rs5956 — CD36

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.

When CD36 is reduced or absent in humans, muscle and adipose fatty acid uptake falls markedly under fasting conditions⁴⁴ 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 sensor⁵⁵ 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.⁶⁶ 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.⁷⁷ 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.

Reassuringly, Rać M et al.⁸⁸ 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.

Interactions

CD36 does not act in isolation. rs1761667⁹⁹ 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.