rs5956 — CD36

Synonymous coding variant in CD36 fatty acid translocase; the minor A allele is associated with lower atheromatous plaque thickness and altered left ventricular diastolic parameters, likely through linked regulatory changes that affect CD36 expression.

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CD36 — The Fatty Acid Gatekeeper

CD36 (also called fatty acid translocase11 fatty acid translocase
CD36 is a multifunctional scavenger receptor that transports long-chain fatty acids across cell membranes, particularly in heart muscle, skeletal muscle, adipose tissue, and the gut) is one of the body's primary gatekeepers for how cells import dietary and circulating fat. It is responsible for a large fraction of long-chain fatty acid uptake in the heart, skeletal muscle, and adipose tissue, and also helps clear oxidized LDL22 oxidized LDL
Low-density lipoprotein that has been chemically modified by reactive oxygen species, making it pro-atherogenic from the bloodstream. The rs5956 variant (G573A in exon 6, Pro191Pro) is a synonymous coding change — the protein sequence itself is unchanged — but synonymous variants in metabolically critical genes are not always neutral. They can alter mRNA stability, codon usage efficiency, or be in tight linkage disequilibrium with nearby regulatory variants33 mRNA stability, codon usage efficiency, or be in tight linkage disequilibrium with nearby regulatory variants
Changes in nucleotide sequence at synonymous positions can affect mRNA secondary structure, codon translation rate, and may tag haplotypes carrying functional variants in promoters or UTRs that influence how much CD36 protein a cell ultimately makes.

The Mechanism

rs5956 lies in exon 6 of CD36 on chromosome 7q11.2 (GRCh38 position chr7:80,663,133), a gene on the forward strand. The G-to-A change at nucleotide position 573 of the coding sequence does not alter the proline at codon 191 (CCG→CCA, both encoding proline). Protein function is therefore unchanged at this position. The biological interest in the A allele stems from its position within a haplotype block that overlaps promoter and enhancer elements of CD36. Lower CD36 surface expression — documented for several CD36 haplotypes carrying variants in regulatory regions — reduces fatty acid import per cell, shifts substrate selection44 substrate selection
The relative proportion of fat versus glucose a cell uses for energy in cardiac and skeletal muscle, and affects how efficiently the body clears postprandial triglyceride-rich lipoproteins.

When CD36 is reduced or absent in humans, muscle and adipose fatty acid uptake falls markedly under fasting conditions55 muscle and adipose fatty acid uptake falls markedly under fasting conditions
Hames et al. Free fatty acid uptake in humans with CD36 deficiency. Diabetes, 2014, forcing cells to rely more heavily on glucose oxidation. The heart is particularly CD36-dependent and cannot compensate as readily as skeletal muscle. At the molecular level, CD36 also acts as a metabolic sensor66 metabolic sensor
Samovski et al. Regulation of AMPK activation by CD36 links fatty acid uptake to beta-oxidation. Diabetes, 2015 that couples fatty acid availability to AMPK activation — the cellular energy gauge — so reduced CD36 expression can blunt the cell's ability to upregulate fat oxidation in response to rising lipid levels.

The Evidence

Direct evidence for rs5956 itself comes from a series of studies in Polish patients with early-onset coronary artery disease (CAD). Rać ME et al.77 Rać ME et al.
Rać ME et al. CD36 gene is associated with thickness of atheromatous plaque and ankle-brachial index in patients with early coronary artery disease. Kardiol Pol, 2012 (n=70, Caucasian) found that carriers of the 573A allele (rs5956-A) had significantly lower carotid atheromatous plaque thickness, suggesting a protective vascular effect of this haplotype — the authors concluded "the 573A allele has a protective effect against atherosclerosis development."

A follow-up study by Rać M et al.88 Rać M et al.
Rać M et al. Association of CD36 gene polymorphisms with echo- and electrocardiographic parameters in patients with early onset coronary artery disease. Arch Med Sci, 2013 (n=100) found that rs5956 heterozygous carriers had a higher frequency of pseudonormal left ventricular diastolic function — a pattern associated with mildly elevated left ventricular filling pressures that can be a precursor to diastolic dysfunction. This apparently paradoxical finding (protective vascular effect but altered cardiac filling) underscores that CD36's role in fatty acid delivery to the heart means that altering its expression has complex, tissue-dependent effects.

Reassuringly, Rać M et al.99 Rać M et al.
Rać M et al. Is CD36 gene polymorphism in region encoding lipid-binding domain associated with early onset CAD? Gene, 2013 found no significant association of rs5956 genotype with early-onset CAD susceptibility overall, and a study in obese children found no association with carbohydrate metabolism or plasma CD36 concentration. The evidence for rs5956 specifically is therefore emerging and limited to observational studies in relatively small CAD cohorts.

Practical Actions

The A allele's associations are modest and the direct mechanistic link for rs5956 itself remains unproven — the variant likely tags a haplotype with regulatory effects rather than acting directly. Practically, this means attending to dietary fat quality is the most evidence-aligned action: CD36 preferentially transports long-chain saturated fatty acids (palmitate, stearate) over short- or medium-chain varieties, and the balance between saturated and unsaturated fat intake modulates CD36 surface expression and lipid uptake. For carriers of the A allele, where subtle differences in CD36 expression may affect how efficiently fat is cleared after meals, keeping postprandial triglyceride load in check through dietary fat quality — rather than quantity alone — is the most targeted approach available given current evidence.

Interactions

CD36 does not act in isolation. rs17616671010 rs1761667 (also in CD36) is a promoter variant with stronger effects on CD36 protein expression and better documented associations with taste perception for fat, fatty acid metabolism, and endocannabinoid levels. The intronic variants rs3173798 and rs3211892 are in the same haplotype region and have been studied alongside rs5956. Interpreting rs5956 in the context of the broader CD36 haplotype — particularly whether rs1761667 is also present — would sharpen the risk picture, but no published compound-genotype analysis specifically combining these variants was available at the time of writing.

Nutrient Interactions

long-chain fatty acids altered_metabolism
saturated fat altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal

Standard CD36 fatty acid transport

CD36 is one of the body's primary importers of long-chain fatty acids into heart muscle, skeletal muscle, and adipose tissue. The GG genotype at rs5956 places you on the most common CD36 haplotype. The available studies in early-onset CAD patients and obese children found no cardiovascular or metabolic differences attributable to the GG genotype versus other genotypes at this locus, and the 573G allele (reference) is present at essentially 100% frequency in East Asian populations, pointing to strong conservation.

AG Intermediate

One copy of the CD36 573A allele — possible modest vascular benefit

The 573A allele is synonymous at the protein level (Pro191Pro) but likely tags a regulatory haplotype influencing CD36 surface expression. Reduced CD36 expression can shift cardiac fuel use away from fatty acids toward glucose, which may be protective against atherosclerotic lipid uptake (fewer oxidized LDL scavenged into plaques) while simultaneously altering the heart's preferred energy substrate balance.

A study by Rać ME et al. (PMID 22993001, n=70) found 573A allele carriers had significantly lower atheromatous plaque thickness and concluded the allele has a protective effect against atherosclerosis. A follow-up (PMID 24049523, n=100) noted AG carriers had higher frequency of pseudonormal LV diastolic function compared to GG. No association with overall CAD susceptibility was found (PMID 23856131). Evidence is emerging and limited to small Caucasian cohorts.

Given CD36's role in postprandial lipid clearance, dietary fat composition — particularly reducing long-chain saturated fat intake — may have a more pronounced effect on lipid handling in individuals on this haplotype.

AA High Risk

Two copies of the CD36 573A allele — rare genotype with limited direct evidence

As a synonymous variant, rs5956-A acts primarily through its association with a CD36 regulatory haplotype. If homozygosity for this haplotype further reduces CD36 surface expression, the cardiac fueling implications become more significant: CD36 is essential for myocardial long-chain fatty acid uptake, and partial CD36 deficiency in humans is associated with markedly reduced cardiac fatty acid utilization at physiological concentrations (Hames et al. PMID 24917573).

The heart normally derives about 60–70% of its energy from fatty acid oxidation. Reduced CD36-mediated fatty acid import can shift cardiac substrate preference toward glucose and ketones. This metabolic shift is not inherently pathological — Type I CD36 deficiency exists in ~0.3–0.5% of the Japanese population — but it does suggest that myocardial lipid handling may be altered. The LV diastolic function signals from rs5956 heterozygote studies may be extrapolated to homozygotes with appropriate caution.

Cardiac imaging and metabolic monitoring are warranted given the rarity of the genotype and the CD36 biology, particularly if other cardiovascular risk factors are present.