CD36 Polymorphisms Research Articles

Orosensory detection of bitter in fat-taster healthy and obese participants: Genetic polymorphism of CD36 and TAS2R38

We assessed orosensory detection of a long-chain fatty acid, linoleic acid (LA), and a bitter taste marker, 6-n-propylthiouracil (PROP), and correlated lipid-taster subjects with PROP detection and polymorphism in genes encoding bitter and lipid taste receptors, respectively, TAS2R38 and CD36, in normal weight and obese subjects. The normal weight (n=52, age=35.3±4.10 years, BMI=23.22±1.44kg/m2) and obese (n=52, age=35.0±5.43 years, BMI=34.29±5.31kg/m2) participants were recruited to determine fat and bitter detection thresholds. The genomic DNA was used to determine single nucleotide polymorphism (SNP) of CD36 (rs1761667) and TAS2R38 (rs1726866 and rs10246939). The study included the participants who could detect LA, i.e., lipid-tasters. There was a positive correlation between BMI and detection thresholds for fat and bitter taste in normal weight and obese subjects. Obese participants showed a positive correlation between LA and PROP detection thresholds. PROP detection thresholds were higher for CD36 SNP (rs1761667) and TAS2R38 SNPs (rs1726866 and rs10246939) in obese participants compared to normal weight subjects. LA detection thresholds were not high for CD36 SNP (rs1761667) or TAS2R38 SNP (rs1726866 and rs10246939) in obese participants. Orosensory detection thresholds for fat and bitter taste are associated with BMI, and CD36 and TAS2R38 genotypes are not always associated with taste phenotypes.

The role of rs1984112_G at CD36 gene in increasing reticulocyte level among sickle cell disease patients

ABSTRACTAims and background: Mediators of adhesion become a potential new target for pharmacological therapy to struggle the complications of sickle cell disease (SCD). Several mechanisms for increased adherence have been postulated and the well-studied are CD36 and VLA4 which encoded by ITGA4. Herein, we sought to determine whether one polymorphism of CD36 namely: rs1984112 and three exons of ITGA4 (4, 5, and 6) are implicated in hemolytic status and clinical events among SCD Tunisian patients.Material and methods: This study enrolled 99 unrelated Tunisian subjects (63SS and 36Sβ). All SCD patients are children (less than 16 years old). The rs1984112 and the ITGA4’s exons 4, 5, and 6 were analyzed for all subjects by PCR/sequencing. The association of each genotype found with both clinical complications and hemolytic status was performed using t-test. Clinical events studied included vaso-occlusive crisis (VOC), osteonecrosis, stroke, frequent infection, priapism, and acute syndrome.Results: The results show that rs1984112_G allele at CD36 gene revealed to be associated with higher levels of reticulocyte count (p < 0.01). The statistical result show a near significance of homozygous mutant GG genotype with VOC (p = 0.051). No association between rs1984112_G allele and the clinical severity of SCD were found. Mutational screening of exon 4, 5, and 6 of ITGA4 gene revealed absence of mutated variant.Conclusion: Our results are similar to those found in Portuguese population which reported the role of rs1984112_G in increasing reticulocyte level among SCD patients. Consequently, the rs1984112_G of CD36 could be considered as a reliable biomarker for predicting patients at high risk for vascular occlusions and thus, allows earlier and more effective therapeutic management.

Alterations in the cardiac proteome of the spontaneously hypertensive rat induced by transgenic expression of CD36

Fatty acid translocase (FAT/CD36) plays an important role in fatty acid uptake by different cell types and may also participate in regulation of calcium homeostasis and eicosanoid production. CD36 deficiency or polymorphisms in the CD36 gene are linked to some physiological irregularities. It is known that the expression of FAT/CD36 is aberrant in the spontaneously hypertensive rat (SHR), one of the most widely studied rat strains in cardiovascular research. In this work, we compared the cardiac proteome of SHR and transgenic SHR-Cd36 rats, who carry a copy of the wild type CD36 gene. Protein expression profiling was based on two-dimensional gel electrophoresis (2DE) coupled to tandem mass spectrometry and label-free LC/MS. These two complementary proteomic approaches allowed us to investigate proteome differences in the left and right heart ventricles of SHR and SHR-Cd36 rats. In total, we identified 26 differently expressed myocardial proteins, out of which 18 were found in the right ventricles and 8 in the left ventricles. Besides that, we determined a great number of proteins uniquely expressed either in the left or right ventricles. These data indicate a large qualitative disparity between the left and right ventricles. Genetic manipulations may affect different proteins in both heart ventricles.Biological significance: This is the first report revealing a relatively broad impact of transgenic expression of CD36 on the heart at the proteome level. Comparison of the protein profiles in both the left and right ventricles revealed differences in several proteins involved especially in energy metabolism. The observed downregulation of the respiratory chain enzymes in transgenic SHR-Cd36 rats may suggest a shift in regulation of energy metabolism due to expression of fatty acid translocase FAT/CD36. This study highlights the important role of cardiac tissue proteomic profiling for mapping of proteins which might be altered by targeted genetic manipulations.

Association of CD36 expression and polymorphism with serum biochemical indices in Cherry Valley duck

Cluster of differentiation 36 (CD36) plays a crucial role in lipid sensing, innate immunity, atherogenesis, and glycolipid metabolism. This aims of this study were to delineate the CD36 mRNA expression profile in 16 duck tissues using relative quantitative real-time PCR and to screen single nucleotide polymorphisms (SNPs) in the duck CD36 gene by PCR-single strand conformation polymorphism and DNA direct sequencing. In addition, this study investigated CD36 gene expression, genetic variation, and their effect on serum biochemical indices in duck. The results showed that CD36 mRNA was expressed in all tissues, and was highly specific to the pituitary and large intestine, and to subcutaneous and abdominal fat. Furthermore, three genotypes of the SNP g.476593 T > C in exon 9 of the duck CD36 gene were identified: MM, MN, and NN. The dominant genotype and allele were MM and M, with frequencies of 0.453 and 0.643, respectively. The genotype distributions deviated from Hardy-Weinberg equilibrium (P < 0.05) and achieved moderate levels of polymorphism in ducks. Correlation results showed that CD36 mRNA was significantly negatively correlated with triglycerides (P < 0.05), and significantly positively correlated with total protein, globulin, low-density lipoprotein cholesterol, and total cholesterol (P < 0.01). All serum biochemical indices measured, with the exception of triglycerides, in birds with the NN genotype were significantly higher than those in birds with the MM genotype. These findings demonstrated that CD36 might be an important genetic marker for the selection of lipid metabolism and meat quality traits in ducks.

CD36 genetic variation, fat intake and liver fibrosis in chronic hepatitis C virus infection.

To analyze the association of the CD36 polymorphism (rs1761667) with dietary intake and liver fibrosis (LF) in chronic hepatitis C (CHC) patients. In this study, 73 patients with CHC were recruited. The CD36 genotype (G > A) was determined by a TaqMan real-time PCR system. Dietary assessment was carried out using a three-day food record to register the daily intake of macronutrients. Serum lipids and liver enzymes were measured by a dry chemistry assay. LF evaluated by transient elastography (Fibroscan(®)) and APRI score was classified as mild LF (F1-F2) and advanced LF (F3-F4). Overall, the CD36 genotypic frequencies were AA (30.1%), AG (54.8%), and GG (15.1%), whereas the allelic A and G frequencies were 57.5% and 42.5%, respectively. CHC patients who were carriers of the CD36 AA genotype had a higher intake of calories attributable to total fat and saturated fatty acids than those with the non-AA genotypes. Additionally, aspartate aminotransferase (AST) serum values were higher in AA genotype carriers compared to non-AA carriers (91.7 IU/L vs 69.8 IU/L, P = 0.02). Moreover, the AA genotype was associated with an increase of 30.23 IU/L of AST (β = 30.23, 95%CI: 9.0-51.46, P = 0.006). Likewise, the AA genotype was associated with advanced LF compared to the AG (OR = 3.60, 95%CI: 1.16-11.15, P = 0.02) or AG + GG genotypes (OR = 3.52, 95%CI: 1.18-10.45, P = 0.02). This study suggests that the CD36 (rs1761667) AA genotype is associated with higher fat intake and more instances of advanced LF in CHC patients.

Is plasma-soluble CD36 associated with density of atheromatous plaque and ankle–brachial index in early-onset coronary artery disease patients?

CD36 is a major macrophage scavenger receptor for oxidised low-density lipoprotein particles. Soluble CD36 (sCD36) is circulating as a ligand-bound complex and may be present in microparticles shed from cells such as platelets, monocytes/macrophages, or adipocytes. Positive association of plasma sCD36 with insulin resistance has been reported, and it has been proposed that sCD36 might represent a marker of macrophage activation and inflammation leading to atherosclerosis. Recently we have identified an association between CD36 polymorphism and low thickness of atheromatous plaque, suggesting its protective effect against atherosclerosis development. To obtain insight into the relationship between plasma concentration of sCD36 and radiological parameters of atherosclerosis in patients with early-onset coronary artery disease (CAD). The study group comprised 70 clinically stable patients (18 women and 52 men) with early CAD (aged no more than 50 years for men and 55 years for women). Fasting blood sample was taken for serum glucose, lipid profile, ApoA1, ApoB, Lp(a), and plasma sCD36 protein measurements. Each subject's weight, height, waist and hip circumference, and systolic and diastolic blood pressure were measured, and the body mass index, waist-to-hip ratio, and mean arterial pressure were calculated. Doppler ultrasound examinations of carotid and peripheral arteries were performed in all patients. Thickness of intima-media complex (IMC) of common carotid (CCA) and brachial arteries, as well as density and thickness of atheromatous plaque at CCA bifurcation, were measured with M'Ath programme. Plasma concentrations of CD36 antigen were measured by ELISA. Correlations between quantitative variables and sCD36 plasma concentration were assessed with the Spearman rank correlation coefficient (Rs). Associations between qualitative variables and sCD36 plasma concentration were tested with the Mann-Whitney U test. We observed no significant correlations between sCD36 concentration and radiological parameters of atherosclerosis. We found only borderline significant negative correlation of sCD36 concentration with thickness of IMC of left brachial artery. We also observed a significantly negative correlation with CCA plaque density, but only in the female subgroup and on the right side. Borderline higher sCD36 plasma concentrations were observed in patients with lower ankle-brachial index value (< 0.9). The results of the study show no strong associations and do not prove either detrimental or beneficial influence of sCD36 on radiological parameters of atherosclerosis. Further research is necessary to assess the association of high plasma sCD36 concentrations with the risk of plaque instability in patients with early-onset CAD.

Associations between orosensory perception of oleic acid, the common single nucleotide polymorphisms (rs1761667 and rs1527483) in the CD36 gene, and 6-n-propylthiouracil (PROP) tasting.

Orosensory perception of dietary fat varies in individuals, thus influencing nutritional status. Several studies associated fat detection and preference with CD36 or 6-n-propylthiouracil (PROP) sensitivity. Other studies have not confirmed the latter association. We analyzed the relationship between orosensory perception of oleic acid, two CD36 variants, and PROP tasting. Thresholds of oleic acid perception were assessed in 64 subjects using a modification of the three-alternative forced-choice procedure. Subjects were classified for PROP taster status and genotyped for TAS2R38 and CD36 (SNPs: rs1761667 and rs1527483). Subjects homozygous for GG of the rs1761667 polymorphism showed higher sensitivity to oleic acid than AA subjects. The capability to detect oleic acid was directly associated with TAS2R38 or PROP responsiveness. PROP non-tasters had a lower papilla density than tasters, and those with genotype GG of the rs1761667 polymorphism had lower oleic acid thresholds than PROP non-tasters with genotype AA. In conclusion, results showed a direct association between orosensory perception of oleic acid and PROP tasting or rs1761667 polymorphism of CD36, which play a significant role in PROP non-tasters, given their low number of taste papillae. Characterization of individual capability to detect fatty acids may have important nutritional implications by explaining variations in human fat preferences.

An association analysis between the variability of the caprine CD36 and CD36-like genes and dairy traits

The CD36 molecule plays a key role in the uptake of long-chain fatty acids. In a previous study, we demonstrated that the CD36 gene is duplicated in goats. Moreover, both copies (CD36 and CD36-like) display highly divergent mRNA expression profiles. Herewith, we have analyzed whether four polymorphisms mapping to CD36 (c.394A>G, c.*141C>T and c.*427T>A) and CD36-like (c.390A>C) genes are associated with milk yield and composition. Murciano-Granadina goats with records for dairy traits (N=309, 1005 registers) and milk fatty acid composition phenotypes (N=176, 490 registers) were genotyped for these four markers and association analyses were carried out. We found a highly significant association between c.*427T>A CD36 polymorphism and milk palmitoleic content (P<0.0001). Besides, the c.*141C>T CD36 SNP also showed a suggestive association (P=0.04) with palmitoleic. These findings are consistent with previous studies showing that CD36 inactivation in adipocytes and neurons involves a decrease in palmitoleic content, thus suggesting a relevant role of this molecule in the specific uptake of this fatty acid. The remaining associations found (CD36 with polyunsaturated fatty acids and CD36-like with oleic and several saturated fatty acids) were significant at the nominal level but not after Bonferroni correction. These results, combined with previously reported expression data, reinforce the interest of investigating the lipid binding properties of CD36 and CD36-like through functional approaches.

Association between rs1049673 polymorphism in CD36 and premature coronary heart disease.

Risk factors for premature coronary heart disease in China can be multiple; we investigated Chinese Han patients with premature coronary heart disease and a possible association with CD36 polymorphism at rs1049673, rs7755, and rs321159 sites. Outpatients were recruited according to chest X-ray coronary arteriography results; they were divided into two groups: early coronary artery lesions (premature coronary heart disease group, test group) and a control group. Coronary arteriography and laboratory blood examinations were conducted to analyze risk factors for coronary heart disease and CD36 polymorphisms. Seventy nine test and 56 control group patients were recruited. Compared with the control, the test groups had a significantly higher proportion of male patients, smoking, diabetes and metabolic syndromes, significantly higher levels of TG, LDL-C, ox-LDL, WBC, UA, FBG, and significantly lower levels of HDL-C. For rs1049673, rs7755, and rs321159 sites, patients with premature coronary heart disease have family genetic predisposition at high LDL-C level with GA, AA, and TT genotypes. Unconditional logistic regression analysis showed that gender, diabetes, high TG, LDL-C level and C carriers of rs1049673 significantly affected risk for premature coronary heart disease.

Common Variants in the CD36 Gene Are Associated With Oral Fat Perception, Fat Preferences, and Obesity in African Americans

Animal studies show that CD36, a fatty acid translocase, is involved in fat detection and preference, but these findings have not been reported in humans. The objective of this study was to determine whether human genetic variation in 5 common CD36 polymorphisms is associated with oral fat perception of Italian salad dressings, self-reported acceptance of high-fat foods and obesity in African-American adults (n = 317). Ratings of perceived oiliness, fat content, and creaminess were assessed on a 170-mm visual analogue scale (VAS) in response to salad dressings that were 5%, 35%, and 55% fat-by-weight content. Acceptance of added fats and oils and high-fat foods was self-reported and anthropometric measures were taken in the laboratory. DNA was isolated from saliva and genotyped at 5 CD36 polymorphisms. Three polymorphisms, rs1761667, rs3840546, and rs1527483 were associated with the outcomes. Participants with the A/A genotype at rs1761667 reported greater perceived creaminess, regardless of the fat concentration of the salad dressings (P < 0.01) and higher mean acceptance of added fats and oils (P = 0.02) compared to those with other genotypes at this site. Individuals who had C/T or T/T genotypes at rs1527483 also perceived greater fat content in the salad dressings, independent of fat concentration (P = 0.03). BMI and waist circumference were higher in participants who were homozygous for a deletion (D/D) at rs3840546, compared to I/D or D/D individuals (P < 0.001), but only 2 D/D individuals were tested, so this finding needs replication. This is the first study to demonstrate an association between common variants in CD36 and fat ingestive behaviors in humans.

Polymorphism of the CD36 Gene and Cardiovascular Risk Factors in Patients with Coronary Artery Disease Manifested at a Young Age

This study investigates potential associations between CD36 gene variants and the presence of risk factors in Caucasians with coronary artery disease (CAD) manifested at a young age. The study group consisted of 90 patients; the men were ≤ 50 years old and the women were ≤ 55 years old. Amplicons of exons 4 and 5 including fragments of introns were analyzed by DHPLC. Two polymorphisms were found: IVS3-6 T/C (rs3173798) and IVS4-10 G/A (rs3211892). The C allele of the IVS3-6 T/C polymorphism was associated with higher prevalence of obesity and diabetes, higher hsCRP, lower Lp(a) serum concentrations, and younger age at myocardial infarction. The A allele of the IVS4-10 G/A polymorphism was associated with older age of myocardial infarction and higher white blood cell count. The functional role of CD36 polymorphisms in CAD development needs further research.

Activation of Vascular Cells by Microparticles and Other Danger Signals Via the CD36 Scavenger Receptor

Abstract SCI-12 Clinically significant thrombotic events are common complications of many systemic diseases associated with chronic inflammation, including atherosclerosis, diabetes mellitus, cancer, and chronic autoimmune rheumatologic disorders. Many of these potentially life-threatening thrombi occur in the arterial circulation and likely relate to inappropriate platelet activation and/or vessel wall injury. CD36 is a type B scavenger receptor expressed on platelets, monocytes, microvascular endothelial cells (MVEC), and vascular smooth muscle cells (VSMC) that recognizes and responds to endogenous and exogenous “danger signals” including advanced glycated proteins (AGE), microbial cell wall components, and oxidized phospholipids that are found on the surface of oxidized LDL (oxLDL) and cell-derived microparticles (MP). Mouse FeCl3 thrombosis model systems revealed that genetic deletion of cd36 rescued the prothrombotic phenotypes associated with hyperlipidemia, oxidant stress, or diabetes/hyperglycemia. Interestingly, compared to wild type mice, fewer MP were incorporated into thrombi formed in cd36 null mice after FeCl3-induced vascular injury. Cd36 deficiency also provides partial protection from atherosclerosis in experimental mouse models. On a cellular level, the prothrombotic, pro-atherogenic, and anti-angiogenic activities of CD36 relate to ligand-dependent alterations of platelet, macrophage, and vessel wall cellular functions. For example, CD36 binding to MP, AGE, or oxLDL “sensitizes” platelets to activation by low doses of agonists, such as ADP. In macrophages, CD36 interactions with oxLDL leads to lipid internalization, foam cell formation, and inhibition of migration. In the vessel wall CD36 promotes VSMC oxidant stress and MVEC apoptosis. Mechanistically, CD36 transmits intracellular signals in response to ligand engagement that involve recruitment of specific Src family kinases to its short cytoplasmic tail, with subsequent activation of specific MAP kinase pathways and Vav family guanine nucleotide exchange factors. These signaling pathways remain incompletely understood, but impact many important cellular processes, including cytoskeletal dynamics, cell polarity, transcription of antioxidant genes controlled by the transcription factor Nrf2, and activation of NADPH oxidases. Specific components of CD36 signaling pathways depend on the cellular context and in some cases involve engagement of co-receptors, including integrins, TLRs, and tetraspanins. Recent targeted genome-wide association studies suggest that cd36 polymorphisms associate with CD36 expression levels on platelets and monocytes as well as with risk of thrombotic, metabolic, and atherosclerotic disorders. Targeting CD36 may therefore provide novel approaches to many important human vascular diseases. Disclosures: No relevant conflicts of interest to declare.

Platelet CD36 surface expression levels affect functional responses to oxidized LDL and are associated with inheritance of specific genetic polymorphisms

AbstractCD36 modulates platelet function via binding to oxidized LDL (oxLDL), cell-derived microparticles, and thrombospondin-1. We hypothesized that the level of platelet CD36 expression may be associated with inheritance of specific genetic polymorphisms and that this would determine platelet reactivity to oxLDL. Analysis of more than 500 subjects revealed that CD36 expression levels were consistent in individual donors over time but varied widely among donors (200-14 000 molecules per platelet). Platelet aggregometry and flow cytometry in a subset of subjects with various CD36 expression levels revealed a high level of correlation (r2 = 0.87) between platelet activation responses to oxLDL and level of CD36 expression. A genome-wide association study of 374 white subjects from the Cleveland Clinic ASCLOGEN study showed strong associations of single nucleotide polymorphisms in CD36 with platelet surface CD36 expression. Most of these findings were replicated in a smaller subset of 25 black subjects. An innovative gene-based genome-wide scan provided further evidence that single nucleotide polymorphisms in CD36 were strongly associated with CD36 expression. These studies show that CD36 expression on platelets varies widely, correlates with functional responses to oxLDL, and is associated with inheritance of specific CD36 genetic polymorphisms, and suggest that inheritance of specific CD36 polymorphisms could affect thrombotic risk.

Lack of Association of CD36 SNPs With Early Onset Obesity: A Meta‐Analysis in 9,973 European Subjects

A recent study suggested that four CD36 polymorphisms (namely rs3211867, rs3211883, rs3211908, and rs1527483) were associated with an increased risk of obesity, an increased BMI and percentage of body fat in European adolescents. We first attempted to confirm these results in three independent case-control genome-wide association studies (GWAS) data totaling 3,509 subjects of French and German origin, but we were unable to find any association of these variants with early onset obesity risk. We then genotyped the four CD36 single-nucleotide polymorphisms (SNPs) in a large population-based study of 4,667 Finnish subjects and we did not replicate any of the recently reported associations with BMI. By combining all available data in a meta-analysis (N = 9,973), we found no evidence for an association of the reported four variants in CD36 with increased obesity risk or increased BMI (0.07 ≤ P values ≤ 0.93). Finally, we assessed the contribution of the full CD36 locus gene variation to obesity risk in 3,509 subjects and we did not detect any significant association with obesity after correction for multiple testing. In summary, we were unable to confirm the recently reported association of variants in CD36 with early onset obesity in populations of European ancestry.

Variability of CD36 Expression on Platelets Is Determined in Part by Genetic Polymorphisms and Can Influence Platelet Function.

CD36 is a cell surface receptor previously characterized on phagocytic cells as a scavenger receptor, on microvascular endothelial cells as a negative regulator of angiogenesis, and on fat, muscle and epithelial cells as a transporter of free fatty acids. Although it was first identified on platelets and termed glycoprotein IV or IIIb, its role in platelet biology has only recently been determined. Our group has shown that CD36 functions as a signaling receptor on platelets, recognizing oxidized lipoproteins and endothelial-derived microparticles, and augmenting activation and aggregation in response to low doses of agonists. The CD36 gene is highly polymorphic; in addition to the well characterized null mutations common in Asian and African populations, there are numerous single nucleotide polymorphisms (SNPs) and insertions/deletions, including some in the promoter region at putative transcription factor binding sites. Systematic studies relating CD36 deficiency or CD36 polymorphisms to arterial thrombosis, coronary disease or cerebrovascular disease are limited. The goal of this study was to characterize the relationship between common CD36 genetic polymorphisms, platelet expression levels, and platelet function. Initial studies of 32 normal healthy volunteers revealed that platelet CD36 expression was highly variable, ranging from as low as less than 2000 molecules per platelet to more than 14,000 molecules per platelet. Individual donors showed consistent levels of CD36 expression on repeated analyses over time. Western blot analysis of selected subjects showed that surface expression levels correlated closely with total CD36 expression. To assess the functional consequences of this variability in CD36 expression we studied platelets from donors with high, medium and low levels of expression. Platelet reactivity to oxidized LDL (oxLDL) was analyzed by flow cytometric measurement of alpha granule secretion (anti-P-selectin antibody binding). We found a strong correlation between platelet activation by oxLDL and level of CD36 expression. To determine the relationship of CD36 genetic polymorphisms with expression levels we measured platelet surface CD36 expression in a population of 550 successive subjects recruited through the Cleveland Clinic Cardiac Catheterization lab. As with the normal volunteers, this group also showed a wide variability in platelet CD36 expression. We then identified 10 SNPs with allelic frequencies >5% from the International HapMap consortium database that “tag” major areas of linkage disequilibrium and genotyped DNA isolated from the 550 subjects using a PCR-based method. Three SNPs were significantly associated with CD36 expression (p values <0.03). For all these SNPs the minor allele was associated with lower levels of CD36 expression (odds ratios 0.5–0.6). We conclude that the variability of CD36 expression on platelets is in part genetically determined and that CD36 genotype can affect platelet function. These studies suggest that CD36 genotype may influence thrombotic risk, particularly in situations where CD36 ligands are present.

Bone marrow chimeric mice reveal a dual role for CD36 in Plasmodium berghei ANKA infection

BackgroundAdhesion of Plasmodium-infected red blood cells (iRBC) to different host cells, ranging from endothelial to red blood cells, is associated to malaria pathology. In vitro studies have shown the relevance of CD36 for adhesion phenotypes of Plasmodium falciparum iRBC such as sequestration, platelet mediated clumping and non-opsonic uptake of iRBC. Different adhesion phenotypes involve different host cells and are associated with different pathological outcomes of disease. Studies with different human populations with CD36 polymorphisms failed to attribute a clear role to CD36 expression in human malaria. Up to the present, no in vivo model has been available to study the relevance of different CD36 adhesion phenotypes to the pathological course of Plasmodium infection.MethodsUsing CD36-deficient mice and their control littermates, CD36 bone marrow chimeric mice, expressing CD36 exclusively in haematopoietic cells or in non-haematopoietic cells, were generated. Irradiated CD36-/- and wild type mice were also reconstituted with syngeneic cells to control for the effects of irradiation. The reconstituted mice were infected with Plasmodium berghei ANKA and analysed for the development of blood parasitaemia and neurological symptoms.ResultsAll mice reconstituted with syngeneic bone marrow cells as well as chimeric mice expressing CD36 exclusively in non-haematopoietic cells died from experimental cerebral malaria between day 6 and 12 after infection. A significant proportion of chimeric mice expressing CD36 only in haematopoietic cells did not die from cerebral malaria.ConclusionThe analysis of bone marrow chimeric mice reveals a dual role of CD36 in P. berghei ANKA infection. Expression of CD36 in haematopoietic cells, most likely macrophages and dendritic cells, has a beneficial effect that is masked in normal mice by adverse effects of CD36 expression in non-haematopoietic cells, most likely endothelial cells.

CD36 polymorphism and its relationship with body mass index and coronary artery disease in a Korean population

CD36 is a multifunctional membrane receptor and a cell-adhesion molecule that is expressed in platelets, monocytes/macrophages, microvascular endothelial cells, cardiac monocytes and adipocytes. In this study, we investigated whether genetic polymorphisms of the CD36 gene are associated with risk of coronary artery disease (CAD) in a Korean population. PCR and polyacrylamide gel electrophoresis or PCR-restriction fragment length polymorphism assays were performed to analyze the following CD36 gene polymorphisms: a (TG) repeat in intron 3 and the base substitution 478C>T (Pro90Ser). A total of 219 patients with significant CAD and 236 control subjects were examined with regard to their genotypes, lipid profiles and other risk factors for CAD. The frequency of (TG) 11- or 12-repeat homozygotes was significantly higher in male CAD patients than in control men (28.4% vs. 15.7%, OR=2.13, p=0.018). Homozygosity for the (TG) 11- or 12-repeat allele was also significantly associated with a higher body mass index (BMI) compared to non-carriers in 134 control men after controlling for age, smoking and hypertension, and explains a 13% BMI variation observed in this study (p=0.015, analysis of covariance). For the 478C >T mutation, which has been reported to be associated with CD36 deficiency, there was no difference in the frequency of the 478T allele between CAD patients and control subjects. However, the 478T allele was found to be closely linked with a (TG) 11- or 12-repeat allele of intron 3 in the control subjects (chi2=18.88, p<0.001). The (TG) repeat polymorphism in intron 3 of the CD36 gene is associated with a higher BMI and cardiovascular risk for men in a Korean population.

CD36 Polymorphism Is Associated with Protection from Cerebral Malaria

The human protein CD36 is a major receptor for Plasmodium falciparum-infected erythrocytes and contributes to the pathology of P. falciparum malaria. We performed variation screening of the CD36 gene and examined the possible association between CD36 polymorphisms and the severity of malaria in 475 adult Thai patients with P. falciparum malaria. Accordingly, we identified nine CD36 polymorphisms with a high-frequency (>15%) minor allele. 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 (P=.016 for -14T-->C and P=.050 for -53G-->T). The analysis of linkage disequilibrium (LD) between the nine common polymorphisms revealed that there are two blocks with strong LD in the CD36 gene and that the -14T-->C and -53G-->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 in3(TG)(12) (i.e., 12 TG repeats in intron 3) allele is most strongly associated with the reduction in the risk of cerebral malaria (odds ratio 0.59; 95% confidence interval 0.40-0.87; P=.0069). We found, by reverse-transcriptase PCR amplification, 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 P. falciparum-infected erythrocytes, 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. Results of the present study suggest that LD mapping has potential for detecting a disease-associated variant on the basis of haplotype blocks.