Association of polymorphism in the thermolabile 5, 10-methylene tetrahydrofolate reductase gene and hyperhomocysteinemia with coronary artery disease

Objective To determine the incidence of methylene tetrahydrofolate reductase (MTHFR) gene 677C→T polymorphism and plasma homocysteine (Hcy) levels in a group of subjects who underwent coronary angiography, in an attempt to establish a correlation between these parameters and the severity of coronary artery disease (CAD) and to investigate the correlation between hyperhomocysteinemia (HHcy) and the presence of 677C→T polymorphism. Background Elevated plasma Hcy level is an independent risk factor for CAD. A common mutation (677C→T) in the gene coding for MTHFR has been reported to reduce the enzymatic activity and is associated with elevated levels of Hcy, especially in subjects with low folate intake. Methods The study group comprised of 84 patients with CAD and 100 age-and-sex matched controls who had no history or clinical evidence of CAD and/or MI. DNA was extracted from peripheral blood and genotypes were determined by polymerase chain reaction, restriction mapping with Hinf1, and gel electrophoresis. Conventional risk factors for CAD were prospectively documented. Results Allele and genotype frequencies in cases and control subjects were compatible with Hardy–Weinberg equilibrium. The frequencies of TT, CT, and CC genotypes among CAD patients were 4.8, 27.4, and 67.8% and in controls were 1.0, 19.0, and 80%. Hcy levels were higher in patients with triple-vessel disease compared to single and double vessel disease (P = 0.002). Multivariate analyses identified HHcy, diabetes mellitus, and hypertension as the independent predictors of CAD. Conclusions HHcy appears to have a graded effect on the risk of CAD as well as the severity and extent of coronary atherosclerosis. Our findings support that homozygous genotype of MTHFR is a genetic risk factor for CAD. A further study with larger sample size including assessment of vitamin status is needed to better clarify the relationship between MTHFR genotypes and CAD.     

亚甲基四氢叶酸还原酶(C677/T)基因的单核苷酸多态性

亚甲基四氢叶酸还原酶(methylene tetrahydrofolatucte redase,MTHFR)是叶酸代谢过程中的关键酶,对叶酸和同型半胱氨酸的代谢以及DNA的合成、修复与甲基化均有重要作用。MTHFR基因变异导致酶热稳定性及活性降低,引起相关代谢及DNA甲基化异常,进而发生相关疾病。MTHFR具有多种变异型,本文对其中常见的一种C677T的多态性及其与疾病的相关性的研究进展做一综述。     

Prevalence of methylenetetrahydrofolate reductase C677T polymorphism in eastern Uttar Pradesh

AIM:

This study was aimed to evaluate the 5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T mutation in eastern Uttar Pradesh population.

MATERIALS AND METHODS:

Polymerase chain reaction (PCR) using specific primers followed by amplicon digestion by Hinf I restriction enzyme was used for MTHFR C677T polymorphism analysis. Total 250 subjects were analyzed.

RESULTS:

The CC genotype was found in 192 subjects, followed by CT in 56 subjects and TT in 2 subject. Genotype frequencies of CC, CT and TT were 0.768, 0.224 and 0.008, respectively. The frequency of C allele was found to be 0.88 and that of T allele was 0.12.

CONCLUSION:

It is evident from the results of the present study that the percentage of homozygous genotype (CC) is highest in the target population.     

Effects of cholesterol ester transfer protein Taq1B gene polymorphism on serum lipoprotein levels in Turkish coronary artery disease patients

To evaluate the effect of cholesterol ester transfer protein (CETP) Taq1B gene polymorphism on serum lipid profile in Turkish coronary artery disease (CAD) patients, we investigated Taq1B gene polymorphism of CETP and serum lipid levels in 111 controls and in 173 CAD patients with myocardial infarction. There were no significant differences in the allele distribution at this polymorphic locus between the population sample and patients with coronary artery disease with myocardial infarction. To detect the association between the Taq1B RFLP and serum lipid levels, we determined the serum concentrations of total cholesterol, triglycerides and high density lipoprotein cholesterol (HDL-C) in the subjects studied and correlated the results to the Taq1B RFLP. Patients with Taq B1B1 genotypes had lower HDL-C levels than patients with B2B2 genotype (p = 0.003). Also in control subjects with Taq B1B1 genotype, lower HDL-C levels (p = 0.05) and higher triglyceride levels (p = 0.017) and body mass index (p = 0.05) were observed compared with control subjects with the B1B2 genotype. It was observed that in our population the distribution of CETP Taq1B genotypes is similar to other populations (except Greeks). The present study demonstrates that CETP Taq1B gene polymorphism may be responsible for low HDL cholesterol levels in patients with CAD and in healthy controls in Turkey.     

Effect of C677T methylenetetrahydrofolate reductase gene polymorphism on plasma homocysteine levels in ethnic groups

The objective of this study was to examine plasma homocysteine levels and C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in two ethnic groups from Slovakia. The samples consisted of general Slovak-Romany population (68 men and 81 women) from Southwestern Slovakia and the Slovak-Caucasians (174 men and 177 women) who participated in the CINDI project. The homocysteine levels were examined by HPLC, the analysis of MTHFR genotypes was done by PCR. The Slovak-Romany men (12.0+/-5.6 (S.D.) micromol/l) and women (9.2+/-2.6 microol/l) have significantly lower plasma homocysteine levels (p<0.024 and p<0.00001) when compared to Caucasians (13.3+/-5.1 micromol/l in men and 11.3+/-4.3 micromol/l in women). The genetic equilibrium is assumed for the gene frequencies of the MTHFR polymorphism in both samples. The distribution of MTHFR genotypes did not differ between the two populations (TT 13 vs. 10.6 %; CT 46.6 vs. 41.7 %; CC 40.4 vs. 47.7 %, chí(2)2 = 2.315, df=2, ns). The effect of MTHFR genotypes on homocysteine levels was not confirmed in the Slovak-Romanies and TT homozygosity significantly increased plasma homocysteine levels only in Slovak-Caucasians (11.5+/-4.4 micromol/l, ns; vs. 14.8+/-4.8 micromol/l, p 0.002, respectively). To our knowledge, this is the first epidemiological study in the Romany population examining distribution of the MTHFR genotypes and their effect on homocysteine levels. Further studies are needed to establish the variety of cardiovascular risk factors among Romanies in order to evaluate the significance of particular factors.     

Methylenetetrahydrofolate reductase C677T mutation in patients with alopecia areata in Turkish population

Objective

Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism and it is thought to influence DNA methylation and nucleic acid synthesis. Mutations in the MTHFR gene have been associated with several autoimmune disorders in previous studies. Alopecia areata (AA) is considered to be a tissue-specific autoimmune disease as the hair follicle has been targeted and antibodies to their own hair follicle structures have been developed. Since there is a common shared pathway between AA and other autoimmune disorders, we aimed to investigate a possible association between the MTHFR gene C677T mutation and AA susceptibility in the Turkish population.

Methods

The study included 136 patients affected by AA and 130 healthy controls. Genomic DNA was isolated and genotyped using a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay for the MTHFR gene C677T mutation.

Results

The distributions of genotype and allele frequencies of MTHFR gene C677T mutation were statistically different between AA patients and the control group (p = 0.036 and p = 0.011, respectively). High differences were also observed when the patients and controls were compared according to CC versus CT + TT (p = 0.012). CT + TT genotypes and T allele of MTHFR gene C677T mutation were found to be a susceptibility factor for AA in the Turkish population.

Conclusion

The results suggest that MTHFR gene C677T mutation may have an effect on the risk of alopecia areata in the Turkish population. This is the first study reporting the association between the MTHFR (C677T) genotype and AA.     

Association of homocysteine and methylene tetrahydrofolate reductase (MTHFR C677T) gene polymorphism with coronary artery disease (CAD) in the population of North India

The implications of the methylene tetrahydrofolate reductase (MTHFR) gene and the level of homocysteine in the pathogenesis of coronary artery disease (CAD) have been extensively studied in various ethnic groups. Our aim was to discover the association of MTHFR (C677T) polymorphism and homocysteine level with CAD in north Indian subjects. The study group consisted of 329 angiographically proven CAD patients, and 331 age and sex matched healthy individuals as controls. MTHFR (C677T) gene polymorphism was detected based on the polymerase chain reaction and restriction digestion with HinfI. Total homocysteine plasma concentration was measured using immunoassay. T allele frequency was found to be significantly higher in patients than in the control group. We found significantly elevated levels of mean homocysteine in the patient group when compared to the control group (p = 0.00). Traditional risk factors such as diabetes, hypertension, smoking habits, a positive family history and lipid profiles (triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol), were found significantly associated through univariate analysis. Furthermore, multivariable logistics regression analysis revealed that CAD is significantly and variably associated with diabetes, hypertension, smoking, triglycerides and HDL-cholesterol. Our findings showed that MTHFR C677T polymorphism and homocysteine levels were associated with coronary artery disease in the selected population.     

Sex-specific effect of the thermolabile C677T mutation in the methylenetetrahydrofolate reductase gene on angiographically assessed coronary artery disease in Brazilians

Hyperhomocysteinemia is associated with increased coronary artery disease (CAD) risk. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of homocysteine and presents a common mutation (C677T) that leads to a thermolabile enzyme, mild hyperhomocysteinemia, and increased CAD risk. The C677T MTHFR mutation was studied in 772 subjects (480 Caucasian Brazilians and 292 African Brazilians) who underwent coronary angiography at the hemodynamic center of the Santa Izabel Hospital in Salvador, Bahia State, Brazil. The 677T allele frequency was increased in Caucasian Brazilians (28.1%) compared to the frequency observed in African Brazilians (18.3%; p < 0.001). In Caucasian Brazilians the frequency of the 677T homozygous genotype was increased in CAD cases (10.4%) compared to control subjects (1.4%; p = 0.014) in males but not in females. In African Brazilians the mutation was not associated with CAD in either sex. The multivariate logistic regression analysis of all the samples shows that the 677T homozygous interaction with sex was a significant CAD predictor, independent of other classical risk factors and ethnic group. The odds ratio associated with male 677T homozygotes was increased 9.2-fold (p = 0.021) compared to the 677C carriers. The present study suggests that the C677T MTHFR mutation is associated with increased CAD risk in a sex-dependent manner in Brazilians.     

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and variations of homocysteine concentrations in patients with Behcet's disease

Background

Behcet's disease (BD) is a chronic, relapsing, multi-systemic inflammatory disorder of unknown causes. This disease is mainly characterized by mucocutaneous, ocular, vascular, and central nervous system manifestations. The aim of this study is to investigate the associations between C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the plasma homocysteine (Hcy), folate, and B12 levels in a relatively large cohort of Tunisian patients with BD.

Methods

The study included 142 patients with BD and 172 healthy controls. The C677T and A1298C polymorphisms were genotyped using PCR-RFLP. Serum Hcy level was determined using a fluorescence polarization immunoassay. Serum folate and vitamin B12 levels were measured by electrochemiluminescence immunoassay.

Results

Genotype and allele frequencies of the two studied MTHFR polymorphisms did not show any significant differences among BD patients compared to controls. Patient carriers of the 677TT variant and the 677 T allele displayed significantly higher Hcy concentration. Moreover, no significant association was found between neither A1298C polymorphism nor the C allele and Hcy, folate, and B12 levels. In multivariate analyses, we reported that 677 T allele, male gender, and creatinine level were independent risk factors for hyperhomocysteinemia (HHC).

Conclusions

In the present study, we report the absence of any significant differences between genotype and allele frequencies for both studied polymorphisms among BD patients compared to healthy controls. Besides, we showed that the T allele of MTHFR C677T polymorphism influenced the Hcy level which is an independent risk factor for HHC in Tunisian BD patients.     

A proteomic approach for the characterization of C677T mutation of the human gene methylenetetrahydrofolate reductase

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of methylenetetrahydrofolate (CH2H4folate) to methyltetrahydrofolate (CH3H4folate). The C677T mutation is a common polymorphism of the human enzyme that leads to the replacement of Ala222Val, thermolability of MTHFR, and mild elevation of plasma homocysteine levels. A mild hyperhomocysteinemia is known to be risk factor for cardiovascular and thrombotic diseases, ischemic stroke, neural tube defects, late on-set dementia, and pregnancy complications. Human plasma of subjects carrying the C677T mutation in the MTHFR gene has been investigated for their protein pattern in order to identify novel molecular hallmarks. 2-D analysis of the plasma protein allowed the identification of a specific pattern associated with the TT mutant genotype. Noteworthy, we found one spot shifted to a more basic pI in mutant individuals, and MS identification corresponded to vitamin D-binding protein (DBP or group component (Gc) globulin). MS/MS peptide sequencing allowed to discriminate different allelic variants in the investigated clinical groups. These data confirmed by molecular genetic analysis highlight the novel association between the C677T MTHFR genotype with the Gc2 polymorphism of the DBP. Moreover, we found a quantitative reduction of Apolipoprotein A-I in mutant individuals, which was associated, in previous studies by others to an increased cardiovascular risk.     

No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme (EC 1.5.1.20), that reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for the homocysteine to methionine conversion. MTHFR is a key enzyme that regulates folate metabolism which has an important role in DNA synthesis, DNA repair and methylation. The association between MTHFR C677T polymorphism and breast cancer has been investigated in several previous studies. Some researchers have shown an association between C677T polymorphism and breast cancer, but not all researchers found this association however. This study was designed to investigate, in the Turkish population, the association of MTHFR C677T polymorphism and breast cancer. Forty women patients with breast cancer and 68 healthy women were included in the study. MTHFR gene polymorphism was determined by the PCR-RFLP method. SPSS 10.0 for windows was used to determine statistical significance. No differences were observed in the distribution of MTHFR genotypes or allele frequencies in the cases versus the controls. It was found that the frequencies of MTHFR polymorphism were 55%, 40%, 5% for CC, CT, TT genotype in patients and 56%, 38%, 6% in healthy controls respectively. Furthermore, association was observed among family history, metastatic risk and MTHFR genotypes in patients. Our data fail to support a relationship between MTHFR C677T and the risk for breast cancer. It may be that there are ethnic differences in terms of this relationship.     

Plasma total homocysteine level and methylenetetrahydrofolate reductase 677C>T genetic polymorphism in Japanese patients with rheumatoid arthritis

Hyperhomocysteinemia is a known risk factor of cardiovascular disease. Homocysteine has been also linked to inflammation in rheumatoid arthritis (RA). In this study, we investigated the relationship between plasma homocysteine levels and single nucleotide polymorphism (SNP) of the gene coding for methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in the biosynthesis of homocysteine, and the correlation between the plasma homocysteine levels and generally used inflammatory markers (C-reactive protein, erythrocyte sedimentation rate and matrix metalloproteinase-3) in 96 Japanese patients with RA. Plasma homocysteine levels in patients with the MTHFR 677TT genotype were significantly higher than in those with the 677CC genotype (p < 0.05). In addition, plasma homocysteine levels were increased along with the elevation of general inflammatory markers. Therefore, we conclude that homocysteine might affect the inflammatory status of patients, and the MTHFR 677C>T SNP could be a predictive factor of hyperhomocysteinemia in patients with RA.     

The C677T mutation of the methylenetetrahydrofolate reductase gene is not associated with the risk of coronary artery disease or venous thrombosis among Chinese in Taiwan

OBJECTIVES: We sought to investigate the association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T mutation and the risk of coronary artery disease (CAD), myocardial infarction (MI) and venous thrombosis (VT) in a Chinese population in Taiwan. METHODS: The subjects included 218 CAD patients, 107 VT patients, and their age- and sex-matched controls. DNA was extracted from the blood and genotypes were determined by polymerase chain reaction, restriction mapping with HinfI and gel electrophoresis. RESULTS: The distribution of MTHFR genotypes was similar in the CAD cases and controls; the genotype TT was present in 6.0% of CAD patients, as compared to 6.9% of CAD control subjects (p = 0.165; odds ratio = 0. 86; 95% confidence interval = 0.40-1.85). The frequency of the T allele was also similar in CAD cases and controls (25.5% vs. 24.8%; p = 0.788). There was no significant association between TT homozygosity and the risk of MI. The genotype distributions and the frequency of the T allele were also similar in VT cases and controls. CONCLUSIONS: Our data suggest that there is no association between the C677T mutation of the human MTHFR gene and the risk of CAD or VT among Chinese in Taiwan.     

Screening of the C677T mutation on the methylenetetrahydrofolate reductase gene in French patients with neural tube defects

We report the analysis of the distribution of the C677T mutation on the methylenetetrahydrofolate reductase (MTHFR) gene in prenatally diagnosed neural tube defects (NTD) cases and controls. In contrast to previous reports, we found the same distribution in fetuses with NTD and controls, which suggests that the MTHFR C677T mutation cannot be regarded as a genetic risk factor for NTD. Received: 23 April 1997 / Accepted: 28 May 1997     

Methylenetetrahydrofolate reductase gene C677T polymorphism,homocysteine, vitamin B12, and DNA damage in coronary artery disease

Elevated levels of plasma homocysteine (Hcy), a risk factor for coronary artery disease (CAD), can result from genetic errors, e.g., the methylenetetrahydrofolate reductase (MTHFR) polymorphism, or nutritional deficiencies, e.g., in vitamin B12 and folate. The mechanism by which Hcy induces atherosclerosis is not fully understood. Recently, Hcy has also been observed to induce DNA damage. In this study, we have investigated whether DNA damage is related to the C677T variant in the MTHFR gene and to plasma levels of Hcy, B12, and folate in patients with CAD. Patients ( n=46) with angiographically proven CAD were studied by using the micronucleus (MN) test, an accepted method for evaluating genetic instability. TT patients had plasma Hcy levels higher than those with the CT or CC genotypes (27.8+/-5.2 vs 13.7+/-2.2 and 12.9+/-1.9 micro mol/l, respectively; P=0.02). Patients with multi-vessel disease had higher plasma Hcy levels (11.6+/-1.2, 22.0+/-4.7, 19.3+/-3.9 micromol/l for one-, two- and three-vessel disease, respectively; P=0.05). The MN index increased with the number of affected vessels (8.4+/-0.7, 11.1+/-2.0, 14.2+/-1.7 for one-, two-, and three-vessels disease, respectively; P=0.02) and was significantly higher in subjects with the TT genotype compared with the CC or CT genotypes (15.7+/-2.4 vs 8.9+/-1.7 and 9.9+/-0.8; P=0.02). The MN index was also correlated negatively with plasma B12 concentration ( r=-0.343; P=0.019) and positively with plasma Hcy ( r=0.429, P=0.005). These data indicate that the MN index is associated with the severity of CAD and is related to the MTHFR polymorphism, suggesting an interesting link between coronary atherosclerosis and genetic instability in humans.     

MTHFR C677T and A1298C gene polymorphisms and their relation to homocysteine level in Egyptian children with congenital heart diseases

Objective

To investigate the association of combined MTHFR C677T and A1298C gene polymorphisms with congenital heart diseases (CHD) in Egyptian children and their mothers and to determine their effect on homocysteine level in these children.

Material and methods

MTHFR C677T and A1298C polymorphisms were genotyped in 160 Egyptian children (80 patients with CHD and 80 healthy controls) and their mothers using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP), while, homocysteine (Hcy) level was measured optically by enzymatic method.

Results

We found that MTHFR 677TT genotype, T allele, 1298CC genotype, and C allele were associated with 2.61, 2.0, 2.91 and 1.99 fold increased risk of CHD in Egyptian children respectively. Furthermore, the frequencies of MTHFR 1298AC and CC genotypes and C allele significantly increased in mothers with CHD affected children. The homocysteine levels were significantly increased in MTHFR 677TT and 1298CC genotypes in children with CHD.

Conclusions

Our study demonstrated an association of MTHFR A1298C polymorphisms with CHD in Egyptian children and their mothers, while, MTHFR C677T polymorphisms were significantly associated with the risk of CHD in the children only. An association between combined MTHFR A1298C and C677T polymorphisms and CHD was recorded in the children and their mothers. Also, homocysteine levels were significantly increased with both MTHFR 677TT and 1298CC genotypes in Egyptian children with CHD.     

Oxidative status and reduced glutathione levels in premature coronary artery disease and coronary artery disease

Identifying patients at risk of developing premature coronary artery disease (PCAD) which occurs at age below 45 years old and constitutes approximately 7–10% of coronary artery disease (CAD) worldwide remains a problem. Oxidative stress has been proposed as a crucial step in the early development of PCAD. This study was conducted to determine the oxidative status of PCAD in comparison to CAD patients. PCAD (<45 years old) and CAD (>60 years old) patients were recruited with age-matched controls (n?=?30, each group). DNA damage score, plasma malondialdehyde (MDA) and protein carbonyl content were measured for oxidative damage markers. Antioxidants such as erythrocyte glutathione (GSH), oxidised glutathione (GSSG), and glutathione peroxidase activity (GPx), superoxide dismutase (SOD) and catalase (CAT) were also determined. DNA damage score and protein carbonyl content were significantly higher in both PCAD and CAD when compared to age-matched controls while MDA level was increased only in PCAD (p<.05). In contrast, GSH, GSH/GSSG ratio, α-tocotrienol isomer, and GPx activity were significantly decreased, but only in PCAD when compared to age-matched controls. The decrease in GSH was associated with PCAD (OR?=?0.569 95%CI [0.375???0.864], p?=?.008) and cut-off values of 6.69?μM with areas under the ROC curves (AUROC) 95%CI: 0.88 [0.80–0.96] (sensitivity of 83.3%; specificity of 80%). However, there were no significant differences in SOD and CAT activities in all groups. A higher level of oxidative stress indicated by elevated MDA levels and low levels of GSH, α-tocotrienol and GPx activity in patients below 45 years old may play a role in the development of PCAD and has potential as biomarkers for PCAD.     

Extracellular vesicles with ubiquitinated adenosine A2A receptor in plasma of patients with coronary artery disease

Extracellular vesicles (EV) can transfer cellular molecules for specific intercellular communication with potential relevance in pathological conditions. We searched for the presence in plasma from coronary artery disease (CAD) patients of EV containing the adenosine A_2A receptor (A_2AR), a signalling receptor associated with myocardial ischaemia and whose expression is related to homocysteine (HCy) metabolism. Using protein organic solvent precipitation for plasma EV preparation and Western blotting for protein identification, we found that plasma from CAD patients contained various amounts of EV with ubiquitin bound to A_2AR. Interestingly, the presence of ubiquitinated A_2AR in EV from patients was dependent on hyperhomocysteinemia, the amount being inversely proportional to A_2AR expression in peripheral mononuclear cells in patients with the highest levels of HCy. CEM, a human T cell line, was also found to released EV containing various amounts of ubiquitinated A_2AR in stimulated conditions depending on the hypoxic status and HCy level of culture medium. Together, these data show that ubiquitinated A_2AR‐containing EV circulate in the plasma of CAD patients and that this presence is related to hyperhomocysteinemia. A_2AR in plasma EV could be a useful tool for diagnosis and a promising drug for the treatment of CAD.     

Homocysteine concentration and adenosine A2A receptor production by peripheral blood mononuclear cells in coronary artery disease patients

Hyperhomocysteinemia is associated with coronary artery disease (CAD). The mechanistic aspects of this relationship are unclear. In CAD patients, homocysteine (HCy) concentration correlates with plasma level of adenosine that controls the coronary circulation via the activation of adenosine A_2A receptors (A_2AR). We addressed in CAD patients the relationship between HCy and A_2AR production, and in cellulo the effect of HCy on A_2AR function. 46 patients with CAD and 20 control healthy subjects were included. We evaluated A_2AR production by peripheral blood mononuclear cells using Western blotting. We studied in cellulo (CEM human T cells) the effect of HCy on A_2A R production as well as on basal and stimulated cAMP production following A_2A R activation by an agonist‐like monoclonal antibody. HCy concentration was higher in CAD patients vs controls (median, range: 16.6 [7‐45] vs 8 [5‐12] µM, P < 0.001). A_2A R production was lower in patients vs controls (1.1[0.62‐1.6] vs 1.53[0.7‐1.9] arbitrary units, P < 0.001). We observed a negative correlation between HCy concentration and A_2A R production (r = ?0.43; P < 0.0001), with decreased A_2A R production above 25 µM HCy. In cellulo, HCy inhibited A_2AR production, as well as basal and stimulated cAMP production. In conclusion, HCy is negatively associated with A_2A R production in CAD patients, as well as with A_2A R and cAMP production in cellulo. The decrease in A_2A R production and function, which is known to hamper coronary blood flow and promote inflammation, may support CAD pathogenesis.