Pharmacogenetics of Cardiovascular Disease: Genetic Variation and Statin Intolerance

Statins are very effective for lowering low-density lipoprotein cholesterol for primary and secondary cardiovascular disease prevention. While statins are usually well tolerated, individual response to statin therapy varies and intolerance, predominantly muscle symptoms, may appear in a significant proportion of patients. Besides clinical factors, variation in genes coding for proteins with drug transporting, immune or enzymatic function have been implicated in the pathogenesis of statin intolerance. In this review, we will characterise the candidate gene variants for development of statin intolerance, describe their population distribution and summarise current knowledge on their biological plausibility. Clinical relevance and current guidelines/recommendations will be also discussed

The Immune Response in the Pathophysiology of Pulmonary Diseases

Chronic obstructive pulmonary disease (COPD) is the world’s third leading cause of death. The number of patients with asthma is increasing in developed countries. We review here the main features of pathophysiology in these obstructive diseases. Tobacco smoke and other air pollution stimulate chronic inflammation in COPD. Asthma is a type 1 hypersensitivity that is a response to various allergens. In both pathologies, chronic inflammatory response leads to airway remodeling, significantly impacting lung function and a patient’s daily activity. Besides imaging techniques, a critical diagnostic tool is a pulmonary function test with characteristic obstructive patterns and respiratory symptoms. Sarcoidosis is discussed as an example of a restrictive disease. Finally, we shortly highlight the direction of current research

Association of MCP-1 -2518 A/G Single Nucleotide Polymorphism with the Serum Level of CRP in Slovak Patients with Ischemic Heart Disease, Angina Pectoris, and Hypertension

The aim of our work was to find if MCP-1 -2518 (A/G) single nucleotide polymorphism (SNP) influences somehow the serum concentrations of high-sensitive CRP (hsCRP) both in patients suffering from ischemic heart disease (IHD), myocardial infarction (MI), angina pectoris (AP), and hypertension (HT) and in control group of healthy subjects. Totally, 263 patients with the diagnosis of IHD, out of them 89 with MI, 145 with AP, 205 with HT, and also 67 healthy subjects were included in the study. First, we estimated the serum levels of hsCRP. We found that patients with AP had significantly higher serum level of hsCRP than both control group of healthy subjects (P = .043) and IHD patients without AP (P = .026). The presence of the mutant G allele statistically significantly correlated with the higher serum levels of hsCRP in patients with IHD (P = .016), AP (P = .004), and HT (P = .013). Higher correlations were found in men (AP: P = .019; HT: P = .047). In all cases the highest levels of hsCRP were found both in patients and healthy controls with homozygous GG genotype

In vitro pharmacoregulation of CC chemokine ligand 5 and its receptor CCR5 in diffuse lung diseases.

BACKGROUND: CC chemokine ligand (CCL)5 and its receptor CCR5 contribute to leukocyte migration into lungs of patients with diffuse lung diseases (DLD). Pharmacological regulation of CCL5 and CCR5 expression was therefore explored in bronchoalveolar cells obtained from patients with DLD. METHODS: Cells from 21 patients were co-cultivated in vitro with tumour necrosis factor-alpha and dexamethasone, cyclosporin A (CyA) or pentoxifylline. Chemokine mRNA expression and protein production was assessed by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: Dexamethasone altered CCL5 mRNA expression and suppressed its protein levels. CyA inhibited chemokine mRNA expression but not protein production. Pentoxifylline did not affected chemokine expression. Both dexamethasone and CyA suppressed CCR5 mRNA transcripts. CONCLUSION: In conclusion, while dexamethasone downregulates the CCL5 functional form, CyA and pentoxifylline have no effects on CCL5 protein. These data provide in vitro correlation for clinical applications of immunomodulators in therapy of DLD

PSMB2 and RPL32 are suitable denominators to normalize gene expression profiles in bronchoalveolar cells

<p>Abstract</p> <p>Background</p> <p>For accuracy of quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), normalisation with suitable reference genes is required. To date, no reference genes have been validated for expression studies of bronchoalveolar (BAL) cells. The aims of this study were to identify gene(s) with stable mRNA expression in BAL cells irrespective of gender, smoking, BAL cellular composition, lung pathology, treatment; and to assess the influence of reference genes on target gene expression data.</p> <p>Results</p> <p>The mRNA expression of ten housekeeping genes (ACTB, ARF1, CANX, G6PD, GAPDH, GPS1, GNB2L1, PSMB2, PSMD2, RPL32) was investigated by qRT-PCR in BAL cells from 71 subjects across a spectrum of lung diseases. The analyses were validated in an independent BAL cohort from 63 sarcoidosis patients and 17 control subjects. A second derivative method was used to calculate expression values (CTt); an equivalence test, applets BestKeeper, geNorm and NormFinder were applied to investigate gene expression stability. Of the investigated genes, PSMB2 (CTt ± SD, 23.66 ± 0.86) and RPL32 (18.65 ± 0.92) were the most stable; both were constantly expressed in BAL samples from parallel investigated cohorts irrespective of evaluated variables. Finally, to demonstrate effect of traditional (ACTB/GAPDH) and novel (PSMB2/RPL32) reference genes as denominators, expression of two cytokines known associated with sarcoidosis was investigated in sarcoid BAL cells. While normalization with PSMB2/RPL32 resulted in elevated IFNG mRNA expression (<it>p </it>= 0.004); no change was observed using GAPDH/ACTB (<it>p </it>> 0.05). CCL2 mRNA up-regulation was observed only when PSMB2/RPL32 were used as denominators (<it>p </it>< 0.03).</p> <p>Conclusion</p> <p>PSMB2 and RPL32 are, therefore, suitable reference genes to normalize qRT-PCR in BAL cells in sarcoidosis, and other interstitial lung disease.</p

CCL5/RANTES Gene Polymorphisms in Slavonic Patients with Myocardial Infarction

Coronary artery inflammation is a critical process in the pathogenesis of myocardial infarction (MI). The chemokine CCL5/RANTES (regulated upon activation, normal T cells expressed and secreted) is expressed in advanced atherosclerotic lesions. Functional polymorphisms of the RANTES gene can, therefore, be involved in the pathogenesis of coronary artery disease. We examined the association of polymorphisms in the RANTES gene with myocardial infarction in Slavonic populations of Czech and Russian origin. A total of 467 post-MI patients and 337 control subjects were genotyped for RANTES promoter G-403A (rs2107538) and intron 1.1 T/C (rs2280789) variants by PCR-SSP. Both RANTES genotypes and allele frequencies did not differ between case and control groups. Haplotype-based analysis also failed to reveal an association between MI and investigated markers. Strong linkage disequilibrium was detected between particular RANTES alleles. The data do not support an association between RANTES G-403A polymorphism and MI, as reported previously