lifestyle risk factors rather than acting as a single catastrophic variant.

The sex-specific dimension adds clinical nuance: the protective A allele showed stronger benefit in women (P=1.63×10⁻⁴) than men (P=0.068), suggesting oestrogen or other sex-specific factors modulate how FOXA binding at this locus translates into atherosclerotic outcomes. Women who are GG at rs4888378 lose the partial protection that even one A allele would confer.