CD36 gene variants and their clinical relevance: a narrative review

Introduction

The cluster of differentiation 36 (CD36) was found over 40 years ago as glycoprotein IV (GPIV) by lectin affinity chromatography on human blood platelet membranes (1). It was later found to be identical to the antigen recognized by the monoclonal antibody OKM5, a marker for monocytes and macrophages (2). Subsequently, CD36 antigen was detected on many other tissues and cells including epithelial cells, vascular endothelium, adipocytes, skeletal and cardiac myocytes, microglia, pancreatic β-cells, dendritic cells, erythroid precursors, hepatocytes, specialized epithelia of the breast, kidney, gut and tongue, kidney glomeruli and tubules cells, retinal pericytes and pigment epithelium cells (3). Biased expression of CD36 gene in breast, adipose, heart, colon and white blood cells, which is higher than that in other 11 human tissues, was found in a transcription profiling by high throughput sequencing of Illumina Inc. (4).

The diverse expression pattern of CD36 is a reflection of its multiple cellular functions. Extensive research aiming at thoroughly understanding of CD36 protein has been carried out since its discovery. Initially, researchers focused on the characteristics of the CD36 gene and protein, its tissue and subcellular localization, and its function. Subsequently, other studies examined the role of CD36 in the pathogenesis of many diseases. Studies have reported that the CD36 protein serves as a receptor for thrombospondin in platelets and various cell lines. Since thrombospondins are widely distributed and involved in a variety of adhesive processes, CD36 protein may have important function as a cell adhesion molecule. The CD36 protein also binds to collagen and anionic phospholipids, and functions as a scavenger receptor that can absorb oxidized low-density lipoproteins (ox-LDL) and long chain fatty acids (LCFA), so it plays a role of fatty acid translocase (FAT) in the transport or serve as a regulator of fatty acid transport. Furthermore, CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes (5). Mutations in the CD36 gene can cause platelet glycoprotein deficiency, and may further lead to immune thrombocytopenia due to CD36 isoantibody (6). The various synonym of CD36, such as platelet GPIV, glycoprotein IIIb (GPIIIb), collagen type I receptor, thrombospondin receptor, PAS IV, FAT, scavenger receptor class B member 3 (SCARB3 or SR-B2), bleeding disorder platelet-type 10 (BDPLT10) and coronary heart disease type 7 (CHDS7), also show a variety of physiological or pathological functions of CD36. In this review, we focus on CD36 gene variants and their clinical relevance especially on thrombocytopenia, malaria, lipid taste perception and obesity, and other metabolic syndromes including atherosclerosis and type 2 diabetes mellitus (T2DM). As a search literature strategy, the gene, Single Nucleotide Polymorphism database (dbSNP) and PubMed electronic database of National Center for Biotechnology Information (NCBI) was searched for publications on clinical relevance of CD36 without time limits using English language as a restriction. The Medical Subject Heading and key words used were: “CD36”, “gene”, “variant”, “polymorphism” and “thrombocytopenia”, “malaria”, “obesity”, “metabolic syndrome”, “atherosclerosis”, “Type 2 diabetes mellitus”, “Colorectal Cancer”, “Alzheimer’s disease”. We present the following article in accordance with the Narrative Review reporting checklist (available at https://dx.doi.org/10.21037/aob-21-49).

CD36 gene and protein

The CD36 gene is located on chromosome 7q21.11 and spans about 77kb. At least 20 alternatively spliced transcript variants have been found for this gene, including 16 coding mRNA, 1 non-coding mRNA and 3 predicted mRNA obtained by automated computational analysis of CD36 mRNA and EST data. A total of 19 exons were found in the CD36 gene, but there were up to 15 exons which could be spliced in a single mRNA variant and of which 12 exons are coding. In two major transcript variants (isoform 1 and 3), exon 1, 2 and 5'-end of exon 3 are non-coding. The coding region contains 1,419 nucleotides, ranging from 3'-end of exon 3 to exon 14, and encodes 472 amino acid (Aa) residues. The 3'-end of exon 14 in isoform 3 and exon 15 in isoform 1 are also non-coding regions (7).

The CD36 transmembrane protein contains both an N-terminal (Aa2–7) and a C-terminal (Aa462–472) cytoplasmic tail with Src-family tyrosine kinases necessary for signal transduction, two transmembranes (Aa8–29 and Aa440–461), and a big extracellular loop (Aa30–439) with hairpin-like membrane topology (8). The heavily glycosylated extracellular domain of CD36 includes three disulfide bridges in the carboxyl-terminal half that were shown to be important for CD36 membrane recruitment. The extracellular domain contains multiple binding sites for ligands and posttranslational modification sites including lipidation, acetylation, glycosylation and phosphorylation (Table 1). Besides the transmembrane form of CD36, soluble form sCD36 is also generated, which is formed by the abscission of extracellular domain of transmembrane CD36. Some data presented suggest a possible protective effect of a higher sCD36 concentration in relation to metabolic syndrome components (13).

So far, a total of 30,703 nucleotide variants of CD36 gene, including 26,531 single nucleotide variants (SNVs) and 4,172 multiple nucleotide variants (MNVs) or deletion/insertion variants (DELINS), have been found and deposited in dbSNP database of NCBI website (14). Most of the gene variants are in the non-coding region and do not cause amino acids changes or functional changes, but a small number of nucleotide variants, including 590 missense mutations in the coding region or flanking splice sites, may affect function of the CD36 protein. In addition, some nucleotide variants in the non-coding region were also found to be associated with protein expression level and some clinical symptoms (15-17).

CD36 gene variants and thrombocytopenia

It has been shown that the Nak^a antigen is located on CD36 and that individuals who do not express CD36 on their platelets can probably be immunized with CD36 antigen, producing anti-Nak^a (anti-CD36) by transfusion or other immune pathways. The first described individual with deficiency of CD36 was a Japanese woman who was refractory to human leucocyte antigen (HLA)-matched platelet transfusions (6). Currently, CD36 deficiency is divided into two subgroups according to the phenotype. In type I deficiency, CD36 is not expressed in either platelets, monocytes or other tissue cells, whereas in type II deficiency, CD36 is expressed in monocytes but not in platelets. It can be inferred that anti-CD36 isoantibody is only produced in type I individuals, but not in type II individuals due to autoimmune tolerance. Production of anti-CD36 isoantibodies is an important risk factor for immune-mediated thrombocytopenia including fetal and neonatal alloimmune thrombocytopenia (FNAIT), platelet transfusion refractoriness (PTR), and posttransfusion purpura (PTP). Platelet CD36 deficiency varies widely between different ethnic groups, with a frequency of 2.6% in Arabians, 3% to 11% in Asians, 8% in sub-Saharan Africans, and less than 0.4% in Caucasians (18-20).

The CD36 gene is highly polymorphic and more than 60 polymorphic sites have been found in exon or flanking intron regions, which can cause amino acids exchanges and is considered to be the molecular basis of CD36 deficiency (Table 2). A genome-wide association study of 374 Caucasian subjects showed strong associations of 23 single nucleotide polymorphisms (SNPs) in CD36 gene with platelet surface CD36 expression (37). Some studies also showed CD36 expression on platelets is associated with -132A>G of 5'-untranslated region (UTR) or a silent allele linked to a (TG)n repeat polymorphism in intron 3 (15,16). Although the molecular basis of CD36 deficiency, especially type II deficiency, is still controversial, these gene mutations may be the potential molecular mechanism leading to CD36 deficiency and iso-immune response.

CD36 gene variants and malaria

A critical step in infection by Plasmodium falciparum, the microorganism that causes the most severe form of malaria, is the adhesion of infected red blood cells (iRBCs) to capillary endothelium. The human protein CD36 is a major receptor for Plasmodium falciparum-iRBCs and may contribute to the development of malaria by sequestering iRBCs and inhibiting the immune response to the parasite. However, it cannot be simply concluded that CD36 is only beneficial to malaria and harmful to the host.

In Plasmodium falciparum malaria, the consequences of erythrocyte adhesion to CD36 depend on the tissue type expressing CD36. Adhesion of iRBCs to CD36 present on monocytes in the spleen enhances phagocytosis and host clearance of the parasite, that is beneficial to the host. Adhesion of iRBCs to CD36 expressed on platelets or endothelium may result in platelet mediated clumping or sequestration, either of which could produce blockage of blood flow to critical organs including brain and reduce the possibility of cerebral malaria. This is also beneficial to the host. Adhesion of iRBCs to CD36 on endothelial cells of skin, fat, or muscle is less harmful to the host while still allowing the parasite to undergo growth and replication (38). Numerous studies have explored the relation between malaria severity and mutations of the CD36 gene. Results have been conflicting, with most studies suggesting a benefit to host associated with CD36 mutations, some showing a disadvantage to host, and some studies showing no effect to host (Table 3).

In the studies of CD36 mutations harmful to the host, Aitman et al. (34) first found that two mutation alleles, 1264T>G (now c.975T>G) and 1439G>C+1444delA (now c.1150G>C+c.1155delA), had higher frequency in cerebral malaria group than anemia malaria group and control malaria group in Gambians and Kenyans. The authors speculated that the gene variants leaded to the CD36 deficiency and then reduced parasite sequestration in organs outside the brain. Another study showed that 539delAC (now c.329-332delAC) allele in exon 5 was detected in three cerebral malaria patients (3/107), but not in mild malaria patients (0/203). It suggested that the 539delAC allele might be a high-risk variant for cerebral malaria in Thais (39).

However, more studies support that CD36 gene mutations were beneficial to the host. Chilongola et al. (40) also examined the 1264T>G mutation known to decrease CD36 expression in Tanzanian children, but they came to the opposite conclusion. They found that strong CD36 expression by the host might worsen anemia as a result of increased splenic clearance, platelet-mediated clumping, or erythrocyte sequestration, whereas CD36 deficiency derived from 1264T>G mutation protects against malarial anemia. Pain et al. (41) identified a non-sense mutation, 188T>G (now also c.975T>G) in exon 10, and looked at the influence of this mutation on the outcome of malaria infection in 693 African children with severe malaria and a similar number of ethnically matched controls. The result showed that heterozygosity for this mutation is associated with protection from severe malaria. Das et al. (42) also investigated the possible association of 188T>G polymorphism in exon 10 with severe clinical manifestations of malaria in 95 adult patients with severe malaria (severe group) and 95 ethnically matched controls (mild group) in India. The frequency of the wild-type (188T) allele of the CD36 gene was 0.91 in the severe group and 0.78 in the mild group of patients, while mutant (188G) allele frequency was 0.09 in the severe group and 0.22 in the mild group. The study shows that the presence of 188T>G mutant allele renders protection against severe malaria. Omi et al. (17) performed systematic variation screening, including all 16 exons with neighboring introns and two promoter regions of the CD36 gene, and examined the possible association between CD36 polymorphisms and the severity of malaria in 475 adult Thai patients with Plasmodium falciparum malaria. Although 1264T>G mutation was not detected, nine CD36 polymorphisms with a high-frequency (>15%) minor allele, including -14T>C, 59T>A, -53G>T, 158C>A, IVS3-6T>C, IVS7+103C>T, IVS8-156A>G, IVS11-150A>C and IVS14-419del9bp, were identified in Thai. Of these, the frequencies of the -14T>C allele in the upstream promoter region and the -53G>T allele in the downstream promoter region were significantly decreased in patients with cerebral malaria compared to those with mild malaria. The analysis of linkage disequilibrium between the nine common polymorphisms revealed that there are two blocks with strong linkage disequilibrium in the CD36 gene and that the 514T>C and 553G>T polymorphisms are within the upstream block of 35 kb from the upstream promoter to exon 8. Further association testing after the second variation screening in the upstream block indicated that the 12TG repeats in intron 3 [in3(TG)₁₂] allele is most strongly associated with the reduction in the risk of cerebral malaria. The study found that in3(TG)₁₂ is involved in the nonproduction of the variant CD36 transcript that lacks exons 4 and 5. Since exon 5 of the gene is known to encode the ligand-binding domain for Plasmodium falciparum-iRBCs, in3(TG)₁₂ itself or a primary variant on the haplotype with in3(TG)₁₂ may be responsible for protection from cerebral malaria in Thailand (17).

In view of the conflicting results of the above study on the association between the 1264T>G polymorphism and severe malaria, Fry et al. (43) employed a largest sample size (4,692 cases and 6,230 controls) from four African population to analyze the association between 1264T>G mutation and malaria. They found that the nonsense allele carrying 1264G was not associated with severe malaria. They further screened 70 variants within and around CD36 gene, including 1439G>C and 1444delA in previously studies, for association study. No mutation was associated with either a higher or lower risk of severe disease.

Although it is still a question whether CD36 and malaria are friend or foe, current research data indicate that the interaction between Plasmodium falciparum and CD36 may be a co-adaptation, which is beneficial to both parasite and host (44).

CD36 gene variants, lipid taste perception and obesity

The epidemic of obesity is posing a serious world-wide threat to human health and world widely that can no longer be ignored. The factors of genetics, environment and dietary habits are involved in development of obesity. Dietary fat is consumed in high amounts by obese subjects because of its olfactory, visual and textural cues. Growing evidence suggests that oral fat sensing plays a significant role in development of obesity. The CD36 glycoprotein expressed on taste bud cells of lingual surface has been shown to be implicated in this mechanism (45). The fatty acids and triacylglycerol in food provide sensory signals that allow the fat to be perceived. As a fatty acid translocase, CD36 receives the sensory signals and determines the individual’s preference degree for dietary lipids. It has been proposed that gene variants and functionality alteration of CD36 might influence the individual’s sensitivity, preference and intake of fat (46).

There is a controversy on how genetic variations in CD36 influence obesity. Ma et al. (47) first investigated associations between common polymorphisms at the CD36 gene, plasma free fatty acid (FFA) levels and risk for cardiovascular disease (CAD) in Caucasians. Two linkage disequilibrium blocks represented by a haplotype tagged by five polymorphisms (-33137A>G or rs1984112, -31118G>A or rs1761667, 25444G>A or rs1527483, 27645del>ins16bp or rs3840546 and 30294G>C or rs1049673) were detected through the screening of 21 polymorphisms evenly spanned the CD36 gene. When the five tag polymorphisms were considered together, men carrying the AGGIG haplotype had 31% higher plasma fatty acid and 20% higher triglycerides than non-carriers. The same haplotype was associated with increased risk of CAD in type 2 diabetic individuals from the US and Italy. Bokor et al. (48) also assessed the relationship between 10 SNPs of CD36 gene and obesity in European adolescents, in which 4 SNPs (rs3211867, rs3211883, rs3211908 and rs1527483) were associated with increased risk of obesity, higher body mass index (BMI) and percentage of body fat (BF%). Further analyses identified a haplotype carrying the minor allele of 4 SNPs (haplotype AAAA) as being associated with obesity and excess adiposity. But this finding was inconsistent with study done by Choquet et al. (49) who found no effect of those four variants on obesity risk in young populations of European ancestry using big data analysis of case-control (n=3,509), population-based (n=4,667), and meta-analysis study designs (n=9,973).

Based on the correlation data between CD36 polymorphisms and obesity, it was speculated that CD36 may play an important role in oral fat perception and individual preferences for fatty foods. The rs1761667, a common variant which lies between two alternative promoters of CD36 gene and associates with reduced CD36 expression on human platelets (37) and mice circumvallate taste papillae (50), is the most studied polymorphism for the association of CD36 variants with fat taste, oro-gustatory thresholds, fat intake and obesity. A study in obese Tunisian women showed that the participants with A-allele of rs1761667 polymorphism exhibited decreased oral sensitivity (high oro-gustatory thresholds) to oleic acid (51). Another study in young Algerian teenagers also showed that the A-allele frequency was higher in obese teenagers than that in lean children, and the obese teenagers exhibited higher lingual detection threshold for oleic acid than lean participants (52). The results suggested that individuals with AA genotype of rs1761667 have reduced sensitivity to fat content, which could lead to increase fat intake and obesity. The role of CD36 polymorphism in taste perception may be more impactful in children due to the lack of cultural influence compared to adults, and taste acuity may decline with age. The positive correlation between fat detection thresholds, BMI, BF% and A-allele of rs1761667 was also confirmed in Japanese (53), Morocans (54) and Poles (55). However, an opposite result was observed in Mexican children. The authors found that G-allele, rather than A-allele, of rs1761667 in CD36 gene was associated with overweight and obesity in Mexican children, and this polymorphism did not appear to modulate the preferences and satisfaction scores to fat (56). A recent study also found that 2 variants (rs1054516 and rs3173798) were associated with higher saturated fatty acids intake, and 1 variant (rs1054516) was associated with higher serum triglycerides among overweight/obese individuals (57), and an earlier study also showed the link between 9 mutations of the CD36 gene and a defect in the accumulation of LCFAs in the human heart (30).

Although some polymorphisms of CD36 have been shown to be related to lipid taste perception and obesity, those studies still lack of repetition and in some cases the results were controversial. Further research is necessary to clarify the truly effective polymorphisms of CD36 gene and its interaction with environmental factors including lipid diet and physical exercise.

CD36 gene variants and other metabolic syndromes

As a multifunctional receptor, CD36 not only plays an important role in thrombocytopenia, malaria, lipid taste perception and obesity, but also is associated with other metabolic syndromes such as hypercholesterolemia, peripheral vascular atherosclerosis, arterial hypertension, cardiomyopathy and other CAD, diabetes, Alzheimer’s disease and colorectal cancer (Table 4).

Atherosclerosis

Macrophage CD36 participates in atherosclerotic arterial lesion formation through its interaction with oxLDL, which triggers signaling cascades for inflammatory responses. CD36 functions in oxLDL uptake and foam cell formation, which is the initial critical stage of atherosclerosis. In addition, oxLDL via CD36 inhibits macrophage migration, which may be a macrophage-trapping mechanism in atherosclerotic lesions. Platelet CD36 also promotes atherosclerotic inflammatory processes and is involved in thrombus formation after atherosclerotic plaque rupture. Both persistent up-regulation of CD36 and deficiency of CD36 increase the risk for atherosclerosis. Abnormally up-regulated CD36 promotes inflammation, foam cell formation, endothelial apoptosis, macrophage trapping and thrombosis. However, CD36 deficiency also causes dyslipidemia, subclinical inflammation and metabolic disorders, which are established risk factors for atherosclerosis. Morii et al. (70) examined the association of CD36 SNPs with certain metabolic characteristics in a young male Japanese population. The G allele in a SNP located at +30,215 (rs7755) on the 3'-UTR was significantly correlated with the plasma LDL-cholesterol concentrations. In contrast, for the SNPs at positions +9,794 (rs3173798) and +10,214 (rs3212165), neither significant correlation nor association was found between genotypes and clinical characteristics. Boghdady et al. (58) studied the relationship between rs1761667 polymorphism and the risk of coronary atherosclerosis in Egyptian population. The frequency of the AG genotype was significantly higher in the CAD group than in the control group. The expression level of CD36 in the CAD group was significantly higher than that in the control group. The AG genotype of rs1761667 was associated with an increased risk of CAD. Momeni-Moghaddam et al. (59) also found that rs1761667 was associated with hypertension and coronary artery disease in a southeastern Iranian population.

Type 2 diabetes mellitus (T2DM)

Corpeleijn et al. (62) found that T2DM was more prevalent in the TT genotype than in the CC genotype in the upstream promoter region (rs1527479, -3489C>T) of the CD36 gene. It showed a direct association of the TT genotype with the presence of T2DM in subjects from a Caucasian population at risk for the metabolic syndrome. This is most evident in women and in obese subjects. But Zeng et al. (63) showed that no significant differences were found in alleles and genotype frequencies of CD36 gene rs1527479 polymorphism between diabetic patients and non-diabetic controls in Chinese Han population. No correlation was also found between the polymorphisms of rs17154181 and rs1761667 sites and macroangiopathy in patients with T2DM in Chinese population (60). Yang et al. (61) also showed that the rs1761667 and rs10499859 polymorphisms of CD36 gene may not be correlated with the occurrence of T2DM combined with carotid atherosclerosis in Chinese Han population.

Colorectal cancer

Kuriki et al. (64) suggest that interactions between moderate-high meat consumption and the CD36 gene 52A>C polymorphism may increase the risk of colorectal cancer. They also found a significant interaction between alcohol consumption and the CD36 gene 52A>C polymorphism related to the metabolism of long-chain fatty acids and oxidized LDL in the etiology of colorectal cancer (65). In addition, CD36 was also found to have potential contributions to key cellular events in oncogenesis or metastasis development of pancreatic cancer and other malignancies, although the relationship between CD36 gene variants and these diseases has not been reported (71).

Alzheimer’s disease

The relationship between a polymorphism of CD36 gene and Alzheimer’s disease was also reported in Czech population. The presence of A allele on rs3211892 has a significant increase in the risk of Alzheimer’s disease. The most likely mechanisms involve changes in cholesterol regulation, formation of reactive oxygen species and/or induction of pathological inflammatory cascades (69).

Conclusions

CD36 gene variants are associated with alloimmune thrombocytopenia, malaria severity, lipid taste perception obesity, and other metabolic syndromes. Some of these correlations are due to gene mutations leading to CD36 protein not expressed. Some are due to CD36 protein expression down-regulation in specific cells, and some are due to the conformation change or inactivation of the ligand binding domain in the protein extracellular domain. There is significant evidence that CD36 on various cells and tissues is involved in the development of different disorders. However, it seems that anti-CD36 induced thrombocytopenia is the only undoubtful relation between complete CD36 absence and disease. But even within thrombocytopenia the impact of single SNV on type I deficiency is under discussion. Concerning disorders other than immune thrombocytopenia data are much more conflicting not only with regard to single variations but also with respect to general inhibitory or inducing effects. Some correlations between CD36 gene variation and clinical symptoms may be only a superficial phenomenon lacking underlying mechanism. Current evidence on CD36 and health-related outcomes is limited and more functional genomics studies are needed to confirm its role and mechanism. Research on the relationship between CD36 gene variants and diseases will help us to further clarify the CD36 gene ontology, the protein function, and pathophysiological basis of related diseases. CD36 is also increasingly becoming a potential biomarker and target for drug development and treatment of specific diseases (72-74).

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (81570170) and Science Research Foundation of Zhejiang Province (LGF19H080004, WKJ-ZJ-2021).

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Brian R. Curtis) for the series “Thrombocytopenia Due to Immunization Against CD36” published in Annals of Blood. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://dx.doi.org/10.21037/aob-21-49

Peer Review File: Available at https://dx.doi.org/10.21037/aob-21-49

Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/aob-21-49). The series “Thrombocytopenia Due to Immunization Against CD36” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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